1303CHAPTER 167 Infections Due to Campylobacter and Related Organisms

appear to be highly similar. C. jejuni can be considered the prototype,

in part because it is by far the most common enteric pathogen in the

group. A prodrome of fever, headache, myalgia, and/or malaise often

occurs 12–48 h before the onset of diarrheal symptoms. The most

common signs and symptoms of the intestinal phase are diarrhea,

abdominal pain, and fever. The degree of diarrhea varies from several

loose watery stools to visibly bloody stools (~10% of cases in adults);

most patients presenting for medical attention have ≥10 bowel movements on the worst day of illness. Abdominal pain usually consists of

cramping and may be the most prominent symptom. Pain is usually

generalized but may become localized; C. jejuni infection may cause

pseudoappendicitis. Fever may be the only initial manifestation of

C. jejuni infection, a situation mimicking the early stages of typhoid

fever. Febrile young children may develop convulsions. Campylobacter enteritis is generally self-limited; however, symptoms persist for

>1 week in 10–20% of patients seeking medical attention, and clinical

relapses occur in 5–10% of untreated patients. Studies of commonsource epidemics indicate that milder illnesses or asymptomatic infections may commonly occur.

C. fetus may cause a diarrheal illness similar to that due to C. jejuni,

especially in immunocompetent hosts. This organism also may cause

either intermittent diarrhea or nonspecific abdominal pain without

localizing signs. Sequelae are uncommon, and the outcome is benign.

C. fetus may also cause a prolonged relapsing systemic illness (with

fever, chills, and myalgias) that has no obvious primary source; this

manifestation is especially common among compromised hosts. Secondary seeding of an organ (e.g., meninges, brain, bone, urinary tract,

or soft tissue) complicates the course, which may be fulminant. C.

fetus infections have a tropism for vascular sites: endocarditis, mycotic

aneurysm, and septic thrombophlebitis may all occur. Infection during

pregnancy often leads to fetal death. A variety of Campylobacter species

and H. cinaedi can cause recurrent cellulitis with fever and bacteremia

in immunocompromised hosts.

■ COMPLICATIONS

Except in infection with C. fetus, bacteremia is uncommon, developing

most often in immunocompromised hosts and at the extremes of age.

Three patterns of extraintestinal infection have been noted: (1) transient bacteremia in a normal host with enteritis (benign course, no

specific treatment needed); (2) sustained bacteremia or focal infection

in a normal host (bacteremia originating from enteritis, with patients

TABLE 167-1 Clinical Features Associated with Infection Due to “Atypical” Campylobacter and Related Species Implicated as Causes of Human Illness

SPECIES COMMON CLINICAL FEATURES LESS COMMON CLINICAL FEATURES ADDITIONAL INFORMATION

Campylobacter coli Fever, diarrhea, abdominal pain Bacteremiaa Clinically indistinguishable from C. jejuni

Campylobacter fetus Bacteremia,a

 sepsis, meningitis,

vascular infections

Diarrhea, relapsing fevers Not usually isolated from media containing

cephalothin or incubated at 42°C

Campylobacter upsaliensis Watery diarrhea, low-grade fever,

abdominal pain

Bacteremia, abscesses Difficult to isolate because of cephalothin

susceptibility

Campylobacter lari Abdominal pain, diarrhea Colitis, appendicitis Seagulls frequently colonized; organism often

transmitted to humans via contaminated water

Campylobacter

hyointestinalis

Watery or bloody diarrhea, vomiting,

abdominal pain

Bacteremia Causes proliferative enteritis in swine

Helicobacter fennelliae Chronic mild diarrhea, abdominal

cramps, proctitis

Bacteremiaa Best treated with fluoroquinolones

Helicobacter cinaedi Chronic mild diarrhea, abdominal

cramps, proctitis

Bacteremiaa Best treated with fluoroquinolones; identified in

healthy hamsters

Campylobacter jejuni

subspecies doylei

Diarrhea Chronic gastritis, bacteremiab Uncertain role as human pathogen

Arcobacter cryaerophilus Diarrhea Bacteremia Poultry, seafood sources. Cultured under aerobic

conditions

Arcobacter butzleri Fever, diarrhea, abdominal pain, nausea;

or asymptomatic

Bacteremia, appendicitis Cultured under aerobic conditions; enzootic in

nonhuman primates

Campylobacter sputorum Pulmonary, perianal, groin, and axillary

abscesses; diarrhea

Bacteremia Three clinically relevant biovars: sputorum, faecalis,

and paraureolyticus

a

In immunocompromised hosts, especially HIV-infected persons. b

In children.

