1279CHAPTER 163 Helicobacter pylori Infections

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: Clinical characteristics, epidemiology and pathogenesis. Expert Rev Anti

Infect Ther 13:567, 2015.

Garnacho-Montero J: Optimum treatment strategies for carbapenemresistant Acinetobacter baumannii: Bacteremia. Expert Rev Anti

Infect Ther 13:769, 2015.

Isler B et al: New treatment options against carbapenem-resistant

Acinetobacter baumannii infections. Antimicrob Agents Chemother

63:e01110, 2018.

Lee CR et al: Biology of Acinetobacter baumannii: Pathogenesis, antibiotic 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.

Munoz-Price LS, Weinstein RA: Acinetobacter infection. N Engl J

Med 358:1271, 2008.

Peleg AY et al: Acinetobacter baumannii: Emergence of a successful

pathogen. Clin Microbiol Rev 21:538, 2008.

Tal-Jasper R et al: Clinical and epidemiological significance of carbapenem resistance in Acinetobacter baumannii infections. Antimicrob 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.

Helicobacter pylori colonizes the stomach in ~50% 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. 324) as well as for gastric adenocarcinoma

and gastric mucosa-associated lymphoid tissue (MALT) lymphoma

(Chap. 80). Treatment for H. pylori has revolutionized the management of peptic ulcer disease, providing a permanent cure in most cases.

Such treatment also represents first-line therapy for patients with lowgrade gastric MALT lymphoma. Treatment of H. pylori is of no benefit

in the treatment of gastric adenocarcinoma, but prevention of H. pylori

colonization or eradicative treatment could potentially prevent gastric

malignancy and peptic ulceration. In contrast, increasing evidence

indicates that lifelong H. pylori colonization may offer some protection

against complications of gastroesophageal reflux disease (GERD),

including esophageal adenocarcinoma. Recent research has focused on

whether H. pylori colonization is also a risk factor for some extragastric

diseases and whether it is protective against some recently emergent

medical problems, such as childhood-onset asthma and other allergic

and metabolic conditions.

163 Helicobacter pylori

Infections

John C. Atherton, Martin J. Blaser

■ 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 proportion 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 buffering 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

associated with low-level inflammation and occasionally with disease. In immunocompromised hosts, several nongastric (intestinal)

Helicobacter species can cause disease with clinical features resembling those of Campylobacter infections; these species are covered in

Chap. 167.

■ EPIDEMIOLOGY

Prevalence and Risk Factors The prevalence of H. pylori among

adults is <30% in most parts of the United States, Europe, and Oceania as opposed to >60% in many parts of Africa, South America, and

West Asia. In the United States, prevalence varies with age: up to 50%

of 60-year-old persons, ~20% of 30-year-old persons, and <10% of

children are colonized. H. pylori is usually acquired in childhood. The

age association is due mostly to a birth-cohort effect whereby current

60-year-olds were more commonly colonized as children than are

current children. Spontaneous acquisition or loss of H. pylori in adulthood 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 development 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 common 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

diagnosis.) Although H. pylori is capable of numerous adaptations that

prevent excessive stimulation of the immune system, colonization is

accompanied 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 downregulation 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.

1280 PART 5 Infectious Diseases

Primary

phenomenon:

Hyperacidity Atrophic

gastritis

Secondary

phenomenon:

Antigenic

stimulation ?

Duodenal

ulceration

Clinical

outcome:

Association with

H. pylori (OR): 3–6 6–50 3–8 0.2–0.6

B-cell

lymphoma

Noncardia gastric

adenocarcinoma

Reflux

esophagitis

and sequelae

Tissue response (inflammation)

FIGURE 163-1 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.)

Bacterial Virulence Factors Several H. pylori virulence factors 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 apparatus, 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 components 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 The best-characterized

host determinants 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 proteins 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. In addition, 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:

antral-predominant 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 colonization causes duodenal ulceration is now becoming clearer. H.

pylori–induced tissue responses in the gastric

antrum diminish the number of somatostatinproducing 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 acid-protective gastric

metaplasia in the duodenum. Gastric metaplasia in the duodenum may become colonized

by H. pylori and subsequently inflamed and

ulcerated.

