CHAPTER

28 CAMPYLOBACTER AND
HELICOBACTER

A 26-year-old woman was admitted to the hospital with a 48-hour history of colicky lower abdominal pain
associated with about 20 watery stools per day, which contained mucus and blood. She was afebrile and had
diffuse abdominal tenderness. No pathogens were isolated on routine stool culture, but specimens were also
inoculated on a Campylobacter-selective medium and incubated microaerophilically at 40° C. Examination of
the plates after 42 hours revealed the presence of flat, nonhemolytic, mucoid colonies that were
subsequently identified as Campylobacter jejuni. Campylobacter and Helicobacter are now widely recognized
as significant human pathogens; however, they were only discovered in the last 20 to 30 years.
1. What properties of Campylobacter and Helicobacter led to their delayed discovery?
2. Campylobacter is associated with what two immune disorders?
3. How does Helicobacter pylori survive in the stomach?
Answers to these questions are available on StudentConsult.com.

• SUMMARIES CLINICALLY SIGNIFICANT ORGANISMS

Campylobacter • Guillain-Barré syndrome is believed to be an Treatment, Prevention, and Control

Trigger Words
Curved rods, gastroenteritis, Guillain-Barré
syndrome, poultry
Biology and Virulence
• Thin, curved, gram-negative rods
• Factors that regulate adhesion, motility, and
invasion into intestinal mucosa are poorly
defined
Epidemiology
• Zoonotic infection; improperly prepared
poultry is a common source of human
infections
• Infections acquired by ingestion of
contaminated food, unpasteurized milk, or
contaminated water
• Person-to-person spread is unusual
• Dose required to establish disease is high
unless the gastric acids are neutralized or
absent
• Worldwide distribution with enteric
infections seen throughout the year
Diseases
• Most common disease is acute enteritis with
diarrhea, malaise, fever, and abdominal pain
autoimmune disease caused by antigenic
cross-reactivity between oligosaccharides in
the bacterial capsule and glycosphingolipids
on the surface of neural tissues
• Most infections are self-limited but can
persist for a week or more
• C. fetus is associated with septicemia and
is disseminated to multiple organs
Diagnosis
• Microscopic detection of thin, S-shaped,
gram-negative rods in stool specimens is
specific but insensitive
• Commercial multiplex nucleic acid
amplification assays are highly sensitive and
specific for enteric pathogens and
particularly useful for detection of C. jejuni
and C. coli infections
• Culture requires use of specialized media
incubated with reduced oxygen, increased
carbon dioxide, and (for thermophilic
species) elevated temperatures; requires
incubation for 2 or more days and is
relatively insensitive unless fresh media are
used
• Detection of Campylobacter antigens in
stool specimens is moderately sensitive and
very specific compared with culture
• For gastroenteritis, infection is self-limited
and is managed by fluid and electrolyte
replacement
• Severe gastroenteritis and septicemia are
treated with erythromycin or azithromycin
• Gastroenteritis is prevented by proper
preparation of food and consumption of
pasteurized milk; preventing contamination
of water supplies also controls infection
• Experimental vaccines targeting the outer
capsular polysaccharides are promising for
control of infections in animal reservoirs
Helicobacter pylori
Trigger Words
Gastritis, peptic ulcers, gastric cancer, urease,
person-to-person
Biology and Virulence
• Curved gram-negative rods
• Urease production at very high levels is
typical of gastric helicobacters (e.g., H.
pylori; important diagnostic test for H. pylori)
and uncommon in intestinal helicobacters
• Multiple factors contribute to gastric
colonization, inflammation, alteration of
gastric acid production, and tissue destruction

280
 CHAPTER 28 CAMPYLOBACTER AND HELICOBACTER   280.e1

Answers
1. Campylobacter is thin, at the resolving power of light
microscopy, and is not typically observed in Gram-
stained specimens. Growth of C. jejuni and Campylo-
bacter coli requires incubation at an elevated temperature
and in a microaerophilic atmosphere supplemented
with carbon dioxide. Helicobacter is also difficult to grow,
requiring enriched media, a microaerophilic atmosphere,
and prolonged incubation.
2. Guillain-Barré syndrome; reactive arthritis.
3. H. pylori blocks acid production in the stomach by pro-
duction of acid-inhibitory proteins and neutralizes gastric
acids with the ammonia produced by urease activity. The
bacteria are actively motile and rapidly penetrate through
the gastric mucus and adhere to gastric epithelial cells,
followed by penetration into the cells.
