Epidemiologic Reviews Copyright © 1991 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

Vol. 13, 1991 Printed in U.S.A.

The Epidemiology of Helicobacter pylori Infection

David N. Taylor1 and Martin J. Blaser2

INTRODUCTION

It is the development of this wide body of evidence that H. pylori is a human pathogen associated with some of the most common gastrointestinal inflammatory disorders in humans, rather than just being a common colonizer, that has provoked great interest in the epidemiology of this infection. In this review, we will discuss the epidemiologic significance of the microbiologic, pathologic, and clinical features of//, pylori infection and then turn to the epidemiologic characteristics of infection.

Curved and spiral-shaped organisms have been observed in the stomachs of humans and other mammals for more than a century. The recent isolation of one of these organisms, Helicobacter (formerly Campylobacter) pylori, and its association with gastroduodenal pathology has caused a resurgence of interest in gastric microbiology. In the short time since the first isolation of H. pylori, evidence for its causal role in the pathogenesis of gastritis and duodenal ulcer has been rapidly accumulating (table 1). H. pylori is nearly always isolated from patients with antral gastritis or duodenal ulcer and is rarely isolated from persons with normal gastric mucosa. H. pylori has a strong affinity for the gastric mucus-producing epithelial cells, and H. pylori-colonized mucosa shows marked inflammatory changes. Infected hosts produce specific local and systemic immune reactions in response to these organisms. Epidemics of H. pylori gastritis have been documented, as have experimental infections in humans and animals. Eradication of the organism leads to elimination of gastritis, and long-term elimination results in significantly lower recurrence rates of duodenal ulcer (reviewed in references 15).

Microbiologic characteristics of H. pylori

In 1983, John Warren, a pathologist in Perth, Australia, reported finding spiral bacteria overlying the gastric mucosa in biopsy samples showing active chronic gastritis (6). Noting that these bacteria resembled campylobacters, Marshall and Warren (7) used Campylobacter-specific methods to isolate these organisms from 11 patients with gastritis. The organisms were isolated after 2-4 days' incubation on chocolate agar at 37°C under microaerobic conditions. The organisms were observed to be oxidase-positive, catalase-positive, and strongly ureasepositive gram-negative curved or spiral rods that were motile by means of multiple flagellae. Originally the organisms were called Campylobacter pyloridis; the name was later changed to Campylobacter pylori (7). A number of important genotypic and phenotypic differences (8, 9) indicated that these organisms should be placed in a new genus now named Helicobacter; H. pylori is the type species (10). H. pylori strains share similar protein profiles in whole cell, outer

Received for publication December 7, 1990, and in final form May 16, 1991. Abbreviation: OR, odds ratio. 1 Department of Enteric Infections, Walter Reed Army Institute of Research, Washington DC. 2 Division of Infectious Diseases, Vanderbilt University School of Medicine, and Department of Veterans Affairs Medical Center, Nashville, TN. Reprint requests to Dr. David N. Taylor, Department of Enteric Infections, Waiter Reed Army Institute of Research, Washington, DC 20307-5100.

42

Helicobacter pylori Infection

TABLE 1. Evidence implicating Helicobacter pylori in the pathogenesis of chronic gastritis* Direct evidence 1. Voluntary ingestion of H. pylori results in gastritis. 2. Experimental animal challenge simulates human infection with resulting chronic gastritis. 3. Antimicrobial therapy that clears infection clears gastritis. Indirect evidence 1. H. pylori only overlies gastric epithelium. 2. H. pylori infection is associated with only certain types of gastroduodenal inflammation, not all types. 3. There is a universal systemic immune response to H. pylori. 4. Levels of H. pylori-specific antibodies decrease with therapy, concomitant with diminution in inflammation. 5. There is clearance of gastric inflammation with use of bismuth salts. 6. H. pylori is associated with epidemic gastritis and hypochlorhydria. • Adapted from Blaser (1).

membrane, and acid-extracted preparations, and several of those proteins are conserved as group antigens (11-13). Restriction endonuclease digestion of H. pylori chromosomal DNA has indicated considerable diversity (14, 15) and has been used to type strains (15). Plasmids appear to be present in a minority of strains (16). A serotyping scheme for H. pylori has not been developed. Lipopolysaccharides are varied (12) and may also form the basis for a typing system. Diagnostic methods

H. pylori infection can be diagnosed by examining gastric biopsy specimens obtained from gastroduodenoscopy. Such specimens can be cultured for the organism, stained, and examined for the presence of bacteria with characteristic morphology, or they can be processed to detect urease activity. While isolation of the organism from the stomach is the most definitive method of diagnosis, for most laboratories it is a less sensitive diagnostic method than histologic examination, particularly in the elderly, in whom other bacterial species may be present

