51 - 168 Helicobacter pylori Infections

168 Helicobacter pylori Infections

■ ■INFECTION CONTROL AND PREVENTION Acinetobacter species are capable of surviving on hospital surfaces for prolonged periods. In the hospital environment, A. baumannii has been associated with establishment of a fecal patina; this term refers to a coating of enteric organisms that can cover the skin of colonized patients and extend to their surrounding environment. Concentrations of enteric organisms are highest in the colonized patient’s rectum, with spread in a target-like concentric pattern covering the patient’s body and the surrounding environment. High-frequency touch areas in rooms occupied by patients colonized with A. baumannii are more likely to be contaminated. The hands, gloves, and gowns of health care workers can be contaminated after entry into the room of a patient colonized with A. baumannii (Fig. 167-1).

Outbreaks caused by A. baumannii are frequently mono- or oligo­ clonal. A common source of infection has been identified in ~50% of outbreaks. These sources include respiratory therapy equipment, the hands of health care workers, bedside humidifiers, warm bathwater, hospital-prepared distilled water, bedpans, urine jugs, heparinized saline solution, mattresses, reusable pressure transducers in arterial lines, and fluids used for pressure lavage of wounds. Control of multidrug-resistant Acinetobacter outbreaks starts with early recognition, with subsequent halting of the spread of infec­ tion throughout a facility and prevention of the establishment of an endemic strain. It is important to identify the outbreak strain and dif­ ferentiate it from nonoutbreak strains so that infection control activi­ ties can be better targeted. Traditionally, the strain was identified with phenotypic typing systems (biotyping) or by determination of antimi­ crobial susceptibility patterns. Whole genome sequencing (WGS) has been proven an effective tool during outbreak investigations, usually deployed in response to an increase in the number of patients infected or colonized with a multidrug-resistant organism. However, an emerg­ ing body of evidence supports the prospective use of WGS for infec­ tion prevention, as it leads to early detection of transmission pathways and the potential for halting spread sooner and limiting cluster sizes through targeted infection prevention interventions. PART 5 Infectious Diseases During outbreaks, the simultaneous introduction of multiple (“bun­ dled”) measures makes it difficult to assess the impact of each indi­ vidual measure. These interventions include aggressive cleaning of the general environment, active surveillance, contact isolation of colonized or infected patients, cohorting of medical staff, reinforcement of com­ pliance with hand hygiene by health care workers, and use of aseptic care devices. Colonization with A. baumannii is a strong predictor of subsequent clinical infection by this organism. Exposure to carbapenems is a risk factor for initial acquisition of this pathogen; therefore, efforts to cur­ tail unnecessary use of antibiotics are fundamental to the prevention of A. baumannii colonization of patients and the organism’s establishment in health care facilities. ■ ■FURTHER READING Adams-Haduch JM et al: Molecular epidemiology of carbapenemnonsusceptible Acinetobacter baumannii in the United States. J Clin Microbiol 49:3849, 2011. Antunes LC et al: Acinetobacter baumannii: Evolution of a global pathogen. Pathog Dis 71:292, 2014. Chen W: Host innate immune responses to Acinetobacter baumannii infection. Front Cell Infect Microbiol 10:486, 2020. Dexter C et al: Community-acquired Acinetobacter baumannii: Clini­ cal characteristics, epidemiology and pathogenesis. Expert Rev Anti Infect Ther 13:567, 2015. Lee CR et al: Biology of Acinetobacter baumannii: Pathogenesis, antibi­ otic resistance mechanisms, and prospective treatment options. Front Cell Infect Microbiol 7:55, 2017. Munoz-Price LS: Controlling multi-drug resistant gram-negative bacilli in your hospital: A transformational journey. J Hosp Infect 89:254, 2015. Ong SWX et al: Genomic surveillance uncovers ongoing transmission of carbapenem-resistant Acinetobacter baumannii (CRAB) and iden­ tifies actionable routes of transmissions in an endemic setting. Infect Control Hosp Epidemiol 44:460, 2023.

