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Editorial: Can Therapy Ever Be Denied for Helicobacter pylori Infection?
GASTROENTEROLOGY 1997;113:5113-5117
Editorial: Can Therapy Ever Be Denied for Helicobacter pylori Infection? Helicobacter pylori infection is a transmissible bacterial infection of the gastric mucosal surface that causes progressive damage with eventual destruction of the stomach. In the United States, the presence of H. pylori infection in patients carries a lifetime risk of developing peptic ulcer of at least 16% and a 10/0-3% risk of developing gastric cancer. An infected individual is also a risk to the community because the infection can be transmitted. A review of the data shows that H. pylori is the only treatable infectious disease with such a high rate of morbidity and mortality that is not the subject of an all-out program to eradicate it from the population. The risk of a serious outcome of untreated asymptomatic H. pylori infection is great, or greater, than with asymptomatic syphilis or tuberculosis. H. pylori infection is a serious public health problem, and thus the presence of H. pylori infection justifies treatment. The question is not whom to treat, but whom to test. The gastroenterology community appears to have been unduly influenced by the fact that H. pylori infection is widespread and often asymptomatic, as well as by the costs and complications of current treatment. H. pylori infection is a serious, worldwide infectious disease with tremendous and unacceptable morbidity and mortality. Although there are no emotional reasons to treat H. pylori infection, there are logical and persuasive scientific reasons to treat. If the tools are available, screening the population for the presence of H. pylori infection with the goal of preventing all H. pylori-related diseases is recommended. Our goal should be to totally eliminate H. pylori from the face of the earth, just as we eliminated smallpox.
I
have been asked to discuss the emotional reasons for treating Helicobacter pylori infection. I was asked to specifically address the following points: (1) the emotional argument for treating people at a higher risk for gastric cancer; (2) the patient demanding testing and treatment; (3) the patient who tested positive when there was no definite diagnosis established; (4) the patient with nonulcer dyspepsia; and (5) in what situation, if any, would I not treat patients with positive test results. The strategy that I will follow is to continue to expand on the concept that H. pylori is a serious transmissible infectious disease. 1•2 I will conclude that H. pylori infection is a serious public health problem and that, when diagnosed, should be treated. The great ailment of modern gastroenterology practice
as it relates to H. pylori infection is the lack of comprehension of the "why and wherefore," rather than the "what to do." Understanding of the "why and wherefore" lies in the better understanding of untreated H. pylori infection. The beneficial effects of treatment in modifying the biological course of H. pylori infection are well-known. The decision of whom to treat must be based on quantitative information about what happens to those who do not receive treatment.
Natural History of H. pylo,; Infection H. pylori infection is an infectious disease that is typically acquired in childhood. The primary feature is progressive damage to gastric structure and function, with clinical manifestations appearing in adulthood, often late in life. The infection is transmissible, with the infection clustering in families with children. 3- 9 H. pylori and infection with Streptococcus mutans, the cause of dental caries, are probably the most common chronic infections in humans. Both are typically asymptomatic and destructive. Dental caries are painful and result in visible loss of function; few would question the desirability of prevention. As the patient and the physician can neither feel nor see gastric damage caused by H. pylori infection, the decision to treat must be based on the risks to the individual and to society. Possible outcomes associated with H. pylori infection include asymptomatic damage to the stomach, with development of hypochlorhydria or achlorhydria. Reduced or absent acid secretion removes the gastric barrier to entry of orally ingested pathogens and increases the risk of enteric infection; it may also reduce the ability to absorb iron, food-bound vitamin B l2 . These are largely silent manifestations. The clinically obvious manifestations are peptic ulcer and gastric malignancy, with approximately one in six infected persons eventually developing peptic ulcer disease. The lifetime risk of gastric adenocarcinoma is somewhat greater than 1 %.10 Symptomatic gastric lymphoma occurs less frequently than gastric adenocarcinoma.