 CHAPTER 28 CAMPYLOBACTER AND HELICOBACTER   281

Epidemiology Diagnosis Treatment, Prevention, and Control

• Infections are common, particularly in
people in a low socioeconomic class or in
developing nations
• Humans are the primary reservoir
• Person-to-person spread is important
(typically fecal-oral)
• Ubiquitous and worldwide, with no seasonal
incidence of disease
Diseases
• H. pylori is an important cause of acute and
chronic gastritis, peptic ulcers, gastric
adenocarcinoma, and mucosa-associated
lymphoid tissue lymphoma
• Microscopy: histologic examination of biopsy
specimens is sensitive and specific
• Urease test relatively sensitive and highly
specific; urea breath test is a noninvasive
test
• H. pylori antigen test is sensitive and
specific; performed with stool specimens
• Culture requires incubation in micro­
aerophilic conditions; growth is slow;
relatively insensitive unless multiple biopsies
are cultured
• Serology useful for demonstrating exposure
to H. pylori
• Multiple regimens have been evaluated for
treatment of H. pylori infections. Combined
therapy with a proton pump inhibitor (e.g.,
omeprazole), a macrolide (e.g.,
clarithromycin), and a β-lactam (e.g.,
amoxicillin) for 2 weeks has had a high
success rate
• Prophylactic treatment of colonized
individuals has not been useful and
potentially has adverse effects, such as
predisposing patients to adenocarcinomas
of the lower esophagus
• Human vaccines are not currently available

T here are two families of related spiral-shaped gram-
negative bacteria of clinical importance: Campylobac­
teraceae, which includes the genera Campylobacter,
Arcobacter, and Sulfurospirillum, and Helicobacteraceae,
which includes Helicobacter and Wolinella.
Members of these families share two important properties
that contribute to problems with recovering the organisms
in culture and identification by traditional biochemical
testing: (1) microaerophilic growth requirements (i.e.,
growth only in the presence of reduced oxygen and increased
carbon dioxide) and (2) inability to ferment or oxidize car-
bohydrates. Because of this, the clinical significance of two
important human pathogens, Campylobacter and Helico-
bacter (Table 28-1), was only recently appreciated.
• Campylobacter
The genus Campylobacter consists of small (0.2 to 0.5 µm
wide and 0.5 to 5.0 µm long), motile, comma-shaped, gram-
negative rods (Figure 28-1). Bacteria in older colonies may
appear coccoid rather than rodlike. A total of 33 species and
14 subspecies are now recognized, many of which are associ-
ated with human disease, but only four species are common
human pathogens (Table 28-2).
The primary diseases caused by campylobacters are gas-
troenteritis and septicemia. Campylobacter is the most
common cause of bacterial gastroenteritis in both developed
and developing countries, with Campylobacter jejuni respon-
sible for most infections and Campylobacter coli associated
with a minority of cases of Campylobacter gastroenteritis in
the United States (more commonly observed in developing
countries). The incidence of gastroenteritis caused by Cam-
pylobacter upsaliensis is unknown because the organism is
inhibited by the antibiotics used in isolation media for other
campylobacters; however, some have estimated that 10% of
Campylobacter gastroenteritis is caused by this bacterium. A
variety of other species are rare causes of gastroenteritis or
systemic infections, with one exception. Unlike other Campy-
lobacter species, Campylobacter fetus is primarily responsi-
ble for causing systemic infections such as bacteremia, septic
thrombophlebitis, arthritis, septic abortion, and meningitis.
Physiology and Structure
Recognition of the role of campylobacters in gastrointestinal
(GI) disease was delayed because the organisms grow best in
an atmosphere of reduced oxygen (5% to 7%) and increased
carbon dioxide (5% to 10%). In addition, C. jejuni grows
better at 42° C than at 37° C. These properties have been
exploited for the selective isolation of pathogenic campylo-
bacters in stool specimens. The small size of the organisms
(0.2 to 0.5 µm in diameter) has also been used to recover the
bacteria by filtration of stool specimens. Campylobacters pass
through 0.45-µm filters, whereas other bacteria are retained.
Although this property led to the initial discovery of campy-
lobacters (stools were filtered looking for viruses), filtration
of stool specimens is a cumbersome procedure and is not
used in clinical laboratories. Campylobacters have a gram-
negative cell wall structure with an outer polysaccharide
capsule; however, instead of cell wall lipopolysaccharides
(LPS) with endotoxin activity found in other gram-negative
bacteria, they express lipooligosaccharides. The capsular
polysaccharides (CPS) contribute to the virulence of the bac-
teria and are the targets of vaccine development.
Pathogenesis and Immunity
Although adhesins, cytotoxic enzymes, and enterotoxins
have been detected in C. jejuni, their specific role in disease
remains poorly defined. It is clear that the risk of disease is
influenced by the infectious dose. The organisms are killed
when exposed to gastric acids, so conditions that decrease
or neutralize gastric acid secretion favor disease. The patient’s
immune status also affects the severity of disease. People
living in a population of high endemic disease develop mea-
surable levels of specific serum and secretory antibodies and
have less severe disease. As would be expected, patients with
hypogammaglobulinemia have prolonged severe disease
with C. jejuni.