Peleg AY et al: Acinetobacter baumannii: Emergence of a successful pathogen. Clin Microbiol Rev 21:538, 2008. Shields RK et al: Navigating available treatment options for carbape­ nem-resistant Acinetobacter baumannii-calcoaceticus complex infec­ tions. Clin Infect Dis 76:S179, 2023. Tamma PD et al: Infectious Diseases Society of America 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections. Clin Infect Dis 2024:ciae403. Available at https://doi.org/10.1093/cid/ ciae403. Accessed February 14, 2025. Tal-Jasper R et al: Clinical and epidemiological significance of car­ bapenem resistance in Acinetobacter baumannii infections. Antimi­ crob Agents Chemother 60:3127, 2016. Wong D et al: Clinical and pathophysiological overview of Acinetobacter infections: A century of challenges. Clin Microbiol Rev 30:409, 2017. Emad M. El-Omar, Martin J. Blaser

Helicobacter pylori

Infections Helicobacter pylori colonizes the stomach in ~40% of the world’s human population, essentially for life unless eradicated by antibiotic treatment. Colonization with this organism is the main risk factor for peptic ulceration (Chap. 335) as well as for gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma (Chap. 85). Treatment for H. pylori has revolutionized the manage­ ment of peptic ulcer disease, providing a permanent cure in most cases. Such treatment also represents first-line therapy for patients with low-grade gastric MALT lymphoma. Treatment of H. pylori is of no benefit in the treatment of gastric adenocarcinoma, but preven­ tion of H. pylori colonization or eradicative treatment could poten­ tially prevent gastric malignancy and peptic ulceration. In contrast, increasing evidence indicates that lifelong H. pylori colonization may offer some protection against complications of gastroesopha­ geal reflux disease (GERD), including esophageal adenocarcinoma, although this point is still uncertain. Recent research has focused on whether H. pylori colonization is also a risk factor for some extra­ gastric diseases and whether it is protective against some recently emergent medical problems, such as childhood-onset asthma and other allergic and metabolic conditions. ■ ■ETIOLOGIC AGENT Helicobacter pylori  H. pylori is a gram-negative bacillus that has naturally colonized humans for at least 100,000 years, and probably throughout human evolution. It lives in gastric mucus, with a propor­ tion of the bacteria adherent to the mucosa and possibly a very small number of the organisms entering cells or penetrating the mucosa; the organism’s distribution is mucosal rather than systemic. Its spiral shape and flagella render H. pylori motile in the mucus environment. The organism has several acid-resistance mechanisms, most notably a highly expressed urease that catalyzes urea hydrolysis to produce buff­ ering ammonia. H. pylori is microaerophilic (i.e., grows in low levels of oxygen), is slow-growing, and requires complex growth media in vitro. Other Helicobacter Species  A small proportion of gastric Helicobacter infections are due to species other than H. pylori, possibly acquired as zoonoses. These non-pylori gastric helicobacters are associ­ ated with low-level inflammation and occasionally with disease. In immu­ nocompromised hosts, several nongastric (intestinal) Helicobacter species can cause disease with clinical features resembling those of Campylobacter infections; these species are covered in Chap. 169.