43

in the stomach and overgrow H. pylori in culture (17). Indirect methods of diagnosing infection include the urea breath test (18, 19) and serology (20-22). The sensitivity and specificity of these techniques are now 95100 percent (18-20). Because of the high accuracy of current serologic testing (18, 20, 21), such assays are useful epidemiologic tools. Although antigenic cross-reaction with Campylobacter species may be significant for certain H. pylori serologic assays (23), other antigen preparations have avoided this problem (21, 24). The serologic response is specific, because persons in whom the presence of the organism cannot be demonstrated have a low false positivity rate (17, 20-22). Serology may be a more accurate method of diagnosis than biopsy, since gastritis can be a patchy phenomenon (17, 25) and biopsy and culture assess only a small area of the stomach. Thus, "false-positive" serology may, in fact, reflect falsely negative biopsy results (26). The main advantage of serologic assays is that they allow screening of large numbers of persons rapidly and at low cost. Antibody titers may, however, take several months to become elevated (27, 28). Untreated infections are not eradicated by the natural immune response, and the antibody titer remains at relatively constant levels over long periods of time, reflecting the chronicity of the infection. However, treatment of//, pylori infection is associated with a decrease in H. pylori-specific antibody levels (28-31). Association of H. pylori with type B gastritis

There are several known causes of chronic gastritis. Type A gastritis involves the gastric fundus and is considered an autoimmune disease that is associated with pernicious anemia (32, 33). Other causes of gastritis include bile reflux, use of nonsteroidal antiinflammatory agents, and alcohol, and the gastric mucosa may be a secondary target for several other diseases (33). The most common form of chronic gastric inflammation is known as type B gastritis, a disease that invariably involves the antrum and that

44

Taylor and Blaser

may affect the fundus to varying degrees (17, 34). Type B gastritis is worldwide in distribution. Its prevalence in developed countries increases with age, from less than 20 percent at age 20 years to approximately 50 percent at age 50 years. Its cause was previously unknown (32-36). Type B gastritis is present in essentially all persons with duodenal ulcers and in most persons with benign gastric ulceration (37). Type B gastritis is also a more common precursor of gastric carcinoma than is type A gastritis (32). Since the initial studies of Marshall and Warren (7), numerous studies in adults and children have shown a very high association of H. pylori infection with type B gastritis (17) and with duodenal ulceration (37-41) (table 2). Studies from every region of the world have confirmed the association of H. pylori infection with chronic antral gastritis (17, 21, 41-48). H. pylori infection is specifically associated with type B gastritis but not with type A gastritis, bile reflux, or secondary gastritis (41, 49-53). Thus, gastric inflammation per se does not provide a sufficient milieu for development or maintenance of H. pylori. Within the stomach, H. pylori will only overlie gastric-type epithelial cells. The organisms do not overlie absorptive-type duodenal epithelial cells, even when these are metaplastic in the stomach (52). Conversely, H. pylori can be found in the duodenum and the esophagus, but only at sites of gastric metaplasia. H. pylori may live freely in the mucus layer or bind directly to the gastric mucosa by means of adherence pedestals (53). TABLE 2. Rates of Helicobacter pylori infection in persons with specified gastroduodenal pathology* % of patients Type of pathology

Active gastritisf Gastric ulcer Duodenal ulcer No gastritis^

No. of studies

No of patients

wt]0 w e r e H PWo"-Positive

Range

Mean

9 8

401 178

64-95 35-86

88 64

8 9

246 230

75-100 0-20

85 9

• Data from Paull and Yardley (33). t Defined as chronic inflammatory changes (usually with increased mononuclear cells) plus neutrophilic infiltrate. t No gastritis apparent on biopsy specimen.

NATURAL HISTORY OF H. PYLORI INFECTION

H. pylori infection, once acquired, persists, as is evidenced by the isolation of strains with identical restriction endonuclease profiles from infected persons taken on multiple occasions over several years (15). Follow-up over 1-2 years indicates that the infection is stable, with little change in histologic grading of gastritis or fluctuation of antibody titer (47). Prolonged elevation of serum antibody titers also suggests that infection persists for years, decades, or possibly a lifetime. Eradication of H. pylori usually results in a healing, or at least a pronounced improvement, of gastritis in adults and children (54, 55). Type B gastritis caused by H. pylori may be either symptomatic or asymptomatic. Early in the course of infection, there may be changes in acid secretion or in proteinlosing enteropathy. Later in the course, infection may be associated with non-ulcer dyspepsia, peptic ulcer disease, atrophic gastritis, or gastric carcinoma (figure 1). The progression of H. pylori type B gastritis to one of these syndromes may require cofactors, including genetic predisposition, smoking, alcohol, diet, or others. Acute symptomatic gastritis

Two well-documented self-inoculation experiments with H. pylori serve to describe the acute infection and incubation period associated with H. pylori infection. Each experimenter had a normal gastric biopsy prior to ingestion of H. pylori. In the first self-inoculation experiment, an Australian investigator neutralized his gastric acid with cimetidine and then swallowed 109 H. pylori organisms (56). Seven days later, he developed epigastric fullness, a sensation of hunger, halitosis, an episode of vomiting, headache, and general irritability. Gastroscopy on the 10th day showed antral gastritis associated with H. pylori. A repeat biopsy taken on the 14th day showed improvement, at which time he began treatment with tinidazole. He had no further symptoms and did

Helicobacter pylori Infection Helicobacter pylori

\ Inflammation

45

Mucus layer

Mucosal epithelium

Active gastritis

Chronic superficial

Pre-pyloric gastric

gastritis

ulceration

Atrophic gastritis

Gastric carcinoma

FIGURE 1. Association of Helicobacter pylori with various pathologic lesions of the upper gastrointestinal tract.

