CHAPTER 310 CHOLERA AND OTHER VIBRIO INFECTIONS

1865

310
CHOLERA AND OTHER VIBRIO
INFECTIONS
EDUARDO GOTUZZO AND CARLOS SEAS

CHOLERA
DEFINITION

Cholera is a feared epidemic diarrheal disease caused by Vibrio cholerae serogroup O1 and, since 1992, by the new serogroup O139. The disease is characterized by acute watery diarrhea. In its more severe form, a person may be
severely dehydrated and in hypovolemic shock; the patient may die in a
matter of a few hours after contracting the infection if treatment is not provided. Cholera is endemic today in Africa and Asia, and cases are also
reported from Latin America, North America, and Europe. Seven pandemics
have been registered in history since 1816; the most recent has lasted more
than 4 decades since its recognition in Indonesia in 1961.

The Pathogen

V. cholerae is a curved gram-negative bacillus that belongs to the family Vibrionaceae and shares common characteristics with the family Enterobacteriaceae. V. cholerae O1 can be classified into three serotypes according to the
presence of somatic antigens and into two biotypes, classic and El Tor,
according to specific phenotypic characteristics. There is no evidence of different clinical spectra among the three serotypes of V. cholerae. The classic
biotype, responsible for the first six pandemics of cholera, causes an approximately equal number of symptomatic and asymptomatic cases, whereas the
El Tor biotype causes more asymptomatic infections. The classic biotype is
confined to the south of Bangladesh, and the El Tor biotype is responsible
for the current pandemic. The O139 serogroup is composed of a variety of
genetically diverse strains, both toxigenic and nontoxigenic; it is genetically
closer to El Tor V. cholerae.

EPIDEMIOLOGY

Cholera has both a predisposition to cause epidemics with pandemic

potential and an ability to remain endemic in all affected areas. People
of all ages are at risk to contract the infection in epidemic settings, whereas
children older than 2 years are mainly affected in endemic areas. V. cholerae
lives in riverine, brackish, and estuarine ecosystems, where both O1 and
non-O1 strains coexist, with non-O1 and nontoxigenic O1 strains predominating over toxigenic O1 strains. In its natural environment, V. cholerae
lives attached to algae or to crustacean shells and copepods, with which
it coexists in a symbiotic manner. Several conditions, such as temperature,
salinity, and availability of nutrients, determine the survival of V. cholerae;
when these conditions are adverse, vibrios survive in a viable, but nonculturable state. More recent data suggest that cholera phages modulate
the abundance of V. cholerae in the environment and determine the beginning and end of epidemics. Phages may also play a role in the emergence
of new V. cholerae serogroups by transferring genetic material to non
toxigenic strains.
From its aquatic environment, V. cholerae is introduced to humans
through contamination of water sources and food. Once humans are
infected, very high attack rates may take place, particularly in previously

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CHAPTER 310 CHOLERA AND OTHER VIBRIO INFECTIONS

nave populations. Acquisition of the disease by drinking contaminated

water from rivers, ponds, lakes, and even tube well sources has been
documented. Drinking unboiled water, introducing hands into containers
used to store drinking water, drinking beverages from street vendors, drinking beverages to which contaminated ice has been added, and drinking
water outside the home are risk factors; these factors contributed to the
acquisition of cholera during the large Peruvian epidemic of 1991. Drinking boiled water, acidic beverages, and carbonated water and using narrownecked vessels for storing water are protective measures. Epidemics of
cholera associated with the ingestion of leftover rice, raw fish, cooked
crabs, seafood, raw oysters, and fresh vegetables and fruits have been
documented. Person-to-person transmission is less likely to occur because
a large inoculum is necessary to transmit disease. High transmission rates
(approximately 50%) are reported among household contacts of patients
with cholera in endemic areas.
Epidemics of cholera tend to occur during the hot season. Factors affecting
climate change and climate variability have an impact on the incidence of
cholera. The El Nio-southern oscillation (ENSO), a periodic phenomenon
representative of global climate variability, affects the transmission of cholera
and vector-borne diseases. ENSO causes the warming of normally cool
waters in the Pacific coastline of Peru, thereby promoting phytoplankton
bloom, zooplankton bloom, and V. cholerae proliferation.
Some host factors are important in the transmission of cholera. The
chronic gastritis associated with Helicobacter pylori predisposes to cholera by
inducing hypochlorhydria, which reduces the ability of the stomach to
contain the infection. An unexplained predisposition to severe disease in
persons with the O blood group has been observed in Asia and more recently
in Latin America. Thus, complex associations among climatic, seasonal, bacterial, and human factors affect cholera transmission. Although for the most
part developing countries are affected by cholera, several developed countries