■ ■EPIDEMIOLOGY Prevalence and Risk Factors  The prevalence of H. pylori among adults is <30% in most parts of the United States, Europe, and Ocea­ nia as opposed to >60% in many parts of Africa, South America, and West Asia. In the United States, prevalence varies with age but has been dropping; an estimated 18% of adults and 14% of children and adolescents are positive. H. pylori is usually acquired in childhood. The age association is due mostly to a birth-cohort effect whereby cur­ rent 60-year-olds were more commonly colonized as children than are current children. Spontaneous acquisition or loss of H. pylori in adult­ hood is uncommon. Childhood acquisition explains why the main risk factors for infection are markers of crowding and social deprivation in childhood. Longitudinal studies have shown declining prevalences over the past half-century, concomitant with socioeconomic develop­ ment and widespread antibacterial treatments. Transmission  Humans are the only important reservoir of H. pylori. Children may acquire the organism from their parents (most often the primary caregiver) or from other children. The former is more com­ mon in developed countries and the latter in less developed countries. Whether transmission takes place more often by the fecal–oral or the oral–oral route is unknown, but H. pylori is easily cultured from vomitus and gastroesophageal refluxate and is much less easily cultured from stool. Most acquisition of H. pylori is during the early years of childhood. ■ ■PATHOLOGY AND PATHOGENESIS Long-term H. pylori colonization induces chronic superficial gastritis, a tissue response in the stomach that includes infiltration of the mucosa by both mononuclear and polymorphonuclear cells. (The term gastritis should be used specifically to describe histologic features; it has also been used to describe endoscopic appearances and even symptoms, but only magnification endoscopy correlates with microscopic findings or even with the presence of H. pylori, and even this is insufficient for diagno­ sis.) Although H. pylori is capable of numerous adaptations that prevent excessive stimulation of the immune system, colonization is accompa­ nied by a considerable persistent local and systemic immune response, including the production of antibodies and cell-mediated responses. However, these responses are ineffective in clearing the bacterium. This inefficient clearing appears to be due in part to H. pylori’s downregula­ tion of the immune system, which fosters its own persistence. Most H. pylori–colonized persons do not develop clinical sequelae. That some persons develop overt disease whereas others do not is related to a combination of factors: bacterial strain differences, host susceptibility to disease, and environmental factors. Bacterial Virulence Factors  Several H. pylori virulence fac­ tors are more common among strains that are associated with disease than among those that are not. The cag island is a group of genes that encodes a bacterial type IV secretion system. Through this system, an effector protein, CagA, is translocated into epithelial cells, where it may be activated by phosphorylation and induces host cell signal transduction; proliferative, cytoskeletal, and inflammatory changes in the cell result. The protein at the tip of the secretory appa­ ratus, CagL, binds to integrins on the cell surface, transducing further signaling. Finally, soluble components of the peptidoglycan cell wall enter the cell, mediated by the same secretory system. These compo­ nents are recognized by the intracellular bacterial receptor Nod1, which stimulates a proinflammatory cytokine response resulting in an enhanced tissue response. Carriage of cag-positive strains increases the risk of both peptic ulcer and gastric adenocarcinoma. A second major host-interaction factor is the vacuolating cytotoxin VacA, which forms pores in cell membranes. VacA is polymorphic, and carriage of more active forms also increases the risk of ulcer disease and gastric cancer. Other bacterial factors that are associated with increased disease risk include adhesins, such as BabA (which binds to blood group antigens on epithelial cells). Host Genetic and Environmental Factors  There are currently no host genetic factors that have been reproducibly associated with risk

of acquisition of H. pylori infection. The best-characterized host deter­ minants of disease are genetic polymorphisms leading to enhanced activation of the innate immune response, including polymorphisms in cytokine genes and in genes encoding bacterial recognition pro­ teins such as Toll-like receptors. For example, colonized people with polymorphisms in the interleukin 1 gene that increase the production of this cytokine in response to H. pylori infection are at increased risk of gastric adenocarcinoma. Another host genetic factor that has been linked with increased risk of gastric cancer in multiple populations is a single-nucleotide polymorphism (SNP) in the prostate stem cell antigen (PSCA) rs2294008. In addition to host genetics, environmental cofactors are important in pathogenesis. Smoking increases the risks of duodenal ulcers and gastric cancer in H. pylori–positive individuals. Diets high in salt and preserved foods increase cancer risk, whereas diets high in antioxidants and vitamin C are modestly protective.