not develop an antibody response to the organism. This infection induced an episode of acute self-limited gastritis. In the second self-inoculation experiment, a New Zealand investigator ingested 3 x 105 H. pylori organisms after first neutralizing stomach acidity (57). After 3 days, he developed severe epigastric pain, stomach cramping, nausea, vomiting, and insomnia that lasted for 5 days. He continued to have mild abdominal symptoms until day 11, when his symptoms ceased. Symptoms have not recurred during the past 3 years. On day 5, biopsies showed intense inflammation of the antrum, normal histologic appearance of the gastric fundus, and a gastric pH of 1.2. By day 8, the fasting gastric pH was 7.6. Following infection, this investigator had an early, transient immunoglobulin M seroconversion, and later he had both immunoglobulin A and immunoglobulin G seroconversion. After a 4-week course of bismuth, organisms and pathology cleared (57). However, rebiopsy a year later showed both the recurrence of H. pylori and chronic inflammation (28). Subsequent courses of norfloxacin and augmentin failed to eradicate the infection. The volunteer remained persistently infected and continued to have chronic type B gastritis. His infection was

associated with an acute self-resolving upper gastrointestinal illness and seroconversion. The infection, pathology, and specific immune response persisted for more than 3 years until combination antimicrobial therapy was successful (28). Epidemic hypochlorhydria with acute gastritis

As is evidenced by the second volunteer's case, hypochlorhydria may accompany the gastritis in the earliest phase of H. pylori infection. Several outbreaks of acute onset hypochlorhydria with marked gastritis have been reported following gastric secretion studies (58). Four of six persons developed an acute upper gastrointestinal illness after undergoing gastric secretion studies in England in which gastric juice was extracted, assessed with a common pH electrode, and reinfused (59). They became markedly hypochlorhydric, with severe gastritis, and retrospective examination showed organisms with the same appearance as H. pylori in the biopsies (58). In another outbreak that occurred in Texas, 17 (46 percent) of 37 healthy volunteers who underwent gastric secretion studies developed hypochlorhydria (60). A ret-

46

Taylor and Blaser

rospective analysis of the biopsy and serum specimens suggested that this outbreak was caused by H. pylori, apparently introduced into the stomachs of volunteers via reinfusion of gastric acid in contact with a presumably contaminated pH electrode (61). About 1 week after the first intubation studies, nine of the 17 subjects became ill, with epigastric pain, nausea, and vomiting lasting 1 -4 days. An increased pH was detected 7-49 days (mean = 25 days) after the illness began, and this also occurred in some subjects who did not develop symptoms. The duration of hypochlorhydria was 2-8 months (mean = 4 months). During periods of hypochlorhydria, all patients had severe fundal and antral gastritis. Serologic response to H. pylori antigens was also demonstrated in most of these patients (62). These laboratory accidents associate H. pylori infection with hypochlorhydria and gastritis similar to that observed in the New Zealand volunteer experiment. Hypochlorhydria was also noted in asymptomatic volunteers with documented H. pylori infection and gastritis, which suggests that hypochlorhydria could be part of a chronic infection as well as part of the acute presentation (63). However, chronically dyspeptic patients with and without H. pylori have similar gastric acid production, which suggests that acid production ultimately normalizes during the course of infection (64, 65). Malabsorption syndromes

Another possible early sequela of//, pylori infection is protein-losing enteropathy. Hill et al. (66) reported on three children from South Africa with transient protein-losing enteropathy associated with acute gastritis from whom H. pylori was identified on the gastric mucosa. With suppression of H. pylori infection with erythromycin, the gastric mucosa returned to normal and the protein loss ceased. H. pylori infection was also found in 53 percent of 77 Gambian children with chronic diarrhea and malnutrition who were 5-36 months old (67). This infection rate was twice the rate in age-matched chil-

dren who were healthy or who had malnutrition without chronic diarrhea. These observations raise the possibility that gastritis and achlorhydria caused by H. pylori infection may play a role in bacterial overgrowth in the stomach and small intestine or otherwise predispose children to chronic diarrhea. Asymptomatic infection

Although there is essentially always histologic evidence of inflammation at the site of//, pylori infection, most infected persons do not have symptoms. Histologic gastritis is a relatively common finding in asymptomatic populations and is usually not apparent by endoscopic visualization of the stomach (17). Histologic gastritis was found in 20-25 percent of healthy medical students in the Netherlands and the United States, and H. pylori was identified in all persons with gastritis but not in persons without inflammation (63, 68). In a study conducted in Los Angeles, California, inflammation was detected in gastric biopsies in 37 percent of 113 adult volunteers who had no upper gastrointestinal symptoms (17). The prevalence of H. pylori infection increased from 10 percent in persons aged 18-29 years to 47 percent in persons aged 60-69 years (17). When US Public Health Service epidemiologists were followed for an average of 7.5 years, the frequency of upper gastrointestinal symptoms was similar in persons who were persistently H. py/on'-seropositive and those who were persistently seronegative (69). Non-ulcer dyspepsia

Non-ulcer dyspepsia can be defined as upper abdominal discomfort in the absence of an ulcer or other focal lesion. The prevalence of non-ulcer dyspepsia among adults in developed countries ranges from 20 percent to 30 percent, with an estimated annual incidence of more than 1 percent; non-ulcer dyspepsia is at least twice as common as peptic ulcer disease (70). A number of conditions—most commonly, gastroesophageal