PATHOGENESIS OF GASTRIC ULCERATION

AND GASTRIC ADENOCARCINOMA 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 stomachs

with extensive atrophic gastritis and hypochlorhydria, 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 dysplasia. 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 stimulation of lymphocyte populations by the persistent H. pylori colonization. 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. 163-1). Despite

similar rates of H. pylori colonization, rates of these diseases among

women are less than half of those among men.

1281CHAPTER 163 Helicobacter pylori Infections

■ PEPTIC ULCER DISEASE

Worldwide, ~70% of duodenal ulcers and ~50% of gastric ulcers are

related to H. pylori colonization (Chap. 324). However, in particular,

the proportion of gastric ulcers caused by aspirin and nonsteroidal

anti-inflammatory drugs (NSAIDs) is increasing, and in many developed 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.

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.

80). 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 common, and

the approaches to histopathologic and cytogenetic evaluations are not

standardized. Many of the diagnosed low-grade gastric B-cell lymphomas are dependent on H. pylori for continuing growth 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. 324). 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. 323), Barrett’s

esophagus (Chap. 323), and adenocarcinoma of the esophagus and

gastric cardia (Chap. 80). 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 conditions; (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, concerns 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 considerations 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 absorption. 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 (protective) 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 noncausal. 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 163-1).

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 performed, 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 presence of H. pylori

urease 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 visualization 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 specific 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

TABLE 163-1 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; useful for

follow-up after treatment;

may be particularly

useful in children

Stool-based tests disliked by

people from some cultures

1282 PART 5 Infectious Diseases

Indication for H. pylori treatment

(e.g., peptic ulcer disease or new-onset dyspepsia)

Test for H. pylori

Urea breath test

or stool antigen test*

Any remaining

symptoms are not

due to H. pylori

H. pylori

not the cause

Second-line treatment

First-line treatment

(Table 163-2)

Positive after

second-line treatment

Wait at least 1 month after

treatment finishes (no antibiotics,

bismuth compounds, or proton

pump inhibitors in the meantime)

Third-line treatment;

endoscopy with H. pylori culture and

sensitivity testing; treat according

to known antibiotic sensitivities

Positive after

third-line treatment

Negative

Negative

Positive

Positive

Refer to specialist

Consider whether treatment

is still indicated

(Table 163-2)

FIGURE 163-2 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.

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 accurate 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. 163-2). 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

unreliable if performed within 4 weeks of intercurrent treatment with

antibiotics or bismuth compounds or within 2 weeks of the discontinuation of proton pump inhibitor (PPI) treatment. In the assessment

of treatment 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 compounds 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. 163-2). 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 conditions include idiopathic thrombocytopenic purpura, vitamin B12

deficiency, and iron-deficiency anemia where other causes have

been carefully excluded. For individuals with a strong family history

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

1283CHAPTER 163 Helicobacter pylori Infections

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 bacteria; (3)

the anxiety that may arise in otherwise healthy people, especially

if treatment is unsuccessful; and (4) the existence of a subset of

people who will develop GERD symptoms after treatment. 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 evidence 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 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.

Clinical failure of monotherapy prompted the development of

multidrug regimens. Current regimens consist of a PPI and two or

three antimicrobial agents given for 10–14 days (Table 163-2). The

optimal regimens vary in different parts of the world, depending

on the known rates of primary antibiotic resistance in most H.

pylori strains in a particular locale. For this reason, guidelines on

optimal regimens for H. pylori eradication in individual countries

are evolving, and physicians should refer to the most up-to-date

local guideline.

The two most important factors in successful H. pylori treatment

are the patient’s close compliance with the regimen and the use of

drugs to which the patient’s strain of H. pylori has not acquired

resistance. Treatment failure following minor lapses in compliance is

common and often leads to acquired resistance. To stress the importance of compliance, written instructions should be given to the

patient, and minor side effects of the regimen should be explained.