Distribution of Gastritis and Differential Disease Risk  The pattern of gastric tissue response is associated with disease risk: antralpredominant gastritis is most closely linked with duodenal ulceration, whereas pan-gastritis and corpus-predominant gastritis are linked with gastric ulceration and adenocarcinoma. This difference probably explains why patients with duodenal ulceration are not at high risk of developing gastric adenocarcinoma later in life, despite being colonized by H. pylori. PATHOGENESIS OF DUODENAL ULCERATION  How gastric coloniza­ tion causes duodenal ulceration is now becoming clearer. H. pylori– induced tissue responses in the gastric antrum diminish the number of somatostatin-producing D cells. Because somatostatin inhibits gastrin release, gastrin levels are higher than in H. pylori–negative persons, and these higher levels lead to increased meal-stimulated acid secretion from the relatively spared gastric corpus. How this situation increases duodenal ulcer risk remains controversial, but the increased acid secretion may contribute to the formation of potentially acidprotective gastric metaplasia in the duodenum. Gastric metaplasia in the duodenum may become colonized by H. pylori and subsequently inflamed and ulcerated. CHAPTER 168 Helicobacter pylori Infections PATHOGENESIS OF GASTRIC ULCERATION AND GASTRIC ADENOCAR­ CINOMA  The pathogenesis of these conditions is less well understood, although both arise in association with pan- or corpus-predominant gastritis. The hormonal changes described above still occur, but the tissue responses in the gastric corpus mean that it produces less acid (hypochlorhydria) despite hypergastrinemia. Gastric ulcers commonly occur at the junction of antral and corpus-type mucosa, an area that is often particularly inflamed. Gastric cancer usually arises in stom­ achs with extensive atrophic gastritis and hypo- or achlorhydria, and probably stems from progressive DNA damage and the survival of abnormal epithelial cell clones. The DNA damage is thought to be due principally to reactive oxygen and nitrogen species arising from inflammatory cells, perhaps in relation to other bacteria that survive in a hypochlorhydric stomach. Longitudinal analyses of gastric biopsy specimens taken years apart from the same patient show that the common intestinal type of gastric adenocarcinoma follows stepwise changes from simple gastritis to gastric atrophy, metaplasia, and dys­ plasia. A second, diffuse type of gastric adenocarcinoma found more commonly in younger adults may arise directly from chronic gastritis without atrophic changes. In recent years, there has been a progressive rise in gastric cancers centered on the gastric corpus and occurring in younger adults (<50 years old) and disproportionately in females; this appears to be in the absence of H. pylori. PATHOGENESIS OF GASTRIC MALT LYMPHOMA  Low-grade B-cell MALT lymphomas are rare malignancies, reported at a rate of ~1 per million population per year prior to the discovery of H. pylori. Since then, reported rates have increased substantially, possibly reflecting overdiagnosis. These tumors arise from the substrate of chronic stimu­ lation of lymphocyte populations by the persistent H. pylori coloniza­ tion. Importantly, there have been numerous reports of these low-grade tumors responding dramatically to H. pylori eradication therapies. However, the boundary between true malignancy and benign lymphoid

hypertrophy is uncertain. Among responders to H. pylori eradication, most do not have the characteristic t(11;18)(q21;q21) translocation of the malignancy and may not have true malignancies but rather benign polyclonal lymphoid proliferation. CagA-positive H. pylori strains have been significantly associated with the t(11;18)(q21;q21)–positive gastric MALT lymphoma compared with translocation-negative cases.

■ ■CLINICAL MANIFESTATIONS Essentially all H. pylori–colonized persons have histologic gastritis, but only ~10–15% develop associated illnesses such as peptic ulceration, gastric adenocarcinoma, or gastric lymphoma (Fig. 168-1). Despite similar rates of H. pylori colonization, rates of these diseases among women are less than half of those among men. ■ ■PEPTIC ULCER DISEASE Worldwide, ~70% of duodenal ulcers and ~50% of gastric ulcers are related to H. pylori colonization (Chap. 335). However, in particular, the proportion of gastric ulcers caused by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is increasing, and in many devel­ oped countries, these drugs have overtaken H. pylori as a cause of gastric ulceration. The main lines of evidence supporting an ulcerpromoting role for H. pylori are that (1) the presence of the organism is a risk factor for the development of ulcers, (2) non-NSAID-induced ulcers rarely develop in the absence of H. pylori, (3) eradication of H. pylori virtually abolishes long-term ulcer relapse, and (4) experimental H. pylori infection of gerbils can cause gastric ulceration. Thus, H. pylori is neither necessary nor sufficient for the development of peptic ulcer disease, but it is a very strong risk factor for its occurrence, and removal of H. pylori changes the natural history of ulcer disease. PART 5 Infectious Diseases Gastric Adenocarcinoma and Lymphoma  Prospective nested case–control studies have shown that H. pylori colonization is a risk factor for adenocarcinomas of the distal (noncardia) stomach (Chap. 85). Long-term experimental infection of gerbils also may result in gastric adenocarcinoma. Moreover, H. pylori may induce primary gastric lymphoma, although this condition is much less com­ mon, and the approaches to histopathologic and cytogenetic evalua­ tions are not standardized. Many of the diagnosed low-grade gastric B-cell lymphomas are dependent on H. pylori for continuing growth Tissue response (inflammation) Primary phenomenon: Hyperacidity Atrophic gastritis Secondary phenomenon: Antigenic stimulation ? B-cell lymphoma Noncardia gastric adenocarcinoma Reflux esophagitis and sequelae Duodenal ulceration Clinical outcome: Association with H. pylori (OR): 3–8 3–6 6–50 0.2–0.6 FIGURE 168-1  Schematic of the relationships between colonization with Helicobacter pylori and diseases of the upper gastrointestinal tract. Essentially all persons colonized with H. pylori develop a host response, which is generally termed chronic gastritis. The nature of the host’s interaction with the particular bacterial population determines the clinical outcome. H. pylori colonization increases the lifetime risk of peptic ulcer disease, noncardia gastric cancer, and B-cell non-Hodgkin’s gastric lymphoma (odds ratios [ORs] for all, >3). In contrast, a growing body of evidence indicates that H. pylori colonization (especially with cagA+ strains) protects against adenocarcinoma of the esophagus (and the sometimes related gastric cardia) and premalignant lesions such as Barrett’s esophagus (ORs, <1). Although the incidences of peptic ulcer disease (cases not due to nonsteroidal anti-inflammatory drugs) and noncardia gastric cancer are declining in developed countries, the incidence of adenocarcinoma of the esophagus is increasing. (Reproduced with permission from MJ Blaser: Hypothesis: The changing relationships of Helicobacter pylori and humans: Implications for health and disease. J Inf Dis 179:1523, 1999.)