Helicobacter pylori Infection

reflux, irritable bowel syndrome, aerophagia, and gallstones—may be diagnosed in up to 75 percent of persons with nonulcer dyspepsia. The etiology is unknown in approximately 25 percent of cases. As may be expected for a syndrome with more than one etiology, the association of non-ulcer dyspepsia with active gastritis and H. pylori has been variable (30-70 percent) (1, 70). As we mentioned above, volunteer studies have indicated that acute infection with H. pylori is often transiently associated with dyspeptic symptoms, but subsequent carriage may be clinically silent. In the US Public Health Service study, seroconverters were more likely to have had persistent upper gastrointestinal pain in the interval between serum samples than persons who had not seroconverted (69). In another study, the association of H. pylori and non-ulcer dyspepsia increased with age in parallel with asymptomatic control populations, suggesting that there may not be a causal relation between infection and non-ulcer dyspepsia (71). Studies of antimicrobial treatment of H. pylori-associated non-ulcer dyspepsia have not shown clear-cut clinical efficacy (72, 73). However, in several controlled trials, eradication of//, pylori infection in patients with non-ulcer dyspepsia resulted in improvement of symptoms. Lambert et al. (74) isolated H. pylori from 61 percent of 82 patients with non-ulcer dyspepsia as compared with 25 percent of age-matched control patients, which indicated that infection is associated with symptoms. The patients with non-ulcer dyspepsia received bismuth subcitrate for 4 weeks in a placebo-controlled treatment trial. H. pylori was cleared from 59 percent of patients who received bismuth and 4 percent of patients who received a placebo. When H. pylori was cleared, there was significant improvement of symptoms and resolution of histologic gastritis. Patients who were H. ^/on-negative responded equally well to bismuth and placebo. Studies by Rokkas et al. (75) and Yang et al. (76) also have shown that non-ulcer dyspepsia patients with gastritis show significant improvement of symptoms after treatment

47

with bismuth salts compared with placebo, a difference not observed in non-ulcer dyspepsia patients without gastritis. Peptic ulcer disease

The association of chronic antral gastritis and duodenal ulcer has long been known. H. pylori has been isolated from the gastric antrum in nearly all patients with duodenal ulcer, which suggests that H. pylori is the probable cause of the gastritis associated with duodenal ulcer (77). Both gastric metaplasia (odds ratio (OR) = 6.2) and H. pylori infection (OR = 7.6) are risk factors associated with duodenal ulceration (39). When H. pylori is present in the duodenum, it only overlies areas of gastric metaplasia (37). The presence of duodenal H. pylori is highly associated (OR = 51.0) with duodenal ulceration (39). The concept has emerged from several studies (37, 39, 40) that both gastric metaplasia and H. pylori infection may be generally necessary for the development of duodenal ulceration, neither alone being sufficient. Gastric metaplasia frequently occurs in the duodenum of patients with duodenal ulcer, which allows duodenal colonization by H. pylori and which may permit inflammation to occur. Gastric metaplasia, induced by smoking, alcohol, and other traditional risk factors for peptic ulcer disease, may predispose patients to duodenal ulceration by permitting colonization by H. pylori. Colonization results in disruption of the mucus layer and inflammatory cell infiltration in the mucosa similar to the process that occurs over gastric epithelial cells in the antrum of the stomach. Factors promoting gastric metaplasia might, therefore, promote ulceration. For example, in one study, peptic ulcers were found in 73 percent of 15 H. pylori -infected persons who were also smokers and in 29 percent of 45 infected persons who were nonsmokers (78). Ulcers were not detected in smokers who were not infected with H. pylori. When duodenal ulcers are treated with H2-receptor antagonists, initial healing of the ulcer occurs in 80-90 percent of cases, but

48

Taylor and Blaser

the relapse rate is more than 80 percent if therapy is discontinued (48, 54). In contrast, when H. pylori is apparently cleared from the stomach and duodenum, ulcers heal with a relapse rate of 0-30 percent during a 12month follow-up period (48, 54, 79). Surprisingly, H. pylori has less often been associated with gastric ulceration (table 2). However, gastric ulceration may be the end result of several pathologic processes, whereas for "idiopathic" duodenal ulcer, a single process may be causative. Iatrogenic gastric ulceration is clearly associated with aspirin and other nonsteroidal antiinflammatory drugs. Gastric ulcer that is not associated with aspirin or nonsteroidal antiinflammatory drugs is associated with H. pylori infection in the presence of type B gastritis (80). Similar to duodenal ulcer disease and gastritis, eradication of infection is associated with ulcer healing. The mechanism by which H. pylori infection causes or contributes to gastric ulcers is not known (70), but disruption of the mucus layer is thought to be important (81). In Langenberg et al.'s (47) study of dyspeptic patients, the histologic characteristics of gastritis did not change significantly during the 1-2 years of persistent infection. In this relatively short period of time, none of nine untreated patients with gastritis developed ulcers. Although it is clear that virtually everyone with duodenal ulceration is infected with H. pylori, it is not apparent why, if this organism plays an etiologic role, most infected persons never develop ulceration. These disparate data suggest the hypothesis that, while H. pylori infection may be necessary, it is not sufficient to cause peptic ulceration; other patient or microorganismrelated factors are also important.