Increasing levels of primary H. pylori resistance to clarithromycin,

levofloxacin, and—to a lesser extent—metronidazole are of growing

concern. In most parts of the world (the main exception being

northwestern Europe), the rate of primary clarithromycin resistance

is sufficiently high that regimens containing clarithromycin plus

one other antibiotic often fail; regimens with clarithromycin and

two other antibiotics remain an option as the other two antibiotics

are likely to eradicate H. pylori even if the strain is clarithromycinresistant. When a patient is known to have been exposed—even

remotely in time—to clarithromycin or a fluoroquinolone, these

antibiotics usually should be avoided. Resistance to amoxicillin or

tetracycline is unusual, even if these antibiotics have been given

previously, and resistance to metronidazole is only partial; thus,

there is no need to avoid using these antibiotics whether or not they

have been previously prescribed. Whichever antibiotic regimen is

used, meta-analyses show that using high rather than moderate

doses of acid-suppressive PPIs with the antibiotics increases the

effectiveness of the regimen. Similarly, use of vonoprazan, a highly

effective potassium-competitive acid blocker, currently licensed in

Japan, was associated with higher eradication rates in conjunction

with amoxicillin and clarithromycin, than when a PPI was used for

acid suppression.

Assessment of antibiotic susceptibilities before treatment would

be optimal but is not usually undertaken because endoscopy and

mucosal biopsy are necessary to obtain H. pylori for culture and

because most microbiology laboratories are inexperienced in H.

pylori culture. If initial H. pylori treatment fails, the usual approach

is empirical re-treatment with another drug regimen (Table 163-2).

The third-line approach ideally should be endoscopy, biopsy, and

culture plus treatment based on documented antibiotic sensitivities.

However, empirical third-line therapies are often used.

TABLE 163-2 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)

Tetracycline HCl (500 mg qid) Metronidazole (500 mg tid)

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) —

a

The recommended first-line regimens for most of the world are shown in bold type. b

This 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. c

Many 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. d

Data 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. e

This regimen may be used as an alternative to regimen 3. f

Metronidazole (500 mg bid) may be used as an alternative. g

This regimen is 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.

It may be less effective where rates of fluoroquinolone use are high and is more likely to be ineffective if there is a personal history of fluoroquinolone use for previous

treatment of other infections.

1284 PART 5 Infectious Diseases

The pseudomonads are a heterogeneous group of gram-negative bacteria that have in common an inability to ferment lactose. Formerly classified in the genus Pseudomonas, the members of this group have been

assigned to three medically important genera—Pseudomonas, Burkholderia, and Stenotrophomonas—whose biologic behaviors encompass

both similarities and marked differences and whose genetic repertoires

differ in many respects. The pathogenicity of most pseudomonads is

based on opportunism; the exceptions are Burkholderia pseudomallei

and Burkholderia mallei, which are primary pathogens.

The genus Pseudomonas now contains >140 species. Pseudomonas

aeruginosa, the major pathogen of the group, is a significant cause of

infections in hospitalized patients and in patients with cystic fibrosis

(CF; Chap. 291). Cytotoxic chemotherapy, mechanical ventilation,

and broad-spectrum antibiotic therapy set up conditions that predispose to colonization and infection of increasing numbers of hospitalized patients by this pathogen. Other significant members of the

genus—Pseudomonas putida, Pseudomonas fluorescens, Pseudomonas

oryzihabitans, and Pseudomonas stutzeri—infect humans infrequently

and are generally opportunists always present in the environment.

The genus Burkholderia comprises >20 species, of which Burkholderia cepacia is most frequently encountered in Western countries.

Similar to P. aeruginosa, B. cepacia (now referred to as the B. cepacia

complex species) is both an opportunistic nosocomial pathogen and

a cause of infection in CF. The other medically important members

of this genus are B. pseudomallei and B. mallei, the etiologic agents of

melioidosis and glanders, respectively.

The genus Stenotrophomonas contains one species of medical significance, Stenotrophomonas maltophilia. This organism is strictly an opportunist that “overgrows” in the setting of broad-spectrum antibiotic use.