C. jejuni GI disease characteristically produces histologic
damage to the mucosal surfaces of the jejunum (as implied
by the name of the species), ileum, and colon. The mucosal
surface appears ulcerated, edematous, and bloody, with crypt
abscesses in the epithelial glands and infiltration of the
lamina propria with neutrophils, mononuclear cells, and
eosinophils. This inflammatory process is consistent with
282   MEDICAL MICROBIOLOGY
Table 28-1 Important Campylobacter and
Helicobacter Species
Organism Historical Derivation
Campylobacter kampylos, curved; bacter, rod (a curved rod)
C. jejuni jejuni, of the jejunum
C. coli coli, of the colon
C. fetus fetus, refers to the initial observation that these
bacteria caused fetal infections
C. upsaliensis upsaliensis, original isolates recovered from the feces
of dogs at an animal clinic in Uppsala, Sweden
Helicobacter helix, spiral; bacter, rod (a spiral rod)
H. pylori pylorus, lower part of the stomach
H. cinaedi cinaedi, of a homosexual (the organism was first
isolated from homosexuals with gastroenteritis)
H. fennelliae fennelliae, named after C. Fennell, who first isolated
the organism
FIGURE 28-1 Mixed culture of bacteria from a fecal specimen.
Campylobacter jejuni is the thin, curved, gram-negative bacteria
(arrow).
invasion of the organisms into the intestinal tissue. However,
the precise roles of cytopathic toxins, enterotoxins, and
endotoxic activity that have been detected in C. jejuni iso-
lates have not been defined. For example, strains lacking
enterotoxin activity are still fully virulent.
C. jejuni and C. upsaliensis have been associated with
Guillain-Barré syndrome, an autoimmune disorder of the
peripheral nervous system characterized by development of
symmetric weakness over several days and recovery requir-
ing months or longer. Although this is an uncommon com-
plication of Campylobacter disease (≈1 in 1000 diagnosed
infections), the syndrome has been associated with specific
serotypes (primarily C. jejuni serotype O:19). It is believed
that the pathogenesis of this disease is related to antigenic
cross-reactivity between the surface lipooligosaccharides of
some strains of Campylobacter and peripheral nerve ganglio-
sides. Thus antibodies directed against specific strains of
Campylobacter can damage neural tissue in the peripheral
Table 28-2 Common Campylobacter Species Associated
with Human Disease
Species Common Human Disease
Reservoir Hosts
C. jejuni Poultry, cattle, Gastroenteritis, extraintestinal
sheep infections, Guillain-Barré syndrome,
reactive arthritis
C. coli Pigs, poultry, Gastroenteritis, extraintestinal
sheep, birds infections
C. fetus Cattle, sheep Vascular infections (e.g.,
septicemia, septic thrombophlebitis,
endocarditis), meningoencephalitis,
gastroenteritis
C. upsaliensis Dogs, cats Gastroenteritis, extraintestinal
infections, Guillain-Barré syndrome
Bold type signifies the most common hosts and diseases.
nervous system. Another immune-related late complication
of Campylobacter infections is reactive arthritis, a condition
characterized by joint pain and swelling involving the hands,
ankles, and knees and persisting from 1 week to several
months. Reactive arthritis is unrelated to the severity of the
diarrheal disease but is more common in patients who have
the HLA-B27 phenotype.
C. jejuni and C. coli rarely cause bacteremia (1.5 cases per
1000 intestinal infections); however, C. fetus has a propensity
to spread from the GI tract to the blood and distal foci. In
vitro studies provide an explanation for this observation: C.
fetus is resistant to complement- and antibody-mediated
serum killing, and C. jejuni and most other Campylobacter
species are killed rapidly. C. fetus is covered with a heat-
stable, capsule-like protein (S protein) that prevents C3b
binding to the bacteria and subsequent complement-
mediated killing in serum. C. fetus loses its virulence if this
protein layer is removed. Bacteremia is particularly common
in debilitated and immunocompromised patients, such as
those with liver disease, diabetes mellitus, chronic alcohol-
ism, or malignancies.
Epidemiology
Campylobacter infections are zoonotic, with a variety of
animals serving as reservoirs (see Table 28-2). Humans
acquire the infections with C. jejuni and C. coli after con-
sumption of contaminated food, milk, or water; contami­
nated poultry are responsible for more than half of the
Campylobacter infections in developed countries. In con-
trast, C. upsaliensis infections are acquired primarily after
contact with domestic dogs (either healthy carriers or pets
with diarrheal disease). Food products that neutralize gastric
acids (e.g., milk) effectively reduce the infectious dose. Fecal-
oral transmission from person-to-person contact may also
occur, but it is uncommon for the disease to be transmitted
by food handlers.
The actual incidence of Campylobacter infections is
unknown because disease is not reported to public health
officials. Epidemiologic surveys indicate that the incidence
of disease has decreased in the last decade, most likely owing
to improved food handling techniques. However, it is
 CHAPTER 28
estimated that between 1.4 and 2 million infections occur
annually in the United States, and these infections are more
common than Salmonella and Shigella infections combined.