Atrophic gastritis and gastric carcinoma

In longitudinal studies of healthy Finns, the prevalence of gastritis has increased with age. For persons with superficial gastritis, it takes 18 years, on average, to develop mild atrophic gastritis and 18 more years to de-

velop severe atrophic gastritis (82). One hypothesis is that H. pylori infection causes type B gastritis, which may, in some cases, progress from superficial to atrophic gastritis and eventually to gastric carcinoma over a span of 40 or more years. There are similarities in the epidemiology of gastric carcinoma and H. pylori that suggest that an association may exist. Gastric carcinoma and H. pylori infection rates are higher among groups of low socioeconomic status and persons from developing countries (83). In the United States and other developed countries, the rates of gastric cancer have decreased in recent decades, while rates of other cancers have increased. H. pylori infection is acquired at increasingly older ages in developed countries. The shorter duration of infection in populations living in developed countries may be one reason why rates of gastric carcinoma are decreasing. H. pylori has not been found at sites of gastric carcinoma (84, 85). This may be because infection does not occur over neoplastic tissue, perhaps because of loss of the appropriate receptor or niche. However, in one case-control study, 65 percent of 37 persons with gastric adenocarcinoma not located at the cardia had serologic evidence of H. pylori infection compared with 38 percent of an asymptomatic control population (relative risk = 2.7, 95 percent confidence interval 1.01-7.01) (86). In a recent study from California, H. pylori was seen overlying adjacent normal mucosa in 89 percent of 37 patients with intestinaltype gastric carcinoma and in 32 percent of 22 persons with diffuse-type gastric carcinoma (87). The association between H. pylori infection and intestinal-type gastric carcinoma was highly significant after controlling for age, sex, and number of nonmalignant tissue biopsies examined. Since chronic gastritis, which is strongly associated with H. pylori infection, is a precursor lesion to intestinal-type gastric carcinoma (32), this correlation is relevant. Among eight children in a family with a high risk of intestinal-type gastric cancer, five children had chronic atrophic gastritis and three had intestinal

Helicobacter pylori Infection

metaplasia in the antrum of the stomach; all were infected with H. pylori (88). In three recent nested case-control studies in which serum was obtained, on average, more than a decade prior to the diagnosis of gastric cancer, the presence of H. pylori antibodies was significantly associated with risk of adenocarcinoma (odds ratios 2.86.0); risk was associated with both intestinal and diffuse-type pathology and with adenocarcinomas of the body and antrum but not ofthecardia(88a,b,c). In a study of Chinese counties (89), a mild (r = 0.4) but significant (p < 0.001) correlation was found between gastric carcinoma and H. pylori seropositivity rates in adult men. China is heterogeneous in that there is a 25-fold range in gastric cancer rates and a threefold range in H. pylori rates by county. High seropositivity rates (93 percent) were also observed in Pasto, Colombia, an area of high gastric cancer risk, compared with Cali, Columbia (63 percent), an area of low risk (90). Other factors, including diet and socioeconomic status, are also clearly involved. The question of the natural history of long term infections can best be answered in developing countries, where H. pylori is acquired at an early age. To study the progression from gastritis to atrophic gastritis and other degenerative sequelae, we need more comprehensive studies with long follow-up periods. Response to treatment

An organism's response to treatment can be helpful in determining its etiologic significance. H. pylori is susceptible in vitro to a wide range of antimicrobial agents, including erythromycin, tetracycline, and usually metronidazole. It is also susceptible to bismuth-containing compounds but not to antacids, H2-receptor antagonists, or sucralfate. Treatment with bismuth salts clears H. pylori infection, and clearance is associated with marked improvement in histology (72, 91), but bismuth compounds have many effects. Nevertheless, results of antibiotic treatments, which are more specific, support

49

these observations. Amoxicillin, nitrofuran, or tetracycline produces clearance of H. pylori in most patients (73, 92, 93). Concomitant with bacterial clearance, histologic scores improve. After cessation of therapy, bacteria are again apparent, and histologic worsening is noted (73, 92, 93). Several studies have shown that successful antimicrobial therapy of H. pyloriassociated gastritis results in a decrease in antibody levels, whereas relapse of infection leads to higher levels (30, 93). In concept, this parallels the diminution in antibody levels seen after treatment of syphilis, brucellosis, or coccidioidomycosis, other chronic infectious diseases. These data suggest that in the future, titration of serum antibody levels will be useful for assessing the efficacy of antimicrobial therapy directed against H. pylori. EPIDEMIOLOGIC CHARACTERISTICS OF H. PYLORI INFECTION Prevalence by age and sex

Since H. pylori is chronic, lasting years to decades, it is not surprising that its prevalence increases progressively with age. In developed countries, it is uncommon for children to be colonized, whereas approximately 50 percent of adults are colonized by the age of 60 (figure 2). In developing countries, colonization may occur during childhood, but prevalence continues to rise in adult age groups to levels well above those observed in populations from developed countries (figure 3). In France, few children (60

Age FIGURE 2. Relation between age and the prevalence of Helicobacter pylori infection among healthy persons in developed countries. United States 1, n = 113; United States 2, n = 53; France, n = 1,199; Finland, n = 500; Australia, n = 785; The Netherlands, n = 401; Wales, n = 1,175. Data from references 17, 23, 94-96, 100, and 110.