Source: Adapted from BM Allos, MJ Blaser: Clin Infect Dis 20:1092, 1995.

■ PATHOLOGY AND PATHOGENESIS

C. jejuni infections may be subclinical, especially in hosts in developing countries who have had multiple prior infections and may be

partially immune. Symptomatic infections mostly occur within

2–4 days (range, 1–7 days) of exposure to the organism. The sites of tissue

injury include the jejunum, ileum, and colon. Biopsies show an acute nonspecific inflammatory reaction, with neutrophils, monocytes, and eosinophils in the lamina propria, as well as damage to the epithelium, including

loss of mucus, glandular degeneration, and crypt abscesses. Biopsy findings may be consistent with Crohn’s disease or ulcerative colitis, but these

“idiopathic” chronic inflammatory diseases should not be diagnosed

unless infectious colitis, specifically including that due to infection with

Campylobacter species and related organisms, has been ruled out.

The components of protective immunity to Campylobacter in

humans are poorly understood. The high frequency of C. jejuni

infections and their severity and recurrence among immunoglobulindeficient patients suggest that antibodies are important in protective

immunity. Experience from field studies and human experimental

infection models suggests that immune protection may be short-lived

or incomplete in the absence of continuous exposure. Knowledge of

the pathogenesis of infection is also incomplete. Both the motility of

the strain and its capacity to adhere to host tissues appear to favor

disease, but classic enterotoxins and cytotoxins (including cytolethal

distending toxin) appear not to play substantial roles in tissue injury

or disease production. The organisms have been visualized within the

epithelium, albeit in low numbers. The documentation of a significant

tissue response and occasionally of C. jejuni bacteremia further suggests that tissue invasion is clinically significant, and in vitro studies

are consistent with this pathogenic feature.

The pathogenesis of C. fetus infections is better defined. Virtually all

clinical isolates of C. fetus possess a proteinaceous capsule-like structure

(an S-layer) that renders the organisms resistant to complement-mediated

killing and opsonization. As a result, C. fetus can cause bacteremia and

can seed sites beyond the intestinal tract. The ability of the organism

to switch the S-layer proteins expressed—a phenomenon that results in

antigenic variability—may contribute to the chronicity and high rate of

recurrence of C. fetus infections in compromised hosts.

■ CLINICAL MANIFESTATIONS

The clinical features of infections due to Campylobacter and the related

Arcobacter and intestinal Helicobacter species causing enteric disease

1304 PART 5 Infectious Diseases

responding well to antimicrobial therapy); and (3) sustained bacteremia or focal infection in a compromised host. Enteritis may not be clinically apparent. Antimicrobial therapy, possibly prolonged, is necessary

for suppression or cure of these infections.

Campylobacter, Arcobacter, and intestinal Helicobacter infections

in patients with AIDS or immunoglobulin-deficient patients (most

often common variable immunodeficiency) may be severe, persistent,

and extraintestinal; relapse after cessation of therapy is common.

Immunoglobulin-deficient patients also may develop osteomyelitis and

an erysipelas-like rash or cellulitis.

Local suppurative complications of infection include cholecystitis,

pancreatitis, and cystitis; distant complications include meningitis,

endocarditis, arthritis, peritonitis, cellulitis, and septic abortion. All

these complications are rare, except in immunocompromised hosts.

Hepatitis, interstitial nephritis, and the hemolytic-uremic syndrome

occasionally complicate acute infection. The two most common

postinfectious sequelae are reactive arthritis and Guillain-Barré syndrome. Reactive arthritis has been reported in up to 2.5% of cases,

although nonspecific rheumatologic symptoms are more common

(~10%). Reactive arthritis may develop several weeks after infection,

especially in persons with the HLA-B27 phenotype. The knees are most

frequently involved, but involvement of the ankles, wrists, and small

joints of the hands is common, with an average of 3.2 joints affected.