The number of Campylobacter infections may be even higher
because C. upsaliensis is not isolated by commonly used
techniques. Disease occurs sporadically through the year,
with a peak incidence during the summer months. Disease
is most commonly observed in infants and young children,
with a second peak of disease in 20- to 40-year-old adults.
The incidence of disease is higher in developing countries,
with symptomatic disease in infants and young children and
asymptomatic carriage frequently observed in adults.
C. fetus infections are relatively uncommon, with fewer
than 250 cases reported in the United States annually. Unlike
C. jejuni, C. fetus primarily infects immunocompromised or
elderly people.
Clinical Diseases (Clinical Case 28-1)
GI infections with C. jejuni, C. coli, and C. upsaliensis
present most commonly as acute enteritis with diarrhea,
fever, and severe abdominal pain. Affected patients can have
10 or more bowel movements per day during the peak of
disease, and stools may be bloody on gross examination. The
disease is generally self-limited, although symptoms may last
for a week or longer. The range of clinical manifestations
includes acute colitis, abdominal pain mimicking acute
appendicitis, and chronic enteric infections that develop
most commonly in immunocompromised patients (e.g.,
patients with acquired immunodeficiency syndrome
[AIDS]). Various extraintestinal infections are reported but
are relatively uncommon. Guillain-Barré syndrome and
reactive arthritis are well-recognized complications of Cam-
pylobacter infections. C. fetus differs from other Campylo-
bacter species in that this species is primarily responsible for
intravascular (e.g., septicemia, endocarditis, septic throm-
bophlebitis) and extraintestinal (e.g., meningoencephalitis,
abscesses) infections.
Clinical Case 28-1 Campylobacter jejuni Enteritis and
Guillain-Barré Syndrome
Scully and associates (N Engl J Med 341:1996–2003, 1999) described
the clinical history of a 74-year-old woman who developed Guillain-Barré
syndrome following an episode of C. jejuni enteritis. After 1 week of fever,
watery diarrhea, nausea, abdominal pain, weakness, and fatigue, the
patient’s speech was noted to be severely slurred. She was taken to the
hospital, where it was noted she was unable to speak, although she was
oriented and able to write coherently. She had perioral numbness, bilateral
ptosis and facial weakness were noted, and her pupils were nonreactive.
Neurologic examination revealed bilateral muscle weakness in her arms
and chest. On the second hospital day, the muscle weakness extended to
her upper legs. On the third hospital day, the patient’s mental status
remained normal, but she could only move her thumb minimally and could
not lift her legs. Sensation to light touch was normal, but deep-tendon
reflexes were absent. C. jejuni was recovered from this patient’s stool
culture, collected at the time of admission, and the clinical diagnosis of
Guillain-Barré syndrome was made. Despite aggressive medical treatment,
the patient had significant neurologic deficits 3 months after discharge to
a rehabilitation facility. This woman illustrates one of the significant com-
plications of Campylobacter enteritis.
CAMPYLOBACTER AND HELICOBACTER   283
Laboratory Diagnosis
Microscopy
Campylobacters are thin and not easily seen when specimens
are Gram stained. Despite the low sensitivity of a Gram stain,
observation of the characteristic thin, S-shaped organisms
in a stool specimen (see Figure 28-1) is useful for a presump-
tive confirmation of Campylobacter infection.
Antigen Detection
A commercial immunoassay for detection of C. jejuni and
C. coli is available. When compared with culture, the test has
a sensitivity of 80% to 90% and a specificity of greater than
95%. Some strains of C. upsaliensis are also reactive in this
test.
Nucleic Acid–Based Tests
Commercial multiplex nucleic acid amplification tests for
enteric pathogens are rapidly gaining acceptance because
they can rapidly detect a comprehensive spectrum of bacte-
rial, viral, and parasitic pathogens with a sensitivity superior
to culture. This is particularly true for Campylobacter infec-
tions, although these molecular assays are generally restricted
to detection of C. jejuni and C. coli and not the other
Campylobacter species.
Culture
C. jejuni, C. coli, and C. upsaliensis went unrecognized for
many years because their isolation requires growth in a
microaerophilic atmosphere (i.e., 5% to 7% oxygen, 5% to
10% carbon dioxide), at an elevated incubation tempera­
ture (i.e., 42° C), and on selective agar media to suppress
nonpathogenic enteric bacteria. The appropriate atmosphere
for growing campylobacters can be produced by disposable
commercial gas generator systems that are added to an incu-
bation jar with the inoculated culture media. The selective
media must contain blood or charcoal to remove toxic
oxygen radicals, and antibiotics are added to inhibit the
growth of contaminating organisms. Unfortunately, the anti-
biotics used in most Campylobacter media may inhibit some
species (e.g., C. upsaliensis). Campylobacters are slow-
growing organisms, usually requiring incubation for 48
hours or longer. C. fetus is not thermophilic and cannot grow
at 42° C; however, its isolation requires a microaerophilic
atmosphere.