H. pylori as an Infectious Disease In 1993, I participated in a debate held as part of the Annual Postgraduate Course of the American Gastroenterological Association. The question was whether
S114
DAVID Y. GRAHAM
every patient with peptic ulcer disease and H. pylori infection should receive anti-H. pylori therapy. I was assigned the "yes" argument. This was a watershed time for conceptual thinking about peptic ulcer disease. I argued that peptic ulcer was not an "acid disease" but was one manifestation of a bacterial infection. Because peptic ulcer was an infectious disease, we should not consider it in any other context. I used analogy to show that recommendations such as reserving therapy for complicated or recurrent peptic ulcer disease were irrational when viewed in the context of standard therapy for an infectious disease. I compared peptic ulcer with urinary tract infection or tuberculosis and showed the similarities. For example, anti secretory therapy was equated to symptomatic therapy for urinary tract infection with pyridium (i.e., treat the pain, not the underlying disease). The concept that we must view peptic ulcer as one manifestation of an infection was accepted and resulted in a paradigm shift. 2 It is now amusing to consider the basis of the arguments for and against therapy that were prevalent before that time. The full implications of the concept that H. pylori infection is simply another infectious disease with many harmful outcomes have continued to evolve. At subsequent symposia at annual meetings of the American Gastroenterological Association, I introduced new concepts as "rules." One rule is, "If a treatment regimen does not work everywhere, and you do not understand why not, avoid it." Another was, "Do not test unless you are willing to treat." This rule was based on the premise that because of the many harmful outcomes of infection, it is impossible to deny treatment once the diagnosis IS established. I will expand on that line of thinking to fulfill my charge here. My opening comments were modeled on a paper that summarized the result of the Oslo study of untreated syphilis. II That report stated, " ... the great ailment of modern syphilological practice is the lack of comprehension of the 'why and wherefore,' rather than the 'what to do.' Comprehension of the 'why and wherefore' lies in a better understanding of the prognosis of untreated syphilis. The beneficial effects of treatment in modifying the biologic course of syphilitic infection is well-known. What was lacking was quantitative information on what happens to those who go untreated." H. pylori infection is not the only serious asymptomatic disease that has provoked arguments about whom and when to treat. I argue that asymptomatic H. pylori infection is as serious a health problem as asymptomatic syphilis or tuberculosis and shares many features with those diseases. Asymptomatic infection is the rule with all three organisms: H. pylori, Treponema pallidum, and Mycobacterium
GASTROENTEROLOGY Vol. 113, No. 6
tuberculosis. Arguments for or against routine therapy of syphilis were based on the natural history of the infection. It was known that (1) untreated syphilis had a favorable outcome in the majority of instances, (2) serious outcomes were more frequent in men than in women, (3) untreated syphilis prolonged the period of community danger of infection, (4) there was no way to predict the outcome of individual cases, and (5) patients with syphilis had a higher morbidity and mortality from other conditions than did those without the infection. It was estimated that 60%-70% of untreated individuals with asymptomatic T pallidum infection lived with a minimum of inconvenience. However, that knowledge provided little encouragement to withhold treatment, because the final outcome in any individual could not be predicted, and syphilis was a transmissible disease, putting others at risk. 11 Similar parallels exist between infection with H. pylori and tuberculosis. 12,13 Recall that only 10% of those with a positive tuberculin skin test eventually develop active tuberculosis. Winn and Prechter l2 ended their chapter on pulmonary tuberculosis with a list of remaining problems that are also applicable to H. pylori infection. They stated that the most important element in tuberculosis control was treatment of infected persons before the development of active disease. However, they noted that new antimicrobial agents were needed to treat disease caused by strains that are resistant to available drugs. They noted that an effective vaccine would have a tremendous impact in areas of the world with high rates of tuberculosis and inadequate healthcare budgets. The same conclusions are true in H. pylori infection. Finally, they suggested that a test that showed the presence of persistent viable tubercle bacilli would be desirable. H. pylori investigators have an advantage over workers in tuberculosis in that the urea breath test provides an accurate noninvasive method to diagnose active infections.
Asymptomatic H. pylori Is as Harmful as Syphilis or Tuberculosis Considerations regarding the desirability of treatmg an infectious disease include the outcome of the disease in a group of individuals (e.g., spontaneous cure vs. serious disease), whether the infection can be successfully treated, and the risks of not treating the infection in relationship to the uninfected population. The patient with a positive breath test for H. pylori infection differs from the patient with a positive tuberculosis skin test or a positive blood test for syphilis because H. pylori is always an active and potentially transmissible infection; in contrast, the risk of transmission of tuberculosis or
December Supplement 1997
syphilis depends on the development of active disease. Asymptomatic H. pylori infection provides a reservoir for transmission of disease to the uninfected community. The risks and modes of transmission of H. pylori remain unclear and poorly studied. It is of concern that infection clusters in families with children, providing an unkind gift to our children. 7,14 Unfortunately, funding for modern science is dominated by "intellectually interesting" questions of mechanism, and there is less interest in mundane and more difficult study questions, such as how to prevent the spread of H. pylori infection. Although asymptomatic destruction of the stomach may not be regarded by all as an important issue, there is little argument that peptic ulcer disease is a serious medical problem. Patients with peptic ulcers experience pain, have reduced quality of life, and suffer the risk of ulcer complication. 15 They also incur the expense of drugs, doctor visits, tests, and lost time from work. They have an increased mortality compared with those without ulcer disease. For example, there are approximately 350,000 hospital admissions for upper gastrointestinal hemorrhage each year in the United States. 16 At least 50% of these patients bleed as a complication of peptic ulcer, with a mortality rate of approximately 10%. The costs and risks of peptic ulcer disease mandate that patients with ulcers should be investigated for the presence of H. pylori infection and should be treated if H. pylori infection is present; cure of the infection should be confirmed to prevent recurrent ulcer, ulcer complications, and costs associated with additional visits, tests, and drugs. H. pylori infection has been etiologically implicated in gastric cancer. This association was no surprise. Before the discovery of H. pylori, the strong association between gastritis and gastric carcinoma was well-known and was responsible for a large body of epidemiological data regarding gastritis. Mayo is credited with saying that cancer never develops in a healthy stomach,17 and histological studies have repeatedly confirmed that gastric carcinoma is rare in the absence of gastritis. Recent studies have used serological data, which tend to underestimate the frequency of H. pylori infection in end-stage disease. It is likely that the estimates derived from those studies of the proportion of gastric cancer attributable to H. pylori underestimate the importance of H. pylori infection. 18 Gastric cancer has undergone a marked reduction in incidence in the last 50 years that appears to relate to changes in diet, food preparation, and food storage more than any reduction in the incidence of H. pylori infection. Presumably, these changes affect some cofactor contributing to cancer development for the general population. The lifetime risk of developing
DENY THERAPY FOR H. PYLORI?