Guillain-Barré syndrome or its Miller Fisher (cranial polyneuropathy)

variant follow either symptomatic or asymptomatic Campylobacter

infections uncommonly—i.e., in 1 of every 1000–2000 cases or, for

certain C. jejuni serotypes (such as O19), in 1 of every 100–200 cases.

Despite the low frequency of this complication, it is estimated that

Campylobacter infections, because of their high incidence, may trigger

20–40% of all cases of Guillain-Barré syndrome. The presence of sialylated lipopolysaccharides on C. jejuni strains prompts a form of molecular mimicry that promotes autoimmune recognition of sialylated

cell-surface molecules on axons. Immunoproliferative small-intestinal

disease (alpha chain disease), a form of lymphoma that originates in

small-intestinal mucosa-associated lymphoid tissue (MALToma), has

been associated with C. jejuni; antimicrobial therapy has led to marked

clinical improvement.

■ DIAGNOSIS

In patients with Campylobacter enteritis, peripheral leukocyte counts

reflect the severity of the inflammatory process. In addition, stools

from nearly all Campylobacter-infected patients presenting for medical attention in the United States contain leukocytes or erythrocytes.

Gram- or Wright-stained fecal smears should be examined in all

suspected cases. When the diagnosis of Campylobacter enteritis is

suspected on the basis of findings indicating inflammatory diarrhea

(fever, fecal leukocytes), clinicians can ask the microbiology laboratory

to attempt the visualization of organisms with characteristic vibrioid

morphology by direct microscopic examination of stools with Gram’s

staining or to use phase-contrast or dark-field microscopy to identify

the organisms’ characteristic “darting” motility. Confirmation of the

diagnosis of Campylobacter infection is based on identification of an

isolate from cultures of stool, blood, or another site; specific species

can be identified by MALDI-TOF (matrix-assisted laser desorption/

ionization–time of flight) mass spectrometry. Campylobacter-specific

media should be used to culture stools from all patients with inflammatory or bloody diarrhea. Because all Campylobacter species are

fastidious, they will not be isolated unless selective media or other

selective techniques are used. Failure to isolate campylobacters from

stool by culture does not entirely rule out their presence. Although

culture remains the diagnostic gold standard, species-specific real-time

polymerase chain reaction (PCR) techniques appear more sensitive

than culture. Although PCR and other culture-independent diagnostic

test (CIDTs), including antigen detection tests, may detect nonviable

bacteria and may be falsely positive, they are now used frequently to

diagnose infection with Campylobacter and other enteric bacteria in

clinical microbiology laboratories. The detection of the organisms in

stool in the United States by culture almost always implies active or

recent infection, but CIDT positivity is more questionable.

In any event, follow-up testing after the clinical resolution of an

acute infection is rarely needed. Campylobacter sputorum and related

organisms found in the oral cavity are commensals that only rarely

have pathogenic significance. Because of the low levels of metabolic

activity of Campylobacter species in standard blood culture media,

Campylobacter bacteremia is difficult to detect.

■ DIFFERENTIAL DIAGNOSIS

The symptoms of Campylobacter enteritis are not sufficiently unusual

to distinguish this illness from that due to Salmonella, Shigella, Yersinia, enterohemorrhagic Escherichia coli, and other pathogens. The

combination of fever and fecal leukocytes or erythrocytes is indicative

of inflammatory diarrhea, and definitive diagnosis is based on culture,

CIDTs, or demonstration of the characteristic organisms on stained

fecal smears. Extraintestinal Campylobacter illness is diagnosed by

culture. Infection due to Campylobacter should be suspected in the

setting of septic abortion, and that due to C. fetus should be suspected

specifically in the setting of septic thrombophlebitis. It is important

to reiterate that (1) the presentation of Campylobacter enteritis may

mimic that of ulcerative colitis or Crohn’s disease, (2) Campylobacter

enteritis is much more common than either of the latter (especially

among young adults), and (3) biopsy may not distinguish among these

entities. Thus, a diagnosis of inflammatory bowel disease should not

be made until Campylobacter infection has been ruled out, especially

in persons with a history of foreign travel, significant animal contact,

immunodeficiency, or exposure incurring a high risk of transmission.