and proliferation, and these tumors may regress either fully or partially after H. pylori eradication. However, they require careful short- and long-term monitoring; any that are not confined to the superficial mucosa (and, indeed, some that are) require additional treatment with chemotherapeutic agents or radiotherapy. Functional Dyspepsia  Many patients have upper gastrointestinal symptoms but have normal results on upper gastrointestinal endoscopy (so-called functional or nonulcer dyspepsia; Chap. 335). Because H. pylori is common, some of these patients will be colonized with the organism. H. pylori eradication leads to symptom resolution up to 15% more commonly than does placebo treatment. Whether such patients have peptic ulcers in remission at the time of endoscopy or whether a small subgroup of patients with “true” functional dyspepsia respond to H. pylori treatment is unclear. Either way, because functional dyspepsia is often persistent and difficult to treat, most consensus conference guidelines recommend H. pylori eradication in these patients. If this advice is followed, it is important to realize that only a small subgroup of patients who are treated will benefit. Protection Against Peptic Esophageal Disease, Including Esophageal Adenocarcinoma  Much interest has focused on a protective role for H. pylori against GERD (Chap. 334), Barrett’s esophagus (Chap. 334), and adenocarcinoma of the esophagus and gastric cardia (Chap. 85). The main lines of evidence for this role are (1) that there is a temporal relationship between a falling prevalence of gastric H. pylori colonization and a rising incidence of these condi­ tions; (2) that, in most studies, the prevalence of H. pylori colonization (especially with proinflammatory cagA+ strains) is significantly lower among patients with these esophageal diseases than among control participants; and (3) that, in prospective nested studies (see above), the presence of H. pylori is inversely related to these cancers. The mechanism underlying this protective effect is likely H. pylori–induced hypochlorhydria. Because, at the individual level, GERD severity may decrease, worsen, or remain unchanged after H. pylori treatment, con­ cerns about GERD should not affect decisions about whether to treat H. pylori in an individual patient if a clear-cut indication exists; if there is no clear indication, clinicians should carefully balance consider­ ations of benefit and harm. Other Pathologies  H. pylori has an increasingly recognized role in other gastric pathologies. It may predispose some patients to iron deficiency through occult blood loss and/ or hypochlorhydria and reduced iron absorp­ tion. In addition, several extragastrointestinal pathologies have been linked with H. pylori colonization, although evidence of causality is less strong. Studies of H. pylori treatment in idiopathic thrombocytopenic purpura have consistently described improvement in or even normalization of platelet counts. Potentially important but even more controversial (pro­ tective) associations are with ischemic heart disease and cerebrovascular disease. However, the strength of the latter associations is reduced if confounding factors are taken into account, and our present knowledge is incomplete. Most authorities consider the associations to be non­ causal. An increasing number of studies have shown an inverse association of cagA+ H. pylori with childhood-onset asthma, hay fever, and atopic disorders. These associations have been shown to be causal in animal models, but the effect size in humans has not been established. ■ ■DIAGNOSIS Tests for H. pylori fall into two groups: tests that require upper gastrointestinal endoscopy and simpler tests that can be performed in the clinic (Table 168-1).