Sl15
gastric cancer is still at least 1% for the general population lO ; the risk in those with H. pylori infection is higher because they represent the sub population at risk. Such a high risk of cancer is unacceptable for a treatable and potentially preventable disease. I believe that studies to understand and prevent transmission, and development of better treatments should take precedence over studies designed to address how 50 years of chronic inflammation leads to cancer.
Can the Presence of Putative Virulence Factors Be Used to Identify Harmful Strains of H. pylori and Whom to Treat? H. pylori and syphilis share the disease feature of having different ourcomes with respect to gender and age of acquisition. For example, the Oslo syphilis study reported that mortality among men with syphilis was twice that of infected women, as was the ratio for both cardiovascular and neurosyphilis. 11 They reported that cardiovascular syphilis did not develop in those infected before age 15, whereas neurosyphilis did not develop in those infected before age 15, or in men infected after age 40. About 16% of those with asymptomatic syphilis developed cardiovascular or neurological disease. The results are similar with asymptomatic M. tuberculosis infection, because only 5%-10% develop clinical disease. Because all syphilis and all tuberculosis infections are considered to be harmful, there has been little interest in identifying virulence factors that could predict worse ourcomes so as to focus therapy on that subpopulation. The possibility that asymptomatic syphilis or tuberculosis might be beneficial or should not be treated has not been a consideration. The initial recommendation to treat all patients with positive tuberculin skin tests was tempered only because of side effects of antituberculosis therapy. In contrast, there has been more interest in whether the different H. pylori-related diseases might be attributed to bacterial virulence factors. Recent candidates include such factors as the presence of cagA. Unfortunately, none of the putative virulence factors provide discrimination between patients with or without ulcer, cancer, or asymptomatic gastritis. 19- 22 Although there has been recent interest in the ability to use heterogeneity in vacA as a marker for peptic ulcer diseases,23 studies in other regions have not borne out the original hypothesis. 24 The presence of different strains circulating in different regions has apparently continued to provide confusing and misleading data regarding the role of potential virulence factors. For example, two European countries (Iceland and Portugal) with the
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DAVID Y. GRAHAM
highest incidences of gastric cancer were shown to have a low proportion of cagA-positive strains. 25 Furthermore, the incidence of gastric cancer continues to decrease, suggesting that if cagA-positive strains were important, the prevalence of cagA-positivity would have decreased in parallel, and it did not. 26 Other bacterial virulence factors, such as the cholera toxin or the diphtheria toxin, are invariably associated with their respective diseases, and the absence of the factor corresponds with absence of the diseases. The association of such virulence factors with disease is applicable everywhere in the world. Putative H. pylori virulence factors such as cagA or vacA subtypes have frequently failed to provide reliable predictive value. Because all H. pylori infections damage the stomach, the concept that one might identify a marker for a "safe" infection is probably wishful thinking. The current concept should be that all H. pylori infections are harmful, none should be tolerated if we had the means to eradicate the infection from mankind.
Whom to Treat for H. pylori Infection This could be restated as, "to whom can we deny therapy for H. pylori infection?" My position is that it is impossible to deny treatment once the diagnosis has been established. Consider the hypothetical conversation between a reluctant physician and a patient with nonulcer dyspepsia and a positive urea breath test: "You have a bacterial infection that is damaging yout- stomach. I do not think the infection is responsible for your symptoms and your lifetime risk of a serious disease is low. I estimate that only 1 in 6 individuals like you will develop peptic ulcer and only 1 to 3 per 100 will develop gastric cancer. Although you can transmit the infection to your spouse, your children and grandchildren, or to others, I do not recommend treatment." Until an effective vaccine or a simple effective therapy with limited or mild side effects is available, the question is not whom to treat but whom to test. This is a public health problem. The gains of therapy are clear, but we are constrained by cost, the existence of drug-resistant H. pylori, and the impracticability of treating 50% of our population. I believe that there is general agreement that all patients with peptic ulcer disease should be tested and those with H. pylori infection should be treated. Testing is also required, as there is no benefit, and only risks, associated with treating noninfected patients with other causes of peptic ulcer disease. Many would test those with suspected peptic ulcer (i.e., those with dyspepsia), because this is a reasonably small proportion of the population and H. pylori may actually cause nonulcer
GASTROENTEROLOGY Vol. 113, No.6
dyspepsia in some patients. I believe that we should have a low threshold for diagnosis and treatment. I would test and treat those at increased risk of gastric cancer or peptic ulcer. Such individuals can be identified with some degree of certainty on the basis of the presence of disease in a first-degree relative. The bottom line is that no one deserves, needs, wants, or benefits from having an H. pylori infection. Positive diagnosis of infection must be followed by treatment. There are no emotional reasons, but there are logical and persuasive scientific reasons, to treat H. pylori infection. If we had the tools, we would recommend screening the population for the presence of H. pylori infection with the goal of preventing all H. pylori-related diseases. Our goal should be to totally eliminate H. pylori from the face of the earth, just as we eliminated smallpox. 1,2 Hopefully, this will become possible in the furure. DAVID Y GRAHAM, M.D. Department of Medicine Veterans Affairs Medical Center and Division of Molecular Virology Baylor College of Medicine Houston, Texas
References 1. Graham DY. Benefits from elimination of' Helicobacter pylori infection include major reduction in the incidence of peptic ulcer disease, gastriC cancer, and primary gastriC lymphoma. Prev Med 1994;23:712-716. 2. Graham DY. Evolution of concepts regarding Helicobacter pylori: from a cause of gastritis to a public health problem. Am J GastroenteroI1994;89:469-472. 3. Malaty HM, Graham DY. Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut 1994;35:742-745. 4. Webb PM, Knight T, Greaves S, Wilson A, Newell DG, Elder J, Forman D. Relation between infection with Helicobacter pylori and living conditions in childhood: evidence for person-to-person transmission in early life. BMJ 1994;308:750-753. 5. Mendall MA, Goggin PM, Molineaux N, Levy J, ToosyT, Strachan 0, Northfield TC. Childhood living conditions and Helicobacter pylori seropositivity in adult life. Lancet 1992;339:896-897. 6. Malaty HM, Kim JG, Kim SO, Graham DY. Prevalence of Helicobacter pylori infection in Korean children: inverse relation to socioeconomic status despite a uniformly high prevalence in adults. Am J EpidemioI1996;143:257-262. 7. Malaty HM, Graham DY, Klein PO, Evans DG, Adam E, Evans OJ. Transmission of Helicobacter pylori infection. Studies in families of healthy individuals. Scand J Gastroenterol 1991;26:927932. 8. Mitchell HM, Bohane TO, Berkowicz J, Hazell SL, Lee A. Antibody to Campylobacter pylori in families of index children with gastrOintestinal illness due to C. pylori. Lancet 1987;2:681682. 9. Drumm B, Perez-Perez GI, Blaser MJ, Sherman PM. Intrafamilial clustering of Helicobacter pylori infection. N Engl J Med 1990; 322:359-363.