such as the United States, Canada, and Australia have reported indigenous
and imported cases. Figure 310-1 shows the distribution of cholera in the
world from 1990 to 2008.

PATHOBIOLOGY

V. cholerae O1 and O139 cause clinical disease by secreting an enterotoxin

that promotes the secretion of fluids and electrolytes by the small intestine.
The infectious dose of bacteria varies with the vehicle. When water is the
vehicle, more bacteria are needed to cause disease (103 to 106), but when the
vehicle is food, lower amounts are needed (102 to 104). The incubation period
varies from 12 to 72 hours. Cholera toxin (CTX) has two subunits, a pentamer B subunit and a monomer A subunit. The B subunit allows binding of
the toxin to a specific receptor, a ganglioside (GM1) located on the surface
of cells lining the mucosa along the intestine of humans and certain suckling
mammals. The active, or A, subunit has two components, A1 and A2, linked
by a disulfide bond. Activation of adenylate cyclase by the A1 component
results in an increase in cyclic adenosine monophosphate in intestinal epithelial cells, which blocks the absorption of sodium and chloride by microvilli
and promotes the secretion of chloride and water by crypt cells. These events
lead to the production of watery diarrhea with electrolyte concentrations
similar to those of plasma, as shown in Table 310-1. A few other toxins have
been isolated from pathogenic V. cholerae, but their roles in genesis of the
disease are less clear.
The genetic material of El Tor V. cholerae O1 is included in two circular
chromosomes, the larger containing 3 megabases and the smaller containing
1.07 megabases. The main virulence genes are ctxA and ctxB, which encode
for CTX subunits A and B, respectively, and tcpA, which codes for toxin
coregulated pilus. Regulation of expression of these genes is complex. Recent
data suggest that vibrios are able to upregulate the expression of CTX in
response to intestinal fluid components, as well as in the presence of certain

Number of Cholera Cases Reported to WHO, 19842008

Number of cases1000

500

Asia
Africa
America

400
300
200
100
0

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Weekly epidemiological record 2009;31:30924.

FIGURE310-1. World distribution of cholera in 2008 based on reports to the World Health Organization (WHO). (Reprinted with permission from the World Health Organization:

Cholera, 2008. Wkly Epidemiol Rec. 2009;31:309-324.)

TABLE 310-1 ELECTROLYTE COMPOSITION OF CHOLERA STOOLS AND SOLUTIONS RECOMMENDED FOR TREATMENT
Cl
100

K+
20

HCO3
44

GLUCOSE

OSMOLARITY

Stools of adults with severe cholera

Na+
130

Intravenous lactated Ringers solution

130

109

28*

271

Intravenous normal saline

154

154

308

Standard oral rehydration solution promoted by the WHO

90

80

20

10

111

311

Reduced-osmolarity oral rehydration solution promoted by the WHO

75

65

20

10

75

Rice-based oral rehydration solution

90

80

20

10

Glucose concentration is in mg/dL, electrolyte concentrations are in mEq/L, and osmolarity is in mOsm/L.
*Lactated Ringers solution contains citrate instead of bicarbonate.

Bicarbonate is replaced by trisodium citrate.

WHO = Word Health Organization.
Modified with permission from Seas C, DuPont HL, Valdez LM, etal. Practical guidelines for the treatment of cholera. Drugs. 1996;51:966-973.

245
270

CHAPTER 310 CHOLERA AND OTHER VIBRIO INFECTIONS

environmental factors. Genes unique to El Tor V. cholerae may encode for

specific features that allow this biotype to better survive in the environment,
as well as to be more infectious to humans.