TREATMENT

Campylobacter Infection

Fluid and electrolyte replacement is central to the treatment of

diarrheal illnesses (Chap. 133). Even among patients presenting

for medical attention with Campylobacter enteritis, not all clearly

benefit from specific antimicrobial therapy. Indications for therapy include high fever, bloody diarrhea, severe diarrhea, persistence for >1 week, and worsening of symptoms. A 3-day course

of azithromycin (500 mg once daily) is the regimen of choice. A

1-day regimen of azithromycin (1000 mg given as two 500-mg

tablets) can also be used. Alternative regimens for adults consist of

fluoroquinolones—ciprofloxacin (500 mg by mouth twice daily for

3 days) or levofloxacin (750 mg daily for 3 days)—but resistance to

this class of agents as well as to tetracyclines is substantial; ~27%

of U.S. human isolates of Campylobacter in 2014 were resistant to

ciprofloxacin, and rates are higher in many other countries; thus,

travel-related Campylobacter infections should be considered a

priori to be fluoroquinolone-resistant. Because macrolide resistance

usually is much less common (<10%), these drugs are the empirical

agents of choice. Patients infected with antibiotic-resistant strains

are at increased risk of adverse outcomes. Use of antimotility agents,

which may prolong the duration of symptoms and have been associated with toxic megacolon and with death, is not recommended.

Of note, C. jejuni and C. coli are resistant to trimethoprim and

β-lactam antibiotics, including penicillin and most cephalosporins.

For patients with immunocompromising conditions and uncomplicated enteritis caused by C. jejuni, therapy duration should be

extended to 7–14 days. For systemic infections, treatment with a

carbapenem (imipenem, 500 mg IV every 6 h; or meropenem, 1–2 g

IV every 8 h) should be started empirically, and susceptibility testing

should always be performed. For life-threatening illness, gentamicin

(1.0–1.7 mg/kg IV every 8 h after a loading dose of 1.5–2 mg/kg)

can be added. In the absence of endovascular involvement, therapy

for systemic infections should be administered for 7–14 days. For

immunocompromised patients with systemic infections due to

C. fetus and for patients with endovascular infections due to any

species, prolonged therapy (up to 4 weeks) is usually necessary.

For recurrent infections in immunocompromised hosts, lifelong

therapy/prophylaxis is sometimes necessary.

1305CHAPTER 168 Cholera and Other Vibrioses

■ PROGNOSIS

Nearly all patients recover fully from Campylobacter enteritis, either

spontaneously or after antimicrobial therapy. Volume depletion probably contributes to the few deaths that are reported. As stated above,

occasional patients develop reactive arthritis or Guillain-Barré syndrome or its variants. Systemic infection with C. fetus is much more

often fatal than that due to related species; this higher mortality rate

reflects in part the population affected. Prognosis depends on the

rapidity with which appropriate therapy is begun. Otherwise healthy

hosts usually survive C. fetus infections without sequelae. Compromised hosts often have recurrent and/or life-threatening infections due

to a variety of Campylobacter species.

■ FURTHER READING

Amour C et al: Epidemiology and impact of Campylobacter infection

in children in 8 low-resource settings: Results from the MAL-ED

Study. Clin Infect Dis 63:1171, 2016.

Costa D, Iraola G: Pathogenomics of emerging Campylobacter Species. Clin Microbiol Rev 32:e00072, 2019.

Dai L et al: New and alternative strategies for the prevention, control,

and treatment of antibiotic-resistant Campylobacter. Transl Res

223:76, 2020.

Fernández-Cruz A et al: Campylobacter bacteremia: Clinical characteristics, incidence, and outcome over 23 years. Medicine (Baltimore)

89:319, 2010.

Man SM: The clinical importance of emerging Campylobacter species.

Nat Rev Gastroenterol Hepatol 8:669, 2011.

Marder EP et al: Incidence and trends of infections with pathogens

transmitted commonly through food and the effect of increasing use

of culture-independent diagnostic tests on surveillance—Foodborne

Diseases Active Surveillance Network, 10 U.S. sites, 2013–2016. Morb

Mortal Wkly Rep 66:397, 2017.