December Supplement 1997
10. Seer cancer statistics review, 1973-1992: Tables and graphs, National Cancer Institute. Bethesda, MD: 1995, NIH Publication No. 96-2789. 11. Clark EG, Danbolt N. The Oslo study of the natural course of untreated syphilis. An epidemiologic investigation based on restudy of the Boeck-Burrsgaard material. Med Clin North Am 1964;48:613-623. 12. Winn RE, Prechter GC. Pulmonary tuberculosis. In: Hoeprich PD, Jordan MC, Ronald AR, eds. Infectious diseases. 5th ed. Philadelphia: Lippincott, 1994:447-464. 13. The use of preventive therapy for tuberculous infection in the United States. Recommendations of the Advisory Committee for elimination oftuberculosis. MMWR Morbid Mortal Wkly Rep 1989;39:No. RR-8:9-12. 14. Graham DY, Klein PD, Evans DG, Fiedorek SC, Evans OJ Jr, Adam E, Malaty HM. HeJicobacter pylori: epidemiology, relationship to gastric cancer, and the role of infants in transmission" Eur J Gastroenterol Hepatol 1992;4(Suppl 1):Sl-S6. 15. Soli AH. Gastric, duodenal, and stress ulcer. In: Sieisenger M, Fordtran J, eds. Gastrointestinal disease. 5th ed. Philadelphia: Saunders, 1993:580-679. 16. Peterson WL. Gastrointestinal bleeding. In: Sieisenger M, Fordtran J, eds. Gastrointestinal disease. Pathophysiology diagnosis management. 4th ed. Philadelphia: Saunders, 1989:397428. 17. Bockus HL. Carcinoma of the stomach. In: Bockus HL, ed. Gastroenterology. 2nd ed. Philadelphia: Saunders, 1963:743801. 18. Forman D. The prevalence of Helicobacter pylori infection in gastric cancer. Aliment Pharmacol Ther 1995;9(Suppl 2): 71-76. 19. Graham DY, Go MF, Genta RM. HeJicobacter pylori, duodenal ulcer, gastric cancer: tunnel vision or blinders? Ann Med 1995;27:589-594. 20. Go MF, Graham DY. The cagA gene is present in the majority of H. pylori strains independent of whether the individual has
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21.
22.
23.
24.
25.
26.
Sl17
duodenal ulcer or asymptomatic gastritis. Helicobacter 1996;1: 107-111. Miehlke S, Kibler K, Kim JG, Figura N, Small SM, Graham DY, Go MF. Allelic variation in the cagA gene of HeJicobacter pylori obtained from Korea compared to the United States. Am J GastroenteroI1996;91:1322-1325. Graham DY, Genta RM, Graham DP, Crabtree JE. Serum CagA antibodies in asymptomatic subjects and patients with peptic ulcer: lack of correlation of IgG antibody in patients with peptic ulcer or asymptomatic HeJicobacter pylori gastritis. J Clin PathoI1996;49:829-832. Atherton JC, Peek RM Jr, Tham KT, CoverTL, Blaser MJ. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology 1997;112:92-99. Go MF, Cissell L, Graham DY. VacA genotype of H. pylori does not predict the nature of the gastroduodenal disease. Gastroenterology 1997;112:A127. Crabtree JE, Webb P, Newell D, Covacci A, Forman D. An epidemiological survey of CagA seropositivity in seventeen worldwide populations. Gut 1996;39(Suppl 2):A82. Perez-Perez GI, Bhat N, Gaensbauer J, Taylor D, Kuipers EJ, Zhang L, You W, Blaser MJ. Country-specific constancy by age in cagA+ proportions of H. pylori infections. Gut 1996;39(Suppl 2):A83.