TABLE 168-1  Tests Commonly Used to Detect Helicobacter pylori TEST ADVANTAGES DISADVANTAGES Tests Based on Endoscopic Biopsy Biopsy urease test Quick, simple Some commercial tests not fully sensitive before 24 h Histology May give additional histologic information Sensitivity dependent on experience and use of special stains Culture Permits determination of antibiotic susceptibility Sensitivity dependent on experience Noninvasive Tests Serology Inexpensive and convenient; not affected by recent antibiotics or proton pump inhibitors to the same extent as breath and stool tests Cannot be used to monitor treatment success; some commercial kits inaccurate, and most less accurate than urea breath test 13C urea breath test Inexpensive and simpler than endoscopy; useful for follow-up after treatment Requires fasting; not as convenient as blood or stool tests Stool antigen test Inexpensive and convenient; Stool-based tests disliked by people from some cultures useful for follow-up after treatment; may be particularly useful in children Endoscopy-Based Tests  Endoscopy is usually unnecessary in the initial management of young patients with simple dyspepsia but is commonly used to exclude malignancy and make a positive diagnosis in older patients or those with “alarm” symptoms. If endoscopy is per­ formed, the most convenient biopsy-based test is the biopsy urease test, in which one large or two small gastric biopsy specimens are placed into a gel containing urea and an indicator. The H. pylori urease enzyme hydrolyses urea in gastric juice and generates ammonia. This leads to a rise in pH and therefore to a color change, which often occurs within minutes but can require up to 24 h. Histologic examination of biopsy specimens for H. pylori also is accurate, provided that a special stain (e.g., a modified Giemsa, silver, or immuno-stain) permitting optimal visual­ ization of the organism is used. If biopsy specimens are obtained from both antrum and corpus, histologic study yields additional information, including the degree and pattern of inflammation and the presence of any atrophy, metaplasia, or dysplasia. Microbiologic culture is most spe­ cific but may be insensitive because of difficulty with H. pylori isolation. Once the organism is cultured, its identity as H. pylori can be confirmed by its typical appearance on Gram’s stain and its positive reactions in oxidase, catalase, and urease tests. Moreover, the organism’s susceptibility to antibiotics can be determined, and this information can be clinically useful in difficult cases. The occasional biopsy specimens containing the less common non-pylori gastric helicobacters give weakly positive results in the biopsy urease test. Positive identification of these bacteria requires visualization of the characteristic long, tight spirals in histologic sections; they cannot easily be cultured. Noninvasive Tests  Noninvasive H. pylori testing is the norm if gastric cancer does not need to be excluded by endoscopy. The longestestablished test (and a very accurate one) is the urea breath test. In this simple test, the patient drinks a solution of urea labeled with the nonradioactive isotope 13C and then blows into a tube. If H. pylori urease is present, the urea is hydrolyzed, and labeled carbon dioxide is detected in breath samples. The stool antigen test, a simple and accu­ rate test using monoclonal antibodies specific for H. pylori antigens, is more convenient and less expensive than the urea breath test, but some patients dislike sampling stool. The simplest tests for ascertaining

H. pylori status are serologic assays measuring specific IgG levels in serum by enzyme-linked immunosorbent assay or immunoblot. The best of these tests are nearly as accurate as other diagnostic methods, but many commercial tests—especially rapid office tests—do not perform well. Use of Tests to Assess Treatment Success  The urea breath test, the stool antigen test, and biopsy-based tests can all be used to assess

the success of treatment (Fig. 168-2). However, because these tests are dependent on H. pylori load, their use <4 weeks after treatment may yield false-negative results. Early suppression of bacterial numbers may lead to false-negative results since regrowth of the organism can result in its detection weeks later. For the same reason, these tests are unreli­ able if performed within 4 weeks of intercurrent treatment with antibi­ otics or bismuth compounds or within 2 weeks of the discontinuation of proton pump inhibitor (PPI) treatment. In the assessment of treat­ ment success, noninvasive tests are normally preferred. However, after gastric ulceration, endoscopy should be repeated to ensure healing and exclude gastric carcinoma by further histologic sampling; if PPIs have been stopped for at least 2 weeks and no antibiotics or bismuth com­ pounds have been given for at least 6 weeks, there is an opportunity to assess treatment success with biopsy-based tests. Serologic tests are not used to monitor treatment success, as the gradual drop in titer of H. pylori–specific antibodies is too slow (requiring >14 weeks) to be of practical use.