PSEUDOMONAS AERUGINOSA

■ EPIDEMIOLOGY

P. aeruginosa is found in most moist environments. Soil, plants, vegetables, tap water, and countertops are all potential reservoirs for this

microbe, as it has simple nutritional needs. Given the ubiquity of P.

aeruginosa, it is clear that simple contact with the organism is not sufficient for colonization or infection. Clinical and experimental observations suggest that infection by P. aeruginosa occurs concomitantly with

compromised host defenses, mucosal trauma, physiologic derangement, and antibiotic-mediated suppression of normal flora. Thus, it

comes as no surprise that the majority of P. aeruginosa infections occur

in intensive care units (ICUs), where these factors frequently converge.

The organism is initially acquired from environmental sources, but

patient-to-patient spread also occurs in CF clinics.

In the past, burned patients appeared to be unusually susceptible to

P. aeruginosa. For example, in 1959–1963, Pseudomonas burn-wound

sepsis was the principal cause of death in 60% of burned patients dying

at the U.S. Army Institute of Surgical Research. For reasons that are

unclear, P. aeruginosa infection in burns is no longer the major problem that it was during the 1950s and 1960s. Similarly, in the 1960s,

P. aeruginosa appeared as a common pathogen in patients receiving

cytotoxic chemotherapy at many institutions in the United States, but it

has subsequently diminished in importance. Despite this subsidence, P.

aeruginosa remains one of the most feared pathogens in this population

because of its high attributable mortality.

In some parts of Asia and Latin America, P. aeruginosa continues

to be the most common cause of gram-negative bacteremia in neutropenic patients.

164 Infections Due to

Pseudomonas, Burkholderia,

and Stenotrophomonas Species

Reuben Ramphal

Non-pylori gastric helicobacters are treated in the same way as

H. pylori. However, in the absence of trials, it is unclear whether a

positive outcome always represents successful treatment or whether

it is sometimes due to natural clearance of the bacteria.

■ PREVENTION

Carriage of H. pylori has considerable public health significance in

economically richer countries, where it is associated with peptic ulcer

disease and gastric adenocarcinoma, and in some, but not all, economically poorer countries, where gastric adenocarcinoma may be an even

more common cause of cancer death late in life. If mass prevention

were contemplated, vaccination would be the most obvious method:

experimental immunization of animals has given promising results,

and the first reported trial in humans has shown some efficacy. Further

trials are ongoing. However, given that H. pylori has co-evolved with

its human host over millennia, preventing colonization on a population basis may have biological and clinical costs. For example, lifelong

absence of H. pylori is a risk factor for GERD complications, including

esophageal adenocarcinoma. We have speculated that the disappearance of H. pylori may also be associated with an increased risk of other

emergent diseases reflecting aspects of the current Western lifestyle,

such as childhood-onset asthma and allergy, as supported by both

epidemiologic and animal model studies.

■ FURTHER READING

Amieva M, Peek RM: Pathobiology of Helicobacter pylori–induced

gastric cancer. Gastroenterology 150:64, 2016.

Anderson WF et al: The changing face of noncardia gastric cancer incidence among US non-Hispanic whites. J Natl Cancer Inst

110:608, 2018.

Arnold IC et al: Helicobacter pylori infection prevents allergic asthma

in mouse models through the induction of regulatory T cells. J Clin

Invest 121:3088, 2011.

Atherton JC, Blaser MJ: Co-adaptation of Helicobacter pylori and

humans: Ancient history and modern implications. J Clin Invest

119:2475, 2009.

Chen Y, Blaser MJ: Inverse associations of Helicobacter pylori with

asthma and allergies. Arch Intern Med 167:821, 2007.

Chen Y et al: Association between Helicobacter pylori and mortality in

the NHANES II study. Gut 62:1262, 2013.

Chow WH et al: An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia

adenocarcinoma. Cancer Res 58:588, 1998.

Deguchi H et al: Current status of Helicobacter pylori diagnosis and

eradication therapy in Japan using a nationwide database. Digestion

101:441, 2020.

Ford AC et al: Helicobacter pylori eradication therapy to prevent

gastric cancer in healthy asymptomatic infected individuals: Systematic review and meta-analysis of randomized controlled trials. BMJ

348:g3174, 2014.

Graham DY et al: Rifabutin-based triple therapy (RHB-105) for Helicobacter pylori eradication: A double-blind, randomized, controlled

trial. Ann Intern Med 172:795, 2020.