Montgomery MP et al: Multidrug-resistant Campylobacter jejuni

outbreak linked to puppy exposure−United States, 2016-2018. Morb

Mortal Wkly Rep 67:1032, 2018.

Riddle MS et al: ACG clinical guideline: Diagnosis, treatment, and

prevention of acute diarrheal infections in adults. Am J Gastroenterol

111:602, 2016.

Same RG, Tamma PD: Campylobacter jejuni infections in children.

Pediatr Rev 39:533, 2018.

Ternhag A et al: A meta-analysis of the effects of antibiotic treatment

on duration of symptoms caused by infection with Campylobacter

species. Clin Infect Dis 44:696, 2007.

Members of the genus Vibrio cause a number of important infectious

syndromes. Classic among them is cholera, a devastating diarrheal

disease caused by Vibrio cholerae that has been responsible for seven

global pandemics and much suffering over the past two centuries.

Epidemic cholera remains a significant public-health concern in the

developing world today. Other vibrioses caused by other Vibrio species

include syndromes of diarrhea, soft tissue infection, or primary sepsis.

All Vibrio species are highly motile, facultatively anaerobic, curved

gram-negative rods with one or more flagella. In nature, vibrios most

commonly reside in tidal rivers and bays under conditions of moderate

salinity. They proliferate in the summer months when water temperatures exceed 20°C. As might be expected, the illnesses they cause also

increase in frequency during the warm months.

168 Cholera and Other

Vibrioses

Matthew K. Waldor, Edward T. Ryan

CHOLERA

■ DEFINITION

Cholera is an acute diarrheal disease that can, in a matter of hours,

result in profound, rapidly progressive dehydration and death. Accordingly, cholera gravis (the severe form) is a much-feared disease, particularly in its epidemic presentation. Fortunately, prompt aggressive

fluid repletion and supportive care can obviate the high mortality that

is historically associated with cholera. Although the term cholera has

occasionally been applied to any severely dehydrating secretory diarrheal illness, whether infectious in etiology or not, it now refers to disease caused by V. cholerae serogroup O1 or O139—i.e., the serogroups

with epidemic potential.

■ MICROBIOLOGY AND EPIDEMIOLOGY

The species V. cholerae is classified into >200 serogroups based on the

carbohydrate constituents of their lipopolysaccharide (LPS) O antigens. Although some non-O1 V. cholerae serogroups (strains that do

not agglutinate in antisera to the O1 group antigen) have occasionally

caused sporadic outbreaks of diarrhea, serogroup O1 was, until the

emergence of serogroup O139 in 1992 (see below), the exclusive cause

of epidemic cholera. The O1 serogroup is further subdivided into two

serotypes, termed Inaba and Ogawa. Two biotypes of V. cholerae O1,

classical and El Tor, have been described, but the former is thought to

be extinct.

The natural habitat of V. cholerae is coastal salt water and brackish estuaries, where the organism lives in close relation to plankton.

V. cholerae can also exist in freshwater in the presence of adequate

nutrients and warmth. Humans become infected incidentally but, once

infected, can act as vehicles for spread. Ingestion of water contaminated

by human feces is the most common means of acquisition of V. cholerae.

Consumption of contaminated food also can contribute to spread.

There is no known animal reservoir. Although the infectious dose is

relatively high, it is markedly reduced in hypochlorhydric persons, in

those using antacids, and when gastric acidity is buffered by a meal.

Cholera is predominantly a pediatric disease in endemic areas, but it

affects adults and children equally when newly introduced into a population. In endemic areas, the burden of disease is often greatest during

“cholera seasons” associated with high temperatures, heavy rainfall,

and flooding, but cholera can occur year-round.

Cholera is native to the Ganges delta on the Indian subcontinent.

Since 1817, seven global pandemics have occurred. The current

(seventh) pandemic—the first due to the El Tor biotype—began in

Indonesia in 1961 and spread in serial waves throughout Asia as

V. cholerae El Tor displaced the endemic classical biotype, which is

thought to have caused the previous six pandemics. In the early 1970s,

El Tor cholera erupted in Africa, causing major epidemics before

becoming a persistent endemic problem. Currently, >95% of cholera

cases reported annually to the World Health Organization (WHO) are

from Africa and Asia (Fig. 168-1), but the true burden and distribution of cholera are unknown because the diagnosis is often syndromic

and many countries with endemic cholera do not report cholera to the

WHO. It is possible that >1–4 million cases of cholera occur yearly

(of which only ~200,000 are reported to the WHO) and that these

cases result in >20,000–140,000 deaths annually (of which <2000 are

reported to the WHO).