TREATMENT Helicobacter pylori Infection INDICATIONS The most clear-cut indications for treatment are H. pylori–related duodenal or gastric ulceration or low-grade gastric B-cell MALT lymphoma. Whether or not the ulcers are currently active, H. pylori should be eradicated in patients with documented ulcer disease to prevent relapse (Fig. 168-2). Guidelines have recommended H. pylori treatment for colonized patients with functional dyspepsia in case they are among the small percentage who will benefit from such therapy (beyond placebo effects). H. pylori eradication in the treatment of conditions not definitively known to respond has also been recommended but is not universally supported; such condi­ tions include idiopathic thrombocytopenic purpura, vitamin B12 deficiency, and iron-deficiency anemia where other causes have been carefully excluded. For individuals with a strong family his­ tory of gastric cancer, treatment to eradicate H. pylori in the hope of reducing cancer risk is reasonable but of unproven value: it slightly reduces future cancer incidence, but there is no evidence it reduces all-cause mortality. For older dyspeptic patients in the community or those who have “alarm” symptoms (e.g., weight loss) associated with their dyspepsia, upper gastrointestinal endoscopy is indicated to seek a diagnosis and test for H. pylori; the decision regarding whether to eradicate the organism can then be based on indication. Endoscopy is usually considered unnecessary for young dyspeptic patients in the community who have no alarm symptoms (with the precise age cutoff dependent on local guidelines). If the community prevalence of H. pylori is below ~20%, such patients are treated with a short course of acid suppression using a PPI. If these patients do not respond or relapse when treatment is stopped, or if the

H. pylori community prevalence is >20%, many national guidelines recommend a strategy of testing for H. pylori noninvasively and eradicating it if it is found. This strategy will benefit patients who have peptic ulcers and the ~5−10% of patients who have functional dyspepsia responsive to H. pylori eradication, but most patients will be treated unnecessarily. Currently, widespread community screening for and treatment of H. pylori as primary prophylaxis for gastric cancer and peptic ulcers are not recommended in most countries, mainly because the extent of the consequent reduction in cancer risk is not known. Several studies have found a modestly reduced cancer risk after treatment, but the period of follow-up is still fairly short, and the magnitude of the effect in different populations remains unclear. Other reasons not to treat H. pylori in asymptomatic populations at present include (1) the adverse side effects (which are common and can be severe in rare cases) of the multiple-antibiotic regimens used; (2) antibiotic resistance, which may emerge in H. pylori or other incidentally carried bac­ teria; (3) the anxiety that may arise in otherwise healthy people, especially if treatment is unsuccessful; and (4) the existence of a CHAPTER 168 Helicobacter pylori Infections