CLINICAL MANIFESTATIONS

Cholera is characterized by watery diarrhea and dehydration, which ranges

from mild to severe and life-threatening. Patients with mild dehydration
cannot be differentiated from those infected by other enteric pathogens
causing watery diarrhea. In contrast, patients with severe dehydration secondary to cholera are easy to identify in that their stools have the appearance
of rice water and no other clinical illness produces such severe dehydration
as quickly (in a matter of a few hours) as cholera. Onset of the disease is
abrupt and characterized by watery diarrhea, vomiting, generalized cramps,
and oliguria. Physical examination shows a feeble pulse, fever is rarely present,
patients look anxious and restless, the eyes are very sunken, mucous membranes are dry, the skin has lost its elasticity and when pinched retracts very
slowly, the voice is almost nonaudible, and intestinal sounds are prominent.
Although watery diarrhea is the hallmark of cholera, some patients do not
have diarrhea but instead have abdominal distention and ileus, a relatively
rare type of cholera called cholera sicca.
Laboratory findings in patients with severe dehydration consist of an
increase in hematocrit, urine specific gravity, and total serum protein; azotemia; metabolic acidosis with a high anion gap; normal or low serum potassium levels; and normal or slightly low sodium and chloride levels. The
calcium and magnesium content in plasma is high as a result of hemoconcentration. Leukocytosis is observed in patients with severe cholera. Hyperglycemia, caused by high concentrations of epinephrine, glucagon, and cortisol
stimulated by hypovolemia, is more commonly seen than hypoglycemia.
Acute renal failure is the most severe complication of cholera. Incidence rates
of 10.6 cases per 1000 were reported in Peru during the first months of the
1991 epidemic. Patients with acute renal failure almost always have a history
of improper rehydration. Cholera in pregnant women carries a bad prognosis.
Pregnant women have more severe clinical illness, especially when the disease
is acquired at the end of the pregnancy. Fetal loss occurs in as many as 50%
of these pregnancies. Cholera in the elderly also carries a bad prognosis
because of an increase in complications, particularly acute renal failure, severe
metabolic acidosis, and pulmonary edema.

DIAGNOSIS

Chaotic movement under darkfield microscopy and a high number of bacteria in a stool sample from patients with diarrhea are characteristic of V. cholerae infection. Specific antisera against the serotype block the movement of
vibrios and allow confirmation of the diagnosis. Under epidemic conditions,
observing bacteria with a darting movement in a stool sample from a suspected patient under darkfield microscopy is adequate to make the diagnosis.
Definitive confirmation requires isolation of the bacterium in culture. Specific medium is needed to isolate V. cholerae from stool. Higher sensitivity and
specificity have been reported with DNA amplification by polymerase chain
reaction for detection of vibrios in stool and environmental samples.

TREATMENT
The objectives of therapy are to restore the fluid losses caused by diarrhea
and vomiting, correct the metabolic acidosis, restore potassium deficits, and
replace continuous fluid losses. Treatment of patients with milder forms of
dehydration is easy, but treatment of patients with severe dehydration requires
experience and proper training. The intravenous route should be restricted to
patients with some dehydration who do not tolerate the oral route, those who
purge more than 10 to 20mL/kg/hr, and all patients with severe dehydration.
Rehydration should be accomplished in two phases: the rehydration phase
and the maintenance phase. The purpose of the rehydration phase is to restore
normal intravascular volume, and it should last no longer than 4 hours. Intravenous fluids should be infused at a rate of 50 to 100mL/kg/hr in severely
dehydrated patients. Lactated Ringers solution is preferred, but other solutions may be used as well (see Table 310-1). All signs of dehydration should
have disappeared and the patient should pass urine at a rate of 0.5mL/kg/hr
or greater after finishing the rehydration phase. The maintenance phase
follows immediately. During this phase the objective is to maintain normal
hydration status by replacing ongoing losses. The oral route is preferred during
this phase, and the use of oral rehydration solutions is highly recommended.
Oral rehydration therapy uses the principle of common transportation of
solutes, electrolytes, and water by the intestine not affected by cholera toxin.
People with diarrhea can undergo successful rehydration with simple