After a century without cholera in Latin America, the current

cholera pandemic reached Central and South America in 1991. Following an initial explosive spread that affected millions, the burden

of disease has markedly decreased in Latin America. In 2010, a severe

cholera outbreak began in Haiti, a country with no recorded history of

this disease. Several lines of evidence indicate that cholera was likely

introduced into Haiti by United Nations security forces from Asia,

raising the possibility that asymptomatic carriers of V. cholerae play

an important role in transmitting cholera over long distances. The

Haitian outbreak involved >800,000 individuals, resulting in thousands

of deaths. In 2016, an outbreak of cholera occurred in Yemen in the

setting of a civil war and population displacement and the breakdown

of health infrastructure. The outbreak is still ongoing and has resulted

1306 PART 5 Infectious Diseases

in over 1.2 million cases and thousands of deaths. The recent history

of cholera has been punctuated by such severe outbreaks, especially

among impoverished or displaced persons. These outbreaks are often

precipitated by war or other circumstances that lead to the breakdown

of public-health measures. Such was similarly the case in the camps for

Rwandan refugees set up in 1994 around Goma, Zaire; in 2008–2009 in

Zimbabwe; and in 2015 in South Sudan and the Democratic Republic

of the Congo.

Sporadic endemic infections due to V. cholerae O1 strains related to

the seventh-pandemic strain have been recognized along the U.S. Gulf

Coast of Louisiana and Texas. These infections are typically associated

with the consumption of contaminated, locally harvested shellfish.

Occasionally, cases in U.S. locations remote from the Gulf Coast have

been linked to shipped-in Gulf Coast seafood.

In October 1992, a large-scale outbreak of clinical cholera caused

by a new serogroup, O139, occurred in southeastern India. The organism appears to be a derivative of El Tor O1 but has a distinct LPS and

an immunologically related O-antigen polysaccharide capsule. (O1

organisms are not encapsulated.) After an initial spread across 11

Asian countries, V. cholerae O139 has once again been almost entirely

replaced by O1 strains. The clinical manifestations of disease caused

by V. cholerae O139 are indistinguishable from those of O1 cholera.

Immunity to one, however, is not protective against the other.

■ PATHOGENESIS

In the final analysis, cholera is a toxin-mediated disease. The watery

diarrhea characteristic of cholera is due to the action of cholera toxin,

a potent protein enterotoxin elaborated by the organism in the small

intestine. The toxin-coregulated pilus (TCP), so named because its

synthesis is regulated in parallel with that of cholera toxin, is essential

for V. cholerae to survive and multiply in (colonize) the small intestine.

Production of cholera toxin, TCP, and several other virulence factors

are coordinately regulated by ToxR. This protein modulates the expression of genes coding for virulence factors in response to environmental

signals via a cascade of regulatory proteins. Additional regulatory

processes, including bacterial responses to the density of the bacterial

population (in a phenomenon known as quorum sensing), modulate

the virulence of V. cholerae.

Once established in the human small bowel, the organism produces

cholera toxin, which consists of a monomeric enzymatic moiety (the

A subunit) and a pentameric binding moiety (the B subunit). The B

pentamer binds to GM1

 ganglioside, a glycolipid on the surface of

epithelial cells that serves as the toxin receptor and makes possible

FIGURE 168-1 World distribution of cholera in 2016–2018. WHO, World Health Organization. (Reproduced with permission from Dr. M. Piarroux, Université de la Méditerranée,

France.)

the delivery of the A subunit to its cytosolic target. The activated A

subunit (A1

) irreversibly transfers ADP-ribose from nicotinamide

adenine dinucleotide to its specific target protein, the GTP-binding

regulatory component of adenylate cyclase. The ADP-ribosylated G

protein upregulates the activity of adenylate cyclase; the result is the

intracellular accumulation of high levels of cyclic adenosine monophosphate (AMP). In intestinal epithelial cells, cyclic AMP inhibits

the absorptive sodium-transport system in villus cells and activates

the secretory chloride-transport system in crypt cells, and these events

lead to the accumulation of sodium chloride in the intestinal lumen.