Identification
A presumptive identification of isolates is based on growth
under selective conditions, typical microscopic morphology,
and positive oxidase and catalase tests.
Antibody Detection
Serologic testing for immunoglobulin (Ig)M and IgG is
useful for epidemiologic surveys but is not used for diagnosis
in an individual patient.
Treatment, Prevention, and Control
Campylobacter gastroenteritis is typically a self-limited
infection managed by the replacement of lost fluids and elec-
trolytes. Antibiotic therapy may be used in patients with
severe infections or septicemia. Campylobacters are suscep-
tible to a variety of antibiotics, including macrolides
284   MEDICAL MICROBIOLOGY
(i.e., erythromycin, azithromycin, clarithromycin), tetracy-
clines, aminoglycosides, chloramphenicol, fluoroquinolones,
clindamycin, amoxicillin/clavulanic acid, and imipenem.
Most isolates are resistant to penicillins, cephalosporins, and
sulfonamide antibiotics. Erythromycin or azithromycin are
the antibiotics of choice for the treatment of enteritis, with
tetracycline or fluoroquinolones used as secondary antibiot-
ics. Resistance to fluoroquinolones has increased, so these
drugs may be less effective. Amoxicillin/clavulanic acid can
be used in place of tetracycline, which is contraindicated in
young children. Systemic infections are treated with an ami-
noglycoside, chloramphenicol, or imipenem.
Exposure to enteric campylobacters is prevented by
proper food preparation (particularly poultry), avoidance of
unpasteurized dairy products, and implementation of safe-
guards to prevent contamination of water supplies. Almost
50 capsular serotypes of C. jejuni are recognized, although
the majority of strains associated with disease are restricted
to a limited number of serotypes. Preliminary studies dem-
onstrate these are attractive targets for vaccines and poten-
tially could reduce the colonization rate in food animals such
as chickens and turkeys.
• Helicobacter
In 1983, spiral gram-negative rods resembling campylobac-
ters were found in patients with type B gastritis (chronic
inflammation of the stomach antrum [pyloric end]). The
organisms were originally classified as Campylobacter but
were subsequently reclassified as a new genus, Helicobacter.
Helicobacters were subsequently subdivided into species
that primarily colonize the stomach (gastric helicobacters)
and those that colonize the intestines (enterohepatic helico­
bacters). The most important species is Helicobacter pylori,
a gastric helicobacter associated with gastritis, peptic ulcers,
gastric adenocarcinoma, and gastric mucosa–associated
lymphoid tissue (MALT) B-cell lymphomas (Table 28-3).
The most important enterohepatic helicobacters associated
with gastroenteritis and bacteremia are Helicobacter
cinaedi and Helicobacter fennelliae, which have been iso-
lated most commonly in immunocompromised patients
(e.g., homosexual men with human immunodeficiency virus
[HIV] infections). Another species of uncertain taxonomy,
Table 28-3 Helicobacter Species Associated with
Human Disease
Species Common Human Disease
Reservoir Hosts
H. pylori Humans, Gastritis, peptic ulcers, gastric
primates, pigs adenocarcinoma, mucosa-associated
lymphoid tissue B-cell lymphomas
H. cinaedi Humans, Gastroenteritis, septicemia,
hamster proctocolitis
H. fennelliae Humans Gastroenteritis, septicemia,
proctocolitis
Bold type signifies the most common hosts and diseases.
currently termed “Helicobacter species flexispira” causes bac-
teremia with cellulitis and wound infections in immuno-
compromised patients (e.g., patients with Bruton X-linked
agammaglobulinemia). The discussion in this chapter will be
restricted to the gastric helicobacter, H. pylori.
Physiology and Structure
Helicobacter species are characterized according to sequence
analysis of their 16S rRNA genes, their cellular fatty acids,
and the presence of polar flagella. Currently, 35 species have
been characterized, but this taxonomy is changing rapidly.
Helicobacters have a bacillary or spiral shape in young cul-
tures (0.5 to 1.0 µm wide × 2 to 4 µm long) and, like cam-
pylobacters, can assume coccoid forms in older cultures
(Figure 28-2).
All gastric helicobacters, including H. pylori, are highly
motile (corkscrew motility) and produce an abundance of
urease. These properties are believed to be important for
survival in gastric acids and rapid movement through the
viscous mucus layer toward a neutral pH environment. Most
helicobacters are catalase- and oxidase-positive and do not
ferment or oxidize carbohydrates, although they can metab-
olize amino acids by fermentative pathways. Lipopolysac-
charide (LPS), consisting of lipid A, core oligosaccharide,
and an O side chain, is present in the outer membrane. H.
pylori lipid A has low endotoxin activity compared with
other gram-negative bacteria, and the O side chain is anti-
genically similar to the Lewis blood group antigens, which
may protect the bacteria from immune clearance.