Received June 30,1997. Accepted July 22,1997. Address reprint requests to: David Y. Graham, M.D., Veterans Affairs Medical Center (1110), 2002 Holcombe Boulevard, Houston, Texas 77030. e-mail: [email protected]; fax: (713) 7901040. Supported by the Department of Veterans Affairs and by the generous support of Hilda Schwartz. © 1997 by the American Gastroenterological Association 0016-5085/97/$3.00
Editorial: Can Therapy Ever Be Denied for Helicobacter pylori Infection? Helicobacter pylori infection is a transmissible bacterial infection of the gastric mucosal surface that causes progressive damage with eventual destruction of the stomach. In the United States, the presence of H. pylori infection in patients carries a lifetime risk of developing peptic ulcer of at least 16% and a 10/0-3% risk of developing gastric cancer. An infected individual is also a risk to the community because the infection can be transmitted. A review of the data shows that H. pylori is the only treatable infectious disease with such a high rate of morbidity and mortality that is not the subject of an all-out program to eradicate it from the population. The risk of a serious outcome of untreated asymptomatic H. pylori infection is great, or greater, than with asymptomatic syphilis or tuberculosis. H. pylori infection is a serious public health problem, and thus the presence of H. pylori infection justifies treatment. The question is not whom to treat, but whom to test. The gastroenterology community appears to have been unduly influenced by the fact that H. pylori infection is widespread and often asymptomatic, as well as by the costs and complications of current treatment. H. pylori infection is a serious, worldwide infectious disease with tremendous and unacceptable morbidity and mortality. Although there are no emotional reasons to treat H. pylori infection, there are logical and persuasive scientific reasons to treat. If the tools are available, screening the population for the presence of H. pylori infection with the goal of preventing all H. pylori-related diseases is recommended. Our goal should be to totally eliminate H. pylori from the face of the earth, just as we eliminated smallpox.
I
have been asked to discuss the emotional reasons for treating Helicobacter pylori infection. I was asked to specifically address the following points: (1) the emotional argument for treating people at a higher risk for gastric cancer; (2) the patient demanding testing and treatment; (3) the patient who tested positive when there was no definite diagnosis established; (4) the patient with nonulcer dyspepsia; and (5) in what situation, if any, would I not treat patients with positive test results. The strategy that I will follow is to continue to expand on the concept that H. pylori is a serious transmissible infectious disease. 1•2 I will conclude that H. pylori infection is a serious public health problem and that, when diagnosed, should be treated. The great ailment of modern gastroenterology practice
as it relates to H. pylori infection is the lack of comprehension of the "why and wherefore," rather than the "what to do." Understanding of the "why and wherefore" lies in the better understanding of untreated H. pylori infection. The beneficial effects of treatment in modifying the biological course of H. pylori infection are well-known. The decision of whom to treat must be based on quantitative information about what happens to those who do not receive treatment.
Natural History of H. pylo,; Infection H. pylori infection is an infectious disease that is typically acquired in childhood. The primary feature is progressive damage to gastric structure and function, with clinical manifestations appearing in adulthood, often late in life. The infection is transmissible, with the infection clustering in families with children. 3- 9 H. pylori and infection with Streptococcus mutans, the cause of dental caries, are probably the most common chronic infections in humans. Both are typically asymptomatic and destructive. Dental caries are painful and result in visible loss of function; few would question the desirability of prevention. As the patient and the physician can neither feel nor see gastric damage caused by H. pylori infection, the decision to treat must be based on the risks to the individual and to society. Possible outcomes associated with H. pylori infection include asymptomatic damage to the stomach, with development of hypochlorhydria or achlorhydria. Reduced or absent acid secretion removes the gastric barrier to entry of orally ingested pathogens and increases the risk of enteric infection; it may also reduce the ability to absorb iron, food-bound vitamin B l2 . These are largely silent manifestations. The clinically obvious manifestations are peptic ulcer and gastric malignancy, with approximately one in six infected persons eventually developing peptic ulcer disease. The lifetime risk of gastric adenocarcinoma is somewhat greater than 1 %.10 Symptomatic gastric lymphoma occurs less frequently than gastric adenocarcinoma.