fection was virtually identical in men and women (96). Incidence data are much more limited at present. If it is assumed that once H. pylori infection is acquired, it persists at least until old age, then the progressive increases in seroprevalence might be considered a surrogate for incidence data. As such, among adults in developed countries, the annual incidence of infection appears to be about 1-2 percent. In the United States, among 366 public health officers, the annual seroconversion rate was 0.49 percent (69). Results from all of these studies suggest that although the prevalence of the infection is high, the incidence is low (0-5 percent per year) among adults in developed countries. Follow-up studies after treatment tend to substantiate the low incidence of infection in developed countries. In the Netherlands, new H. pylori infections did not occur during a mean of 11 months of follow-up in 22 patients who were cleared of the infection (47), and in Australia, only one of 24 pa-

tients followed for a similar period of time was believed to have been reinfected (54). In contrast, among persons at an Australian institution for the mentally retarded where the prevalence of H. pylori is especially high (73 percent), the annual incidence was determined to be 5 percent per year (99). For populations in developing countries, the prevalence of//, pylori infection is higher. In Vietnam, about 40 percent of teenagers were found to be infected (96) (figure 3). On the Ivory Coast, most children (55 percent) between the ages of 3 and 6 years were infected (96). In rural Thailand, 18 percent of children aged 5-9 years were infected—a rate that reached 55 percent by age 30 and 75 percent by age 50 (24). In contrast, in an urban Thai orphanage, 74 percent of children aged 1-4 years were seropositive. Sixty percent of persons from the People's Republic of China who were aged 20-39 years were infected (99). These data suggest that in developing countries, H. pylori infection is acquired earlier in life and more frequently

Helicobacter pylori Infection

51

% infected

— -

Algeria

—I—

Ivory Coast

-*-

Vietnam

-B-

Thailand PNG

Peru

5

10 15 20 25 30 35 40 45 50 55 >60

Age FIGURE 3. Relation between age and the prevalence of Helicobacter pylori among healthy persons in developing countries. Algeria, n = 277; Ivory Coast, n = 374; Vietnam, n = 365; Thailand, n = 161; Papua New Guinea (PNG), n = 157; Peru, n = 361. Data from references 23, 24, 96, and 97.

than in developed countries. In Thailand and Vietnam, there appears to be a slight decrease in seroprevalence in the elderly (24, 96). Temporal trends

It is possible that the age-related increase in H. pylori prevalence in developed countries could be explained by a cohort effect in which exposure to H. pylori was more prevalent in the past; consequently, increased prevalence of infection in older persons observed would reflect higher infection rates a generation ago. In the US Public Health Service study, paired sera were examined an average of 7.5 years apart (69). Among 30 people who were seropositive both times, the serum antibody titers were similar, indicating that the serologic response to infection is chronic and not self-limited. The seropositivity rate was slightly but significantly higher among those whose blood was sampled early in the study (1969-1974) than among persons of similar age whose blood

was sampled more recently; this suggests a small cohort effect. Since today's industrialized countries were once developing countries, it is not unreasonable to hypothesize that H. pylori rates were higher in the past, just as were rates for other pathogens (such as Salmonella typhi and hepatitis A) that mirror levels of economic development. Ethnic differences

Among adults in the United States, healthy Hispanic and black populations have seropositivity rates severalfold higher than those of non-Hispanic white populations (101, 102). In a Maryland study, the overall seropositivity rate among blacks was 57 percent, compared with 26 percent for whites (103) (figure 4). This association was independent of age, sex, diet, and geographic location (urban vs. rural). In a Denver study of men visiting a clinic for treatment of sexually transmitted diseases, 42 percent of healthy Hispanic and black men were seropositive compared with 12 percent of non-

52

Taylor and Blaser percent positive 100

0-9

10-19

20-29

H

30-39 40-49 age (years)

black

50-59

60-69

>69

E23 white

FIGURE 4. Relation between age and the seroprevalence of Helicobacter pylori in blacks (solid bars) and whites (hatched bars) living in Maryland. Data from Hopkins et al. (102).

Hispanic white men (103). Among asymptomatic persons in Los Angeles who volunteered for endoscopy, age-specific seroprevalence rates were significantly higher among Hispanics than among non-Hispanic whites (101). Similarly, the frequency of//. pylori infection was higher in blacks (70 percent) than in whites (34 percent) in a study of 485 asymptomatic adults in Houston, Texas (104). This difference remained significant after adjustment for age, sex, educational level, income, and use of tobacco and alcohol. In New Zealand, seropositivity among adults varied among persons of Tongan (70 percent), Samoan (44 percent), Cook Island (39 percent), and Caucasian (15 percent) extraction (105). Dwyer et al. (106) found that 43 percent of Ethiopians, 40 percent of Salvadorans, and 18 percent of Vietnamese refugees were seropositive upon entry into Australia, whereas seropositivity rates among native-born Caucasians were considerably lower. In a population of Australian aborigines in which duodenal ulcers are rarely diagnosed, only 0.5 percent had antibodies to H. pylori, in contrast to 15 percent of Caucasian Australians (107). The lack of H. pylori infection in a population with a low incidence of duodenal ulcers lends further support to the hypothesis that H. pylori may be a necessary factor for the development of duodenal ulcers, and it also suggests some degree of ethnic variability. In Singapore, ethnic Chinese have a rate

of peptic ulcer disease that is seven times higher than that of Malaysians (108). Similarly, antral gastritis and H. pylori infection are twice as common in Singaporean Chinese. Whether these differences reflect an increase in susceptibility among certain ethnic groups or differences in type and extent of exposure to H. pylori remains to be determined. Socioeconomic differences