Growth of H. pylori and other helicobacters requires a
complex medium supplemented with blood, serum, char-
coal, starch, or egg yolk in microaerophilic conditions
(decreased oxygen and increased carbon dioxide) and in a
temperature range between 30° C and 37° C. Because helico-
bacters are relatively difficult to isolate in culture and identify
by biochemical testing, most diseases caused by H. pylori are
confirmed by nonculture techniques (see later).
Coccoid Bacilli Coccoid
FIGURE 28-2 Scanning electron micrograph of Helicobacter pylori
in a 7-day culture. Bacillary and coccoid forms are bound to para-
magnetic beads used in immunomagnetic separation. (Courtesy
Dr. L. Engstrand, Uppsala, Sweden.)
 CHAPTER 28
Pathogenesis and Immunity
H. pylori is a remarkable bacterium in its ability to establish
lifelong colonization in the stomach of untreated humans.
Most research into the virulence factors in helicobacters has
focused on H. pylori. Multiple factors contribute to the
gastric colonization, inflammation, alteration of gastric acid
production, and tissue destruction that are characteristic of
H. pylori disease. Initial colonization is facilitated by (1)
blockage of acid production by a bacterial acid–inhibitory
protein and (2) neutralization of gastric acids with the
ammonia produced by bacterial urease activity. The actively
motile helicobacters can then pass through the gastric mucus
and adhere to the gastric epithelial cells by multiple surface
adhesion proteins. Surface proteins can also bind host pro-
teins and help the bacteria evade the immune system. Local-
ized tissue damage is mediated by urease byproducts,
mucinase, phospholipases, and the activity of vacuolating
cytotoxin A (VacA), a protein that after penetration into
epithelial cells damages the cells by producing vacuoles.
Another important virulence factor of H. pylori is the
cytotoxin-associated gene (cagA) that resides on a pathoge-
nicity island containing approximately 30 genes. These genes
encode a structure (type VI secretion system) that acts like
a syringe to inject the CagA protein into the host epithelial
cells, which interferes with the normal cytoskeletal structure
of the epithelial cells. The cag phosphoribosylanthranilate
isomerase (PAI) genes also induce interleukin (IL)-8 pro­
duction, which attracts neutrophils. Release of proteases and
reactive oxygen molecules by these neutrophils is believed to
contribute to gastritis and gastric ulcers.
Epidemiology
An enormous amount of information about the prevalence
of H. pylori has been collected since 1984 when the organism
was first isolated in culture. The highest incidence of carriage
is found in developing countries, where 70% to 90% of the
population is colonized, most before the age of 10 years. The
prevalence of H. pylori in industrial countries such as
the United States is less than 40% and is decreasing because
of improved hygiene and active treatment of colonized indi-
viduals. These studies have also demonstrated that 70% to
100% of patients with gastritis, gastric ulcers, or duodenal
ulcers are infected with H. pylori. Humans are the primary
reservoir for H. pylori, and colonization is believed to
persist for life unless the host is specifically treated. Trans-
mission is most likely via the fecal-oral route.
An interesting observation about H. pylori colonization
has been made. This organism is clearly associated with dis-
eases such as gastritis, gastric ulcers, gastric adenocarci-
noma, and gastric MALT lymphomas. It is anticipated that
treatment of colonized or infected individuals will lead to a
reduction of these diseases. However, colonization with H.
pylori appears to offer protection from gastroesophageal
reflux disease and adenocarcinomas of the lower esophagus
and gastric cardia. Thus it may be unwise to eliminate H.
pylori in patients without symptomatic disease. Certainly,
the complex relationship between H. pylori and its host
remains to be defined.
Clinical Diseases (Clinical Case 28-2)
Disease caused by helicobacters is directly related to their
site of colonization. For example, H. pylori is associated with
CAMPYLOBACTER AND HELICOBACTER   285
Clinical Case 28-2 The Discovery of
Helicobacter pylori
In 1984, Australian physicians Marshall and Warren reported a discovery
that completely changed the approach to treatment of gastritis and peptic
ulcer disease, as well as set the foundation for understanding the cause
of gastric adenocarcinomas and mucosa-associated lymphoid tissue lym-
phomas (Lancet i:1311–1315, 1984). In an analysis of gastric biopsy
specimens from 100 consecutive patients presenting for gastroscopy, they
demonstrated curved gram-negative rods resembling Campylobacter in
58 patients. The bacteria were observed in most patients with active
gastritis, gastric ulcers, and duodenal ulcers. Although similar organisms
were observed associated with gastric tissues 45 years earlier, this report
stimulated resurgence in investigations of the role of this “new” organism
in gastric diseases. Despite the skepticism that greeted their initial report,
the significance of their work with Campylobacter was recognized in 2005
when Marshall and Warren received the Nobel Prize in Medicine.