H. pylori as an Infectious Disease In 1993, I participated in a debate held as part of the Annual Postgraduate Course of the American Gastroenterological Association. The question was whether
S114
DAVID Y. GRAHAM
every patient with peptic ulcer disease and H. pylori infection should receive anti-H. pylori therapy. I was assigned the "yes" argument. This was a watershed time for conceptual thinking about peptic ulcer disease. I argued that peptic ulcer was not an "acid disease" but was one manifestation of a bacterial infection. Because peptic ulcer was an infectious disease, we should not consider it in any other context. I used analogy to show that recommendations such as reserving therapy for complicated or recurrent peptic ulcer disease were irrational when viewed in the context of standard therapy for an infectious disease. I compared peptic ulcer with urinary tract infection or tuberculosis and showed the similarities. For example, anti secretory therapy was equated to symptomatic therapy for urinary tract infection with pyridium (i.e., treat the pain, not the underlying disease). The concept that we must view peptic ulcer as one manifestation of an infection was accepted and resulted in a paradigm shift. 2 It is now amusing to consider the basis of the arguments for and against therapy that were prevalent before that time. The full implications of the concept that H. pylori infection is simply another infectious disease with many harmful outcomes have continued to evolve. At subsequent symposia at annual meetings of the American Gastroenterological Association, I introduced new concepts as "rules." One rule is, "If a treatment regimen does not work everywhere, and you do not understand why not, avoid it." Another was, "Do not test unless you are willing to treat." This rule was based on the premise that because of the many harmful outcomes of infection, it is impossible to deny treatment once the diagnosis IS established. I will expand on that line of thinking to fulfill my charge here. My opening comments were modeled on a paper that summarized the result of the Oslo study of untreated syphilis. II That report stated, " ... the great ailment of modern syphilological practice is the lack of comprehension of the 'why and wherefore,' rather than the 'what to do.' Comprehension of the 'why and wherefore' lies in a better understanding of the prognosis of untreated syphilis. The beneficial effects of treatment in modifying the biologic course of syphilitic infection is well-known. What was lacking was quantitative information on what happens to those who go untreated." H. pylori infection is not the only serious asymptomatic disease that has provoked arguments about whom and when to treat. I argue that asymptomatic H. pylori infection is as serious a health problem as asymptomatic syphilis or tuberculosis and shares many features with those diseases. Asymptomatic infection is the rule with all three organisms: H. pylori, Treponema pallidum, and Mycobacterium
GASTROENTEROLOGY Vol. 113, No. 6
tuberculosis. Arguments for or against routine therapy of syphilis were based on the natural history of the infection. It was known that (1) untreated syphilis had a favorable outcome in the majority of instances, (2) serious outcomes were more frequent in men than in women, (3) untreated syphilis prolonged the period of community danger of infection, (4) there was no way to predict the outcome of individual cases, and (5) patients with syphilis had a higher morbidity and mortality from other conditions than did those without the infection. It was estimated that 60%-70% of untreated individuals with asymptomatic T pallidum infection lived with a minimum of inconvenience. However, that knowledge provided little encouragement to withhold treatment, because the final outcome in any individual could not be predicted, and syphilis was a transmissible disease, putting others at risk. 11 Similar parallels exist between infection with H. pylori and tuberculosis. 12,13 Recall that only 10% of those with a positive tuberculin skin test eventually develop active tuberculosis. Winn and Prechter l2 ended their chapter on pulmonary tuberculosis with a list of remaining problems that are also applicable to H. pylori infection. They stated that the most important element in tuberculosis control was treatment of infected persons before the development of active disease. However, they noted that new antimicrobial agents were needed to treat disease caused by strains that are resistant to available drugs. They noted that an effective vaccine would have a tremendous impact in areas of the world with high rates of tuberculosis and inadequate healthcare budgets. The same conclusions are true in H. pylori infection. Finally, they suggested that a test that showed the presence of persistent viable tubercle bacilli would be desirable. H. pylori investigators have an advantage over workers in tuberculosis in that the urea breath test provides an accurate noninvasive method to diagnose active infections.
Asymptomatic H. pylori Is as Harmful as Syphilis or Tuberculosis Considerations regarding the desirability of treatmg an infectious disease include the outcome of the disease in a group of individuals (e.g., spontaneous cure vs. serious disease), whether the infection can be successfully treated, and the risks of not treating the infection in relationship to the uninfected population. The patient with a positive breath test for H. pylori infection differs from the patient with a positive tuberculosis skin test or a positive blood test for syphilis because H. pylori is always an active and potentially transmissible infection; in contrast, the risk of transmission of tuberculosis or
December Supplement 1997
syphilis depends on the development of active disease. Asymptomatic H. pylori infection provides a reservoir for transmission of disease to the uninfected community. The risks and modes of transmission of H. pylori remain unclear and poorly studied. It is of concern that infection clusters in families with children, providing an unkind gift to our children. 7,14 Unfortunately, funding for modern science is dominated by "intellectually interesting" questions of mechanism, and there is less interest in mundane and more difficult study questions, such as how to prevent the spread of H. pylori infection. Although asymptomatic destruction of the stomach may not be regarded by all as an important issue, there is little argument that peptic ulcer disease is a serious medical problem. Patients with peptic ulcers experience pain, have reduced quality of life, and suffer the risk of ulcer complication. 15 They also incur the expense of drugs, doctor visits, tests, and lost time from work. They have an increased mortality compared with those without ulcer disease. For example, there are approximately 350,000 hospital admissions for upper gastrointestinal hemorrhage each year in the United States. 16 At least 50% of these patients bleed as a complication of peptic ulcer, with a mortality rate of approximately 10%. The costs and risks of peptic ulcer disease mandate that patients with ulcers should be investigated for the presence of H. pylori infection and should be treated if H. pylori infection is present; cure of the infection should be confirmed to prevent recurrent ulcer, ulcer complications, and costs associated with additional visits, tests, and drugs. H. pylori infection has been etiologically implicated in gastric cancer. This association was no surprise. Before the discovery of H. pylori, the strong association between gastritis and gastric carcinoma was well-known and was responsible for a large body of epidemiological data regarding gastritis. Mayo is credited with saying that cancer never develops in a healthy stomach,17 and histological studies have repeatedly confirmed that gastric carcinoma is rare in the absence of gastritis. Recent studies have used serological data, which tend to underestimate the frequency of H. pylori infection in end-stage disease. It is likely that the estimates derived from those studies of the proportion of gastric cancer attributable to H. pylori underestimate the importance of H. pylori infection. 18 Gastric cancer has undergone a marked reduction in incidence in the last 50 years that appears to relate to changes in diet, food preparation, and food storage more than any reduction in the incidence of H. pylori infection. Presumably, these changes affect some cofactor contributing to cancer development for the general population. The lifetime risk of developing
DENY THERAPY FOR H. PYLORI?