Hooi JKY et al: Global prevalence of Helicobacter pylori infection:

Systematic review and meta-analysis. Gastroenterology 153:420,

2017.

Kuo S-H et al: First-line antibiotic therapy in Helicobacter pylorinegative low-grade gastric mucosa-associated lymphoid tissue lymphoma. Scientific Rep 7:14333, 2017.

Linz B et al: An African origin for the intimate association between

humans and Helicobacter pylori. Nature 445:915, 2007.

Maixner F et al: The 5300-year-old Helicobacter pylori genome of the

Iceman. Science 351:162, 2016.

Marshall BJ, Warren JR: Unidentified curved bacilli in the stomach

of patients with gastritis and peptic ulceration. Lancet 1:1311, 1984.

Plummer M et al: Global burden of gastric cancer attributable to Helicobacter pylori. Int J Cancer 136:487, 2015.

1285CHAPTER 164 Infections Due to Pseudomonas, Burkholderia, and Stenotrophomonas Species

In contrast to the trends for burned patients and neutropenic

patients in the United States, the incidence of P. aeruginosa infections

among patients with CF has not changed. P. aeruginosa remains the

most common contributing factor to respiratory failure in CF and is

responsible for the majority of deaths among CF patients.

■ LABORATORY FEATURES

P. aeruginosa is a nonfastidious, motile, gram-negative rod that grows

on most common laboratory media, including blood and MacConkey

agars. It is easily identified in the laboratory on primary-isolation agar

plates by pigment production that confers a yellow to dark green or

even bluish appearance. Colonies have a shiny “gun-metal” appearance

and a characteristic fruity odor. Two of the identifying biochemical

characteristics of P. aeruginosa are an inability to ferment lactose on

MacConkey agar and a positive reaction in the oxidase test. Most

strains are identified on the basis of these readily detectable laboratory features even before extensive biochemical testing is done. Some

isolates from CF patients are easily identified by their mucoid appearance, which is due to the production of large amounts of the mucoid

exopolysaccharide or alginate.

■ PATHOGENESIS

Unraveling the mechanisms that underlie disease caused by P. aeruginosa has proved challenging. Of the common gram-negative bacteria,

no other species produces such a large number of putative virulence

factors (Table 164-1). Yet P. aeruginosa rarely initiates an infectious

process in the absence of host injury or compromise, and few of its

putative virulence factors have been shown definitively to be involved

in disease in humans. Despite its metabolic versatility and possession

of multiple colonizing factors, P. aeruginosa exhibits no competitive

advantage over enteric bacteria in the human gut; it is not a normal

inhabitant of the healthy human gastrointestinal tract, despite the host’s

continuous environmental exposure to the organism.

Virulence Attributes Involved in Acute P. aeruginosa Infections •  MOTILITY AND COLONIZATION A general tenet of bacterial

pathogenesis is that most bacteria must adhere to surfaces or colonize

a host niche in order to initiate disease. Most gram-negative bacteria

examined thus far possess adherence factors called adhesins. P. aeruginosa is no exception. Among its many adhesins are its pili, which

demonstrate adhesive properties for a variety of cells and adhere best

to injured cell surfaces. In the organism’s flagellum, the flagellin molecule binds to cells, and the flagellar cap attaches to mucins through the

recognition of glycan chains. Other P. aeruginosa adhesins include the

outer core of the lipopolysaccharide (LPS) molecule, which binds to

the cystic fibrosis transmembrane conductance regulator (CFTR) and

aids in internalization of the organism, and the alginate coat of mucoid

strains, which enhances adhesion to cells and mucins. In addition,

membrane proteins and lectins have been proposed as colonization

factors. The deletion of any given adhesin is not sufficient to abrogate

TABLE 164-1 Main Putative Virulence Factors of Pseudomonas

aeruginosa

SUBSTANCE/

ORGANELLE FUNCTION

VIRULENCE IN ANIMAL

DISEASE

Pili Adhesion to cells ?

Flagella Adhesion, motility,

inflammation

Yes

Lipopolysaccharide Antiphagocytic activity,

inflammation

Yes

Type III secretion system Toxic activity (ExoU,

ExoS)

Yes

Type II secretion system Toxic activity Yes

Proteases Proteolytic activity ?