H. pylori infection is more prevalent in groups of low socioeconomic status. In an Arkansas study of 247 healthy children, H. pylori infection was more common in lowincome families than in high-income families (109). Similarly, in Wales, the ageadjusted prevalence of H. pylori infection was highest in the lowest social classes (62 percent), lower in the middle class (57 percent), and lowest in the upper classes (49 percent) (110). H. pylori seroprevalence was also associated with lower socioeconomic status in a study of Irish soldiers (111). Similar trends were observed in populations in the developing world. In Saudi Arabia, H. pylori infections were found in 77 percent of non-college graduates and 54 percent of college graduates (112). In Peru, among persons under 30 years of age, H. pylori seropositivity rates were 88 percent and 82 percent for men and women, respectively, in public clinics and 66 percent and 43 percent for men and women, respectively, in private clinics (97).

Helicobacter pylori Infection

Modes of transmission

Perhaps the most compelling questions about the epidemiology of H. pylori infection center around transmission. Our failure to understand the dynamics of transmission makes it difficult to recommend methods of prevention. Nonhuman reservoirs. Although H. pylori has been isolated only in humans, a similar, or possibly identical, organism has been isolated from nonhuman primates (113). Human contact with such animals would not be sufficiently frequent to explain widespread infection if these animals represented a reservoir of infection. Organisms similar to, but not identical with, H. pylori have been isolated in swine, but the extremely high prevalence of infection in Algeria (96) and Saudi Arabia (112), two countries that are predominantly Muslim, effectively eliminates the possibility of transmission from that source. To our knowledge, no experimental data implicating any other environmental reservoir exist. Nevertheless, seropositivity rates were found to be higher in Italian abattoir workers than in clerks who had had no exposure to animal parts (31), although there were numerous confounding factors. Webberley et al. (114), in England, compared age- and sex-matched Asian lifelong vegans and meat-eaters and found no significant difference in H. pylori infection rates. A study of Seventh-Day Adventists, another vegetarian group, in Maryland also showed no significant differences in H. pylori infection rates in comparison with meat-eating controls (102). In another survey, Canadian farmers had higher seroprevalence rates at younger ages than did other Canadians without exposure to animals (115). Whether these data indicate higher rates of infection with human strains of//, pylori and, if so, whether socioeconomic differences might be important is not yet known. Person-to-person transmission in institutionalized populations. The lack of a plausible environmental reservoir, the extensive prevalence of//, pylori infection in humans, the clustering of cases in families, and higher

53

seropositivity rates in persons living in institutions suggest that humans are the major reservoir of H. pylori and that person-toperson contact is the primary mode of transmission. At a Bangkok orphanage, where enteric infections are hyperendemic, H. pylori seropositivity was 74 percent in children aged 2-4 years, well above the rates in children living in rural Thailand (24) (figure 3). Furthermore, the age-related acquisition of antibodies to H. pylori in rural Thailand was similar to that of hepatitis A. Berkowicz and Lee (116) found that inmates of a mental institution were H. py/on-seropositive much more frequently than were healthy blood donors in all age groups examined. Similarly, in Germany, persons living in closed communities such as psychiatric centers and orphanages had higher seropositivity rates than did control groups (117). Person-to-person transmission in families. Drumm et al. (21) found that parents and siblings of children with H. pylori infection were infected significantly more often than were parents and siblings of children who were H. pylori-negative (table 3). In particular, infection in a child was associated with a seropositive mother. The prevalence of//. pylori infection was determined in 277 cou-

TABLE 3. Familial clustering of Helicobacter pylori infections: H. pylori seropositivity in parents and siblings of children who underwent upper endoscopy, Toronto, Ontario, Canada* No. tested

Mean age (years)

H. pylori serology (% positive)

H. pylori-pos/f/Ve children Siblings Mothers Fathers

22 18 16

17 41 44

82 83 63

H. pylori-negaf/Ve children Controlst Mothers Fathers

37 17 16

16 40 41

14 12 38

'Significant differences were observed in the siblings (p < 0.001) and in the mothers (p < 0.001), but not in the fathers (p > 0.05), of the two groups of children. Adapted from Drumm etal. (21). t Asymptomatic Toronto children of similar ages to siblings.

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pies (mean age = 36.5 years) visiting an infertility clinic in New York (118). The seroprevalence of H. pylori was similar in females (16 percent) and males (19 percent), but infection was highly associated with being born outside of the United States. In only 18 couples (6.6 percent) were both persons seropositive. Although being the partner of an H. pylori -infected person increased someone's risk of being infected, this effect was entirely explained by age and national origin. Sexual transmission. In a survey conducted among men visiting a Denver, Colorado, sexually transmitted disease clinic, heterosexual men were more likely to be seropositive than were homosexual men, but that difference could be explained by ethnic differences in the group (103). In separate analyses of homosexual men and heterosexual men, there was no significant difference in lifetime number of sex partners or in history of previous sexually transmitted diseases among those infected with H. pylori compared with those who were not infected. Human immunodeficiency virus status was also not a risk factor. These studies indicate that if sexual transmission of//, pylori infection occurs, it is uncommon at best. Nevertheless, oral transmission remains a possibility. H. pylori has not been isolated from saliva (119, 120), but using technology based on the polymerase chain reaction, Gobert et al. (121) detected H. pylori genome in saliva from six of 10 infected persons. An H. pylori strain was isolated from dental plaque that was identical to the strain colonizing that person's stomach (120). In a study of mother-child pairs in Burkina Faso, Albengue et al. (122) showed that maternal premastication of food was a risk factor for acquisition of H. pylori infection in young children. Among populations in developing countries in which there is early acquisition of enterically transmitted pathogens such as hepatitis A and enterotoxigenic Escherichia coli, there is also early acquisition of orally transmitted agents such as cytomegalovirus and Epstein-Barr virus.