Sl15
gastric cancer is still at least 1% for the general population lO ; the risk in those with H. pylori infection is higher because they represent the sub population at risk. Such a high risk of cancer is unacceptable for a treatable and potentially preventable disease. I believe that studies to understand and prevent transmission, and development of better treatments should take precedence over studies designed to address how 50 years of chronic inflammation leads to cancer.
Can the Presence of Putative Virulence Factors Be Used to Identify Harmful Strains of H. pylori and Whom to Treat? H. pylori and syphilis share the disease feature of having different ourcomes with respect to gender and age of acquisition. For example, the Oslo syphilis study reported that mortality among men with syphilis was twice that of infected women, as was the ratio for both cardiovascular and neurosyphilis. 11 They reported that cardiovascular syphilis did not develop in those infected before age 15, whereas neurosyphilis did not develop in those infected before age 15, or in men infected after age 40. About 16% of those with asymptomatic syphilis developed cardiovascular or neurological disease. The results are similar with asymptomatic M. tuberculosis infection, because only 5%-10% develop clinical disease. Because all syphilis and all tuberculosis infections are considered to be harmful, there has been little interest in identifying virulence factors that could predict worse ourcomes so as to focus therapy on that subpopulation. The possibility that asymptomatic syphilis or tuberculosis might be beneficial or should not be treated has not been a consideration. The initial recommendation to treat all patients with positive tuberculin skin tests was tempered only because of side effects of antituberculosis therapy. In contrast, there has been more interest in whether the different H. pylori-related diseases might be attributed to bacterial virulence factors. Recent candidates include such factors as the presence of cagA. Unfortunately, none of the putative virulence factors provide discrimination between patients with or without ulcer, cancer, or asymptomatic gastritis. 19- 22 Although there has been recent interest in the ability to use heterogeneity in vacA as a marker for peptic ulcer diseases,23 studies in other regions have not borne out the original hypothesis. 24 The presence of different strains circulating in different regions has apparently continued to provide confusing and misleading data regarding the role of potential virulence factors. For example, two European countries (Iceland and Portugal) with the
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highest incidences of gastric cancer were shown to have a low proportion of cagA-positive strains. 25 Furthermore, the incidence of gastric cancer continues to decrease, suggesting that if cagA-positive strains were important, the prevalence of cagA-positivity would have decreased in parallel, and it did not. 26 Other bacterial virulence factors, such as the cholera toxin or the diphtheria toxin, are invariably associated with their respective diseases, and the absence of the factor corresponds with absence of the diseases. The association of such virulence factors with disease is applicable everywhere in the world. Putative H. pylori virulence factors such as cagA or vacA subtypes have frequently failed to provide reliable predictive value. Because all H. pylori infections damage the stomach, the concept that one might identify a marker for a "safe" infection is probably wishful thinking. The current concept should be that all H. pylori infections are harmful, none should be tolerated if we had the means to eradicate the infection from mankind.
Whom to Treat for H. pylori Infection This could be restated as, "to whom can we deny therapy for H. pylori infection?" My position is that it is impossible to deny treatment once the diagnosis has been established. Consider the hypothetical conversation between a reluctant physician and a patient with nonulcer dyspepsia and a positive urea breath test: "You have a bacterial infection that is damaging yout- stomach. I do not think the infection is responsible for your symptoms and your lifetime risk of a serious disease is low. I estimate that only 1 in 6 individuals like you will develop peptic ulcer and only 1 to 3 per 100 will develop gastric cancer. Although you can transmit the infection to your spouse, your children and grandchildren, or to others, I do not recommend treatment." Until an effective vaccine or a simple effective therapy with limited or mild side effects is available, the question is not whom to treat but whom to test. This is a public health problem. The gains of therapy are clear, but we are constrained by cost, the existence of drug-resistant H. pylori, and the impracticability of treating 50% of our population. I believe that there is general agreement that all patients with peptic ulcer disease should be tested and those with H. pylori infection should be treated. Testing is also required, as there is no benefit, and only risks, associated with treating noninfected patients with other causes of peptic ulcer disease. Many would test those with suspected peptic ulcer (i.e., those with dyspepsia), because this is a reasonably small proportion of the population and H. pylori may actually cause nonulcer
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dyspepsia in some patients. I believe that we should have a low threshold for diagnosis and treatment. I would test and treat those at increased risk of gastric cancer or peptic ulcer. Such individuals can be identified with some degree of certainty on the basis of the presence of disease in a first-degree relative. The bottom line is that no one deserves, needs, wants, or benefits from having an H. pylori infection. Positive diagnosis of infection must be followed by treatment. There are no emotional reasons, but there are logical and persuasive scientific reasons, to treat H. pylori infection. If we had the tools, we would recommend screening the population for the presence of H. pylori infection with the goal of preventing all H. pylori-related diseases. Our goal should be to totally eliminate H. pylori from the face of the earth, just as we eliminated smallpox. 1,2 Hopefully, this will become possible in the furure. DAVID Y GRAHAM, M.D. Department of Medicine Veterans Affairs Medical Center and Division of Molecular Virology Baylor College of Medicine Houston, Texas
References 1. Graham DY. Benefits from elimination of' Helicobacter pylori infection include major reduction in the incidence of peptic ulcer disease, gastriC cancer, and primary gastriC lymphoma. Prev Med 1994;23:712-716. 2. Graham DY. Evolution of concepts regarding Helicobacter pylori: from a cause of gastritis to a public health problem. Am J GastroenteroI1994;89:469-472. 3. Malaty HM, Graham DY. Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut 1994;35:742-745. 4. Webb PM, Knight T, Greaves S, Wilson A, Newell DG, Elder J, Forman D. Relation between infection with Helicobacter pylori and living conditions in childhood: evidence for person-to-person transmission in early life. BMJ 1994;308:750-753. 5. Mendall MA, Goggin PM, Molineaux N, Levy J, ToosyT, Strachan 0, Northfield TC. Childhood living conditions and Helicobacter pylori seropositivity in adult life. Lancet 1992;339:896-897. 6. Malaty HM, Kim JG, Kim SO, Graham DY. Prevalence of Helicobacter pylori infection in Korean children: inverse relation to socioeconomic status despite a uniformly high prevalence in adults. Am J EpidemioI1996;143:257-262. 7. Malaty HM, Graham DY, Klein PO, Evans DG, Adam E, Evans OJ. Transmission of Helicobacter pylori infection. Studies in families of healthy individuals. Scand J Gastroenterol 1991;26:927932. 8. Mitchell HM, Bohane TO, Berkowicz J, Hazell SL, Lee A. Antibody to Campylobacter pylori in families of index children with gastrOintestinal illness due to C. pylori. Lancet 1987;2:681682. 9. Drumm B, Perez-Perez GI, Blaser MJ, Sherman PM. Intrafamilial clustering of Helicobacter pylori infection. N Engl J Med 1990; 322:359-363.