Phospholipases Cytotoxicity ?

Exotoxin A Cytotoxicity ?

Pyocyanin Cytotoxicity Yes

the ability of P. aeruginosa to colonize surfaces. Motility is important in

host invasion via mucosal surfaces in some animal models of infection;

however, nonmotile strains are not uniformly avirulent. It has been

well demonstrated that nonmotile strains of P. aeruginosa are poorly

phagocytosed, possibly leading to enhancement of the virulence of this

organism.

EVASION OF HOST DEFENSES The transition from bacterial colonization to disease requires the evasion of host defenses followed by invasion by the microorganism. P. aeruginosa appears to be well equipped

for evasion. Attached bacteria inject four known toxins (ExoS or ExoU,

ExoT, and ExoY) via a type III secretion system that allows the bacteria

to evade phagocytic cells either by direct cytotoxicity or by inhibition

of phagocytosis. Clinical studies suggest that the mortality rate is

higher among patients infected by strains that secrete the ExoU toxin.

Another secretion system—the type II system—secretes toxins that can

kill animals, and some of its secreted toxins, such as exotoxin A, have

the potential to kill phagocytic cells. Multiple proteases secreted by this

system may degrade host effector molecules, such as cytokines and

chemokines, that are released in response to infection.

TISSUE INJURY Among gram-negative bacteria, P. aeruginosa probably produces the largest number of substances that are toxic to cells

and thus have the potential to injure tissues. The toxins secreted by

the organism’s type III secretion system are capable of injuring tissue.

However, their delivery requires the adherence of the organism to cells.

Thus, the effects of these toxins are likely to be local or to depend on

the presence of large numbers of bacteria at the site of an infection

or in the bloodstream. On the other hand, diffusible toxins, secreted

by the organism’s type II secretion system, can act freely wherever

they come into contact with cells. Possible effectors of this system

include exotoxin A, at least four different proteases, and at least two

phospholipases. In addition to these secreted toxins, rhamnolipids,

pyocyanins—the pigments that confer the characteristic color and

odor of P. aeruginosa colonies—and hydrocyanic acid, are produced by

P. aeruginosa and are all capable of causing host tissue injury and even

neutrophil death.

INFLAMMATORY COMPONENTS The inflammatory responses to the

lipid A component of Pseudomonas LPS and to its flagellin, mediated

through the Toll-like receptor (TLR) system (principally TLR4 and

TLR5, respectively), are thought to represent important factors in disease causation. Although these inflammatory responses are required

for successful defense against P. aeruginosa (i.e., in their absence, animals are defenseless against P. aeruginosa infection), florid responses

are likely to result in disease. Thus, when the sepsis syndrome and

septic shock develop in P. aeruginosa infection, they are probably the

result of the host response to one or both of these substances, but

injury to the lung by Pseudomonas toxins may also result in sepsis

syndromes, possibly by causing cell death and the release of cellular

components (e.g., heat-shock proteins) that may activate the TLR or

another proinflammatory system. Thus, the virulence of this bacterium

in acute infections is likely to be multifactorial with a great redundancy

of effector molecules being produced.

Chronic P. aeruginosa Infections Chronic infection due to P.

aeruginosa occurs mainly in the lungs in the setting of structural

pulmonary diseases. The classic example is CF; others include bronchiectasis and chronic relapsing panbronchiolitis, a disease seen in

Japan and some Pacific Islands. A hallmark of these illnesses is severely

defective mucociliary clearance leading to mucus stasis and mucus

accumulation in the lungs. There is probably a common factor that

selects for P. aeruginosa colonization in these lung diseases—perhaps

the adhesiveness of P. aeruginosa for mucus, a phenomenon that is

not noted for most other common gram-negative bacteria, and/or the

ability of P. aeruginosa to evade host defenses in mucus. Furthermore,

P. aeruginosa undergoes evolutionary adaptations and diversification in

ways that allow its prolonged survival in the lung without an early fatal

outcome for the host. The strains found in CF patients exhibit minimal

production of virulence factors. Many strains lose the ability to produce pili and flagella, and most become complement-sensitive because