Indication for H. pylori treatment (e.g., peptic ulcer disease or new-onset dyspepsia) Test for H. pylori Positive First-line treatment (Table 168-2) Wait at least 1 month after treatment finishes (no antibiotics, bismuth compounds, or proton pump inhibitors in the meantime) Positive Urea breath test or stool antigen test* Second-line treatment (Table 168-2) Positive after second-line treatment Third-line treatment; endoscopy with H. pylori culture and sensitivity testing; treat according to known antibiotic sensitivities FIGURE 168-2  Algorithm for the management of Helicobacter pylori infection. *Note that either the urea breath test or the stool antigen test can be used in this algorithm. Occasionally, endoscopy and a biopsy-based test are used instead of either of these tests in follow-up after treatment. The main indication for these invasive tests is in follow-up after gastric ulceration; in this condition, as opposed to duodenal ulceration, it is important to check healing and exclude underlying gastric adenocarcinoma. However, even in this situation, patients undergoing endoscopy may still be receiving proton pump inhibitor therapy, which precludes H. pylori testing. Thus, a urea breath test or a stool antigen test is still required at a suitable interval after the end of therapy to determine whether treatment has been successful (see text). Some authorities use empirical third-line regimens, of which several have been described. PART 5 Infectious Diseases subset of people who will develop GERD symptoms after treat­ ment. Despite the absence of screening strategies, many doctors treat H. pylori if it is known to be present (particularly in children and younger adults), even when the patient is asymptomatic. The rationale is that it reduces patient concern and may reduce future gastric cancer risk and that any reduction in risk is likely to be greater in younger patients. However, such practices do not factor in any potential benefits of H. pylori colonization. Overall, despite widespread clinical activity in this area, most treatment of persons with asymptomatic H. pylori carriage is given with no firm evi­ dence base. Because a proportion of patients (up to 70%) of those diagnosed with gastric low-grade B-cell MALT lymphomas respond to H. pylori eradication, it should be used in all cases, regardless of whether H. pylori can be detected by the diagnostic modalities used since there may be falsely negative results. However, not all of these cases represent true malignancies, so the reported success TABLE 168-2  Commonly Recommended Treatment Regimens for Helicobacter pylori REGIMENa (DURATION) DRUG 1 DRUG 2 DRUG 3 DRUG 4 Regimen 1: OCM (14 days)b Omeprazole (20 mg bidc) Clarithromycin (500 mg bid) Metronidazole (500 mg bid) — Regimen 2: OCA (14 days)b Omeprazole (20 mg bidc) Clarithromycin (500 mg bid) Amoxicillin (1 g bid) — Regimen 3: OBTM (14 days)d Omeprazole (20 mg bidc) Bismuth subsalicylate

(2 tabs qid) Regimen 4: concomitant (14 days)e Omeprazole (20 mg bidc) Amoxicillin (1 g bid) Clarithromycin (500 mg bid) Tinidazole (500 mg bidf) Regimen 5: OAL (10 days)g Omeprazole (20 mg bidc) Amoxicillin (1 g bid) Levofloxacin (500 mg bid or 200 mg bid) — aThe recommended first-line regimens for most of the world are shown in bold type. bThis regimen should be used only for populations in which the prevalence of clarithromycin-resistant strains is known to be <20%. In practice, this restriction limits the regimens’ appropriate range mainly to northern Europe. cMany authorities and some guidelines recommend doubling this dose of omeprazole as trials show resultant increased efficacy with some antibiotic combinations. Omeprazole may be replaced with any proton pump inhibitor (PPI) at an equivalent dosage. Because extensive metabolizers of PPIs are prevalent among Caucasian populations, many authorities recommend esomeprazole (40 mg bid) or rabeprazole (20 mg bid), particularly for regimens 4 and 5. dData supporting this regimen come mainly from Europe and are based on the use of bismuth subcitrate (1 tablet qid) and metronidazole (400 mg tid). This is a recommended first-line regimen in most countries and is the recommended secondline regimen in northern Europe. eThis regimen may be used as an alternative to regimen 3. fMetronidazole (500 mg bid) may be used as an alternative. gThese regimens are used as second-line treatment in many countries (particularly where quadruple or concomitant therapy is used as the first-line regimen) and as third-line treatment in others. They may be less effective where rates of fluoroquinolone use are high and are more likely to be ineffective if there is a personal history of fluoroquinolone use for previous treatment of other infections.

Negative H. pylori not the cause Any remaining symptoms are not due to H. pylori Negative Positive after third-line treatment Refer to specialist Consider whether treatment is still indicated rate may reflect the eradication of benign processes. Examination of tissues for the characteristic chromosomal translocations should be done to help distinguish benign and malignant processes and to guide further therapeutic approaches. These generally are slowly progressive tumors, so the time needed for H. pylori eradication and subsequent evaluation will not interfere with the use of subsequent chemotherapy and/or radiotherapy, if needed. REGIMENS Although H. pylori is susceptible to a wide range of antibiotics in vitro, monotherapy is not usually successful, probably because of inadequate active antibiotic delivery to the colonization niche. Clini­ cal failure of monotherapy prompted the development of multidrug regimens. Current regimens consist of a PPI and two or three antimi­ crobial agents given for 10–14 days (Table 168-2). The optimal regi­ mens vary in different parts of the world, depending on the known Tetracycline HCl (500 mg qid) Metronidazole (500 mg tid)