gastritis, whereas the enterohepatic species cause gastroen-
teritis. Colonization with H. pylori invariably leads to histo-
logic evidence of gastritis (i.e., infiltration of neutrophils and
mononuclear cells into the gastric mucosa). The acute phase
of gastritis is characterized by a feeling of fullness, nausea,
vomiting, and hypochlorhydria (decreased acid production
in the stomach). This can evolve into chronic gastritis, with
disease confined to the gastric antrum (where few acid-
secreting parietal cells are present) in individuals with
normal acid secretion, or involve the entire stomach (pan-
gastritis) if acid secretion is suppressed. Approximately 10%
to 15% of patients with chronic gastritis will progress to
develop peptic ulcers. The ulcers develop at the sites of
intense inflammation, commonly involving the junction
between the corpus and antrum (gastric ulcer) or the proxi-
mal duodenum (duodenal ulcer). H. pylori is responsible for
85% of the gastric ulcers and 95% of the duodenal ulcers.
Recognition of the role of H. pylori has dramatically changed
the treatment and prognosis of peptic ulcer disease.
Chronic gastritis eventually leads to replacement of the
normal gastric mucosa with fibrosis and proliferation of
intestinal-type epithelium. This process increases the patient’s
risk for gastric cancer by almost 100-fold. This risk is influ-
enced by the strain of H. pylori and the host’s response (cagA-
positive strains and high levels of IL-1 production are
associated with a higher risk for cancer). Infection with H.
pylori is also associated with infiltration of lymphoid tissue
into the gastric mucosa. In a small number of patients, a
monoclonal population of B cells may develop and evolve
into a MALT lymphoma.
Laboratory Diagnosis
Microscopy
H. pylori is detected by histologic examination of gastric
biopsy specimens. Although the organism can be seen in
specimens stained with hematoxylin-eosin or Gram stain,
the Warthin-Starry silver stain is the most sensitive. When
an adequate specimen is collected and examined by an expe-
rienced microscopist, the test sensitivity and specificity
approaches 100% and is considered diagnostic. Because this
is an invasive test, alternative test procedures are preferred
for routine diagnosis. The microscopic examination of stool
specimens for helicobacters is not reliable, because the
286   MEDICAL MICROBIOLOGY
organisms are difficult to see and nonpathogenic helicobac-
ters may be present.
Antigen Detection
Biopsy specimens can also be tested for the presence of bac-
terial urease activity. The abundance of urease produced by
H. pylori permits detection of the alkaline byproduct in less
than 2 hours. The sensitivity of the direct test with biopsy
specimens varies from 75% to 95%; however, the specificity
approaches 100%. Thus a positive reaction is compelling evi-
dence of an active infection. As with microscopy, the limita-
tion of this method is the requirement for a biopsy specimen.
Noninvasive urease testing of human breath (urea breath
test) following consumption of an isotopically labeled urea
solution has excellent sensitivity and specificity. Unfortu-
nately, this assay is relatively expensive because of the cost of
the detection instruments.
A number of polyclonal and monoclonal immunoassays
for H. pylori antigens excreted in stool have been developed
and demonstrated to have sensitivities and specificities
exceeding 95%. These tests are easy to perform, inexpensive,
and able to be used on stool specimens rather than biopsies.
These assays are now widely recommended for both detec-
tion of H. pylori infections and confirmation of cure after
antibiotic treatment.
Nucleic Acid–Based Tests
Currently, nucleic acid–based amplification tests for H.
pylori and enterohepatic helicobacters are restricted to
research laboratories and not used in clinical laboratories.
Culture
H. pylori adheres to gastric mucosa and is not recovered in
stool or blood specimens. The bacteria can be isolated in
culture if the specimen is inoculated onto an enriched
medium supplemented with blood, hemin, or charcoal and
incubated in a microaerophilic atmosphere for up to 2 weeks.
However, diagnosis of H. pylori infections is most commonly
by noninvasive methods (e.g., immunoassay), with culture
reserved for antibiotic susceptibility tests.
Identification
Presumptive identification of isolates is based on their
growth characteristics under selective conditions, typical
microscopic morphologic findings, and detection of oxidase,
catalase, and urease activity.
Antibody Detection
Serology is an important screening test for the diagnosis of
H. pylori, with a variety of commercial tests available.
Although IgM antibodies disappear rapidly, IgA and IgG
antibodies can persist for months to years. Because the
antibody titers persist for many years, the test cannot be
used to discriminate between past and current infection.
Furthermore, the titer of antibodies measured does not cor-
relate with the severity of disease or the response to therapy.
However, the tests are useful for documenting exposure to
the bacteria, either for epidemiologic studies or for the initial
evaluation of a symptomatic patient.