latrogenic transmission

As was discussed above, reinoculation of gastric juice from a potentially contaminated pH electrode was associated with outbreaks of H. pylori gastritis among subjects in experimental studies. Endoscopic transmission may be a more common risk. Three instances of subclinical reinfection with H. pylori were observed in two successfully treated patients during follow-up of//, pylori gastritis. The reinfections occurred 1 and 21 months (patient 1) and 32 months (patient 2) after the completion of antibacterial treatment. Patient-to-patient transmission was proven by restriction enzyme analysis of bacterial DNA. The endoscope had been mechanically cleaned between patients with a detergent and treated with 70 percent ethanol. The frequency of documented endoscopic transmission of H. pylori infection in uninfected patients was 1.1 percent in this study, corresponding to three iatrogenic acquisitions of manifest infection for every 1,000 gastroduodenoscopies (123). Contact with secretions from infected patients may also subject endoscopists to the risk of infection. The prevalence of H. pylori infection in a group of gastroenterologists was 52 percent, compared with 21 percent in an agematched group of blood donors (p < 0.01) (124). Despite evidence that person-to-person transmission may occur, H. pylori has rarely been isolated outside of the stomach. It has not been isolated from feces. Fecal-oral transmission may be unlikely, since the organism is not aerotolerant and does not appear to be able to persist in the environment. Nevertheless, finding H. pylori-like bacteria overlying heterotopic gastric mucosa in the colon indicates that fecal dissemination is a possibility. SUMMARY

The evidence that H. pylori causes gastritis in humans comes from both primary and secondary observations (table 1). The most important primary observations are the hu-

Helicobacter pylori Infection

man volunteer studies, the animal models, and the treatment studies with antimicrobial agents. Supporting information comes from studies showing the specific association of H. pylori infection with type B gastritis and with gastric (but not intestinal) epithelial cells; the specific ultrastructural lesions, including adherence pedestals; the ubiquity and stability of the immune response; the response to bismuth treatment; and the association with epidemic gastritis and hypochlorhydria. It is important to note that all of Koch's postulates have been fulfilled, and despite nearly universal initial skepticism, no evidence exists against the hypothTABLE 4. Salient features of Helicobacter pylori infection Type of organism: gram-negative, helical rod, flagellated at one pole, strongly urease positive, microaerophilic Reservoir: humans Mode of transmission: presumed person-to-person Route of infection: oral Site of infection: stomach or duodenum at site of gastric epithelial cells Infectious dose (ID) ID100: 10 5 -10 9 in two volunteers ID50: unknown Clinical features 1) Acute symptomatic infection Incubation period: 3-7 days Duration of illness: 2-7 days 2) Hypochlorhydria Prevalence: >50% of those acutely infected Incubation period: 25 days (range, 7-49 days) Duration: 4 months (range, 2-8 months) 3) Gastritis (histologic) Incubation period: 3-7 days Duration: years, possibly lifelong Risk factors for symptoms: unknown Incidence (new cases): 1-5 per 100 population per year Prevalence: varies by race and age in developed countries US blacks = Hispanics > Caucasians Older > younger (figures 2 and 3) Female: male 1:1 Higher rates in persons from developing countries (figures 2 and 3) 4) Duodenal ulcer Incubation period: variable Duration: years, eradication of organism associated with ulcer healing Incidence: 1-3 per 1,000 population per year in developed countries Risk factor predisposing persons with asymptomatic H. pylori gastritis to duodenal ulcer: unkown 5) Gastric carcinoma Incubation period: decades Atrophic gastritis and intestinal metaplasia are precursor lesions. H. pylori infection seen in adjacent gastric tissue

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esis that H. pylori plays an etiologic role in type B gastritis. Therefore, it is reasonable to conclude that H. pylori is a pathogen in humans. The known features of//, pylori infection are listed in table 4. Infection is chronic and common throughout the world, with a higher prevalence in developing countries than in developed countries. The prevalence of H. pylori infection increases with age in parallel with that of gastritis. Acquisition of H. pylori infection does not appear to have any seasonality, and infection is equally common among men and women. Without a significant animal or environmental reservoir for human strains of H. pylori, person-to-person contact appears to be the most likely mode of transmission. Exactly how the organism is transmitted from the stomach of one person to that of another remains unclear. Also unknown are the factors which determine who becomes ill after infection; why one person has gastritis alone while another person develops a duodenal ulcer; and how the traditional risk factors for ulcer disease, such as smoking, aspirin, and alcohol, interact with H. pylori infection. Finally, the long term neoplastic consequences of infection must be understood. Further elucidation of the natural history of//, pylori and the consequences of H. pylori infection is the most important goal for future study.

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The epidemiology of Helicobacter pylori infection.

The evidence that H. pylori causes gastritis in humans comes from both primary and secondary observations. The most important primary observations are...
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