Because water moves passively to maintain osmolality, isotonic fluid

accumulates in the lumen. When the volume of that fluid exceeds

the capacity of the rest of the gut to resorb it, watery diarrhea results.

Unless the wasted fluid and electrolytes are adequately replaced, shock

(due to profound dehydration) and acidosis (due to loss of bicarbonate)

follow. Although perturbation of the adenylate cyclase pathway is the

primary mechanism by which cholera toxin causes excess fluid secretion, cholera toxin also enhances intestinal secretion via prostaglandins

and/or neural histamine receptors.

The V. cholerae genome is composed of two circular chromosomes. Lateral gene transfer has played a key role in the evolution

of epidemic V. cholerae. The genes encoding cholera toxin

(ctxAB) are part of the genome of a bacteriophage, CTXΦ. The receptor for this phage on the V. cholerae surface is the intestinal colonization factor TCP. Because ctxAB is part of a mobile genetic element

(CTXΦ), horizontal transfer of this bacteriophage may account for the

emergence of new toxigenic V. cholerae serogroups. Many of the other

genes important for V. cholerae pathogenicity, including the genes

encoding the biosynthesis of TCP, those encoding accessory colonization factors, and those regulating virulence gene expression, are clustered together in the V. cholerae pathogenicity island. Similar clustering

of virulence genes is found in other bacterial pathogens. It is believed

that pathogenicity islands are acquired by horizontal gene transfer. V.

cholerae O139 is probably derived from an El Tor O1 strain that

acquired the genes for O139 O-antigen synthesis by horizontal gene

transfer.

■ CLINICAL MANIFESTATIONS

Individuals infected with V. cholerae O1 or O139 exhibit a range of

clinical manifestations. Some individuals are asymptomatic or have

only mild diarrhea; others present with the sudden onset of explosive

and life-threatening diarrhea (cholera gravis). The reasons for the

range in signs and symptoms of disease are incompletely understood

1307CHAPTER 168 Cholera and Other Vibrioses

but include the level of preexisting immunity, blood type (persons

with type O blood are at greatest risk of severe disease if infected,

whereas those with type AB are at least risk), and nutritional status. In

a nonimmune individual, after a 24- to 48-h incubation period, cholera characteristically begins with the sudden onset of painless watery

diarrhea that may quickly become voluminous. Patients often vomit.

In severe cases, volume loss can exceed 250 mL/kg in the first 24 h. If

fluids and electrolytes are not replaced, hypovolemic shock and death

may ensue. Fever is usually absent. Muscle cramps due to electrolyte

disturbances are common. The stool has a characteristic appearance: a

nonbilious, gray, slightly cloudy fluid with flecks of mucus, no blood,

and a somewhat fishy, inoffensive odor. It has been called “rice-water”

stool because of its resemblance to the water in which rice has been

washed (Fig. 168-2). Clinical symptoms parallel volume contraction:

at losses of <5% of normal body weight, thirst develops; at 5–10%, postural hypotension, weakness, tachycardia, and decreased skin turgor

are documented; and at >10%, oliguria, weak or absent pulses, sunken

eyes (and, in infants, sunken fontanelles), wrinkled (“washerwoman”)

skin, somnolence, and coma are characteristic. Complications derive

exclusively from the effects of volume and electrolyte depletion and

include renal failure due to acute tubular necrosis. Thus, if the patient

is adequately treated with fluid and electrolytes, complications are

averted and the process is self-limited, resolving in a few days.

Laboratory data usually reveal an elevated hematocrit (due to hemoconcentration) in nonanemic patients; mild neutrophilic leukocytosis;

elevated levels of blood urea nitrogen and creatinine consistent with

prerenal azotemia; normal sodium, potassium, and chloride levels; a

markedly reduced bicarbonate level (<15 mmol/L); and an elevated

anion gap (due to increases in serum lactate, protein, and phosphate).

Arterial pH is usually low (~7.2).