Treatment, Prevention, and Control
Numerous antibiotic regimens have been evaluated for treat-
ing H. pylori infections. Use of a single antibiotic or an anti-
biotic combined with bismuth is ineffective. The greatest
success in curing gastritis or peptic ulcer disease has been
accomplished with the combination of a proton pump
inhibitor (e.g., omeprazole), a macrolide (e.g., clarithromy-
cin), and a β-lactam (e.g., amoxicillin), with administration
for 7 to 10 days initially. Treatment failure is most commonly
associated with clarithromycin resistance. Susceptibility
testing should be performed if the patient does not respond
to therapy. Metronidazole can also be used in combination
therapy, but resistance is commonplace.
Infection with H. pylori stimulates a strong TH1 cell–
mediated inflammatory response. Use of H. pylori antigens
in experimental vaccines that stimulate TH1 cells leads to
enhanced inflammation. In contrast, use of antigens in com-
bination with mucosal adjuvants that induce a TH2 cell
response is protective in an animal model and can eradicate
existing infections. The effectiveness of these vaccines in
humans remains to be demonstrated.
Bibliography
Algood H, Cover T: Helicobacter pylori persistence: an overview of interac-
tions between H. pylori and host immune defenses, Clin Microbiol Rev
19:597–613, 2006.
Farinha P, Gascoyne R: Helicobacter pylori and MALT lymphoma, Gastro-
enterology 128:1579–1605, 2005.
Garza-Gonzalez E, Perez-Perez GI, Maldonado-Garza HJ, et al: A review
of Helicobacter pylori diagnosis, treatment, and methods to detect
eradication, World J Gastroenterol 20:1438–1449, 2014.
Iovine N: Resistance mechanisms in Campylobacter jejuni, Virulence 4:230–
240, 2013.
Kabir S: The current status of Helicobacter pylori vaccines: a review, Helico-
bacter 12:89–102, 2007.
Kusters JG, van Vliet A, Kuipers EJ: Pathogenesis of Helicobacter pylori
infection, Clin Microbiol Rev 19:449–490, 2006.
Nachamkin I, Allos BM, Ho T: Campylobacter species and Guillain-Barré
syndrome, Clin Microbiol Rev 11:555–567, 1998.
Passaro D, Chosy EJ, Parsonnet J: Helicobacter pylori: consensus and con-
troversy, Clin Infect Dis 35:298–304, 2002.
Pike B, Guerry P, Poly F: Global distribution of Campylobacter jejuni Penner
serotypes: a systematic review, PLoS ONE 8:1–8, 2013.
Plummer P: LuxS and quorum-sensing in Campylobacter, Front Cell Infect
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 CHAPTER 28 CAMPYLOBACTER AND HELICOBACTER   286.e1

Case Study and Questions

A mother and her 4-year-old son came to the local emer-
gency room with a 1-day history of diarrhea and abdominal
cramping. Both patients had low-grade fevers, and blood was
grossly evident in the child’s stool specimen. The symptoms
had developed 18 hours after the patients had consumed a
dinner consisting of mixed green salad, chicken, corn, bread,
and apple pie. Culture of blood samples was negative for
organisms, but Campylobacter jejuni was isolated from stool
specimens of both the mother and the child.
1. Which food that they consumed is most likely responsible
for these infections? What measures should be used to
prevent these infections?
2. Name three Campylobacter species that have been associ-
ated with gastroenteritis. Name the species of Campylo-
bacter most commonly associated with septicemia.
3. What diseases have been associated with Helicobacter
pylori? Helicobacter cinaedi? Helicobacter fennelliae?
4. H. pylori has multiple virulence factors. Which factors are
responsible for interfering with gastric acid secretion? For
adhering to the gastric epithelium? For disrupting the
gastric mucus? For interfering with phagocytic killing?

Answers
1. C. jejuni infections have been associated with a large
variety of food products; however, the most common
source of infections is contaminated poultry. Completely
cooking all poultry and disinfecting all surfaces where
uncooked poultry is prepared can avoid infections.
2. The three species of Campylobacter most commonly
associated with gastroenteritis are C. jejuni, C. coli, and
C. upsaliensis. C. fetus is the species most commonly
associated with septicemia.
3. Diseases caused by H. pylori include gastritis, peptic
ulcers, gastric adenocarcinoma, and gastric MALT B-cell
lymphomas. H. cinaedi and H. fennelliae colonize the GI
tract and have been associated with proctitis, proctocoli-
tis, and enteritis in homosexual males.
4. H. pylori produce an acid-inhibitory protein that induces
hypochlorhydria during acute infection by blocking
acid secretion from parietal cells. Urease produced by
H. pylori also neutralizes gastric acids by degrading urea
to ammonia. H. pylori produces a variety of adhesins that
mediate binding to the gastric epithelium, including sialic
acid–binding adhesion, Lewis blood group adhesion, and
various other hemagglutinins. Mucinase and phospho­
lipases disrupt the gastric mucus, and superoxide dis-
mutase and catalase interfere with phagocytic killing.