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10. Seer cancer statistics review, 1973-1992: Tables and graphs, National Cancer Institute. Bethesda, MD: 1995, NIH Publication No. 96-2789. 11. Clark EG, Danbolt N. The Oslo study of the natural course of untreated syphilis. An epidemiologic investigation based on restudy of the Boeck-Burrsgaard material. Med Clin North Am 1964;48:613-623. 12. Winn RE, Prechter GC. Pulmonary tuberculosis. In: Hoeprich PD, Jordan MC, Ronald AR, eds. Infectious diseases. 5th ed. Philadelphia: Lippincott, 1994:447-464. 13. The use of preventive therapy for tuberculous infection in the United States. Recommendations of the Advisory Committee for elimination oftuberculosis. MMWR Morbid Mortal Wkly Rep 1989;39:No. RR-8:9-12. 14. Graham DY, Klein PD, Evans DG, Fiedorek SC, Evans OJ Jr, Adam E, Malaty HM. HeJicobacter pylori: epidemiology, relationship to gastric cancer, and the role of infants in transmission" Eur J Gastroenterol Hepatol 1992;4(Suppl 1):Sl-S6. 15. Soli AH. Gastric, duodenal, and stress ulcer. In: Sieisenger M, Fordtran J, eds. Gastrointestinal disease. 5th ed. Philadelphia: Saunders, 1993:580-679. 16. Peterson WL. Gastrointestinal bleeding. In: Sieisenger M, Fordtran J, eds. Gastrointestinal disease. Pathophysiology diagnosis management. 4th ed. Philadelphia: Saunders, 1989:397428. 17. Bockus HL. Carcinoma of the stomach. In: Bockus HL, ed. Gastroenterology. 2nd ed. Philadelphia: Saunders, 1963:743801. 18. Forman D. The prevalence of Helicobacter pylori infection in gastric cancer. Aliment Pharmacol Ther 1995;9(Suppl 2): 71-76. 19. Graham DY, Go MF, Genta RM. HeJicobacter pylori, duodenal ulcer, gastric cancer: tunnel vision or blinders? Ann Med 1995;27:589-594. 20. Go MF, Graham DY. The cagA gene is present in the majority of H. pylori strains independent of whether the individual has
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duodenal ulcer or asymptomatic gastritis. Helicobacter 1996;1: 107-111. Miehlke S, Kibler K, Kim JG, Figura N, Small SM, Graham DY, Go MF. Allelic variation in the cagA gene of HeJicobacter pylori obtained from Korea compared to the United States. Am J GastroenteroI1996;91:1322-1325. Graham DY, Genta RM, Graham DP, Crabtree JE. Serum CagA antibodies in asymptomatic subjects and patients with peptic ulcer: lack of correlation of IgG antibody in patients with peptic ulcer or asymptomatic HeJicobacter pylori gastritis. J Clin PathoI1996;49:829-832. Atherton JC, Peek RM Jr, Tham KT, CoverTL, Blaser MJ. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology 1997;112:92-99. Go MF, Cissell L, Graham DY. VacA genotype of H. pylori does not predict the nature of the gastroduodenal disease. Gastroenterology 1997;112:A127. Crabtree JE, Webb P, Newell D, Covacci A, Forman D. An epidemiological survey of CagA seropositivity in seventeen worldwide populations. Gut 1996;39(Suppl 2):A82. Perez-Perez GI, Bhat N, Gaensbauer J, Taylor D, Kuipers EJ, Zhang L, You W, Blaser MJ. Country-specific constancy by age in cagA+ proportions of H. pylori infections. Gut 1996;39(Suppl 2):A83.
Received June 30,1997. Accepted July 22,1997. Address reprint requests to: David Y. Graham, M.D., Veterans Affairs Medical Center (1110), 2002 Holcombe Boulevard, Houston, Texas 77030. e-mail: [email protected]; fax: (713) 7901040. Supported by the Department of Veterans Affairs and by the generous support of Hilda Schwartz. © 1997 by the American Gastroenterological Association 0016-5085/97/$3.00