■ DIAGNOSIS

Cholera should be suspected when a patient ≥5 years of age develops

acute watery diarrhea in an area known to have cholera or develops

severe dehydration or dies from acute watery diarrhea, even in an area

where cholera is not known to be present. The clinical suspicion of

cholera can be confirmed by the identification of V. cholerae in stool;

however, the organism must be specifically sought. With experience, it

can be detected directly by dark-field microscopy on a wet mount of

fresh stool, and its serotype can be discerned by immobilization with

specific antisera. Laboratory isolation of the organism requires the use

of a selective medium such as taurocholate–tellurite–gelatin (TTG)

agar or thiosulfate–citrate–bile salts–sucrose (TCBS) agar. If a delay in

sample processing is expected, Carey-Blair transport medium and/or

alkaline-peptone water-enrichment medium may be used as well. In

endemic areas, there is little need for biochemical confirmation and

characterization, although these tasks may be worthwhile in places

where V. cholerae is an uncommon isolate. Standard microbiologic biochemical testing for Enterobacteriaceae will suffice for identification

of V. cholerae. All vibrios are oxidase-positive. Point-of-care antigendetection cholera dipstick assays are now commercially available for

use in the field or where laboratory facilities are lacking.

TREATMENT

Cholera

Death from cholera is due to hypovolemic shock; thus, treatment

of individuals with cholera first and foremost requires fluid resuscitation and management. In light of the level of dehydration

(Table 168-1) and the patient’s age and weight, euvolemia should

first be rapidly restored, and adequate hydration should then be

maintained to replace ongoing fluid losses (Table 168-2). Administration of oral rehydration solution (ORS) takes advantage of the

FIGURE 168-2 Rice-water cholera stool. Note floating mucus and gray watery

appearance. (Courtesy of Dr. A. S. G. Faruque, International Centre for Diarrhoeal

Disease Research, Dhaka; with permission.)

TABLE 168-1 Assessing the Degree of Dehydration in Patients

with Cholera

DEGREE OF DEHYDRATION CLINICAL FINDINGS

None or mild, but diarrhea Thirst in some cases; <5% loss of total body weight

Moderate Thirst, postural hypotension, weakness,

tachycardia, decreased skin turgor, dry mouth/

tongue, no tears; 5–10% loss of total body weight

Severe Unconsciousness, lethargy, or “floppiness”; weak

or absent pulse; inability to drink; sunken eyes (and,

in infants, sunken fontanelles); >10% loss of total

body weight

TABLE 168-2 Treatment of Cholera, Based on Degree of Dehydrationa

DEGREE OF DEHYDRATION,

PATIENT’S AGE (WEIGHT) TREATMENTb

None or Mild, but Diarrheac

<2 years 1/4–1/2 cup (50–100 mL) of ORS, to a maximum

of 0.5 L/d

2–9 years 1/2–1 cup (100–200 mL) of ORS, to a maximum

of 1 L/d

≥10 years As much ORS as desired, to a maximum of 2 L/d

Moderatec,d

<4 months (<5 kg) 200–400 mL of ORS

4–11 months (5–<8 kg) 400–600 mL of ORS

12–23 months (8–<11 kg) 600–800 mL of ORS

2–4 years (11–<16 kg) 800–1200 mL of ORS

5–14 years (16–<30 kg) 1200–2200 mL of ORS

≥15 years (≥30 kg) 2200–4000 mL of ORS

Severec

All ages and weights Undertake IV fluid replacement with Ringer’s

lactate (or, if not available, normal saline). Give

100 mL/kg in the first 3-h period (or the first 6-h

period for children <12 months old); start rapidly,

then slow down. Give a total of 200 mL/kg

in the first 24 h. Continue until the patient is

awake, can ingest ORS, and no longer has a

weak pulse.

a

Adapted from World Health Organization: First steps for managing an outbreak of

acute diarrhoea. Global Task Force on Cholera Control, 2009 (updated 2010; http://

www.who.int/cholera/publications/firststeps/en/). b

Continue normal feeding during

treatment. c

Reassess regularly; monitor stool and vomit output. d

Volumes of ORS

listed should be given within the first 4 h.

Abbreviation: ORS, oral rehydration solution.