1867

solutions containing glucose and electrolytes. The World Health Organization

recommends an oral rehydration solution with reduced osmolarity
(245mOsm/L) to treat all diarrheal diseases. This solution contains lower
sodium than the standard oral rehydration solution promoted since 1975 (75
vs. 90mEq/L). No more symptomatic hyponatremia is observed with the
reduced-osmolarity than with the standard solution. The addition of L-histidine to rice-based oral rehydration solutions has recently been shown to
reduce the volume and duration of diarrhea and the unscheduled use of
intravenous therapy in adult cholera patients.1 Patients without severe dehydration who tolerate the oral route can be rehydrated with oral rehydration
solutions exclusively and discharged promptly from the health center. Recommendations for treating cholera patients are shown in Table 310-2. Treatment
of cholera caused by V. cholerae O139 is the same as described earlier.
Antimicrobial agents are not life-saving and always need to be accompanied by fluid therapy. Effective antibiotics in patients with severe dehydration
decrease the duration of diarrhea and the volume of stool by nearly half. Oral
tetracycline and doxycycline are the agents of choice in areas of the globe
where sensitive strains predominate A single dose of doxycycline (300mg) is
the preferred regimen. Pregnant women can be treated with erythromycin or
furazolidone. Because of the emergence of resistance to tetracyclines and
other antimicrobials in many endemic areas, the quinolones and, more
recently, azithromycin have been tested in clinical trials. A single-dose regimen
of azithromycin (20mg/kg) showed clinical and bacteriologic results that in
children were comparable to a 3-day regimen with erythromycin and, in
adults, comparable to a single-dose regimen of ciprofloxacin (1g).2,3 The
addition of oral zinc (30mg/day) to an erythromycin regimen in children
reduced the duration of diarrhea in 12%, with an additional 11% reduction in
the volume of diarrhea in comparison to placebo.4 Antimotility agents such
as loperamide or diphenoxylate, adsorbents, analgesics, and antiemetics are
not recommended. Antisecretory drugs, including racecadotril, an encephalinase inhibitor, are not useful in patients with severe cholera. Chemoprophylaxis of household contacts of cholera cases is not routinely recommended.

PREVENTION

Access to potable water and ensuring proper management of excreta to avoid

contamination of other water sources are important measures to reduce
transmission of cholera. Alternative ways to prevent cholera transmission are
necessary in developing countries. Water can be made safer to drink by
boiling, adding chlorine, or filtering it with cloth made of cotton. An inability
to implement these measures to curtail cholera transmission has prompted a
search for vaccines. An ideal vaccine against cholera should elicit a fast and
long-lasting immune response with minimal side effects. Parenteral vaccines
are no longer recommended. Two oral vaccines, the two-dose regimen of the
inactivated vaccine WC-BS (whole cell plus B subunit) and a single dose of
the live attenuated CVD 103-HgR vaccine, have been tested extensively in
epidemic settings and in field trials in endemic areas. Although the WC-BS
vaccine showed good short-term protective efficacy (85% at 6 months), the
results at 3 and 5 years were less impressive (60%), particularly in children.
A large effectiveness study in Mozambique confirmed the high short-term

TABLE 310-2 RECOMMENDATIONS FOR TREATING CHOLERA

PATIENTS
1. Determine the degree of dehydration on arrival.
2. Rehydrate the patient in two phases:
Rehydration phaselasts 2 to 4 hours
Maintenance phaselasts until the end of the diarrheal episode
3. Register and periodically review input and output in predesigned charts.
4. Use the intravenous route in the following situations:
In all severely dehydrated patients, in whom the speed of infusion varies from 50
to 100mL/kg/hr
Patients with some dehydration who are unable to tolerate the oral route
Patients with high stool output (>10mL/kg/hr) during the maintenance phase
5. Use oral rehydration solutions, glucose or rice based, during the maintenance
phase to match ongoing losses. Volumes of 800 to 1000mL/hr are usually
required. Low-osmolarity solutions are not recommended.
6. Start an oral antimicrobial agent in patients with severe cholera when full
rehydration has been achieved and oral tolerance is confirmed. Single-dose
doxycycline, 300mg, is the preferred regimen. Erythromycin or a quinolone is a
suitable alternative.
7. Discharge patients only if oral tolerance is adequate (1000mL/hr), urine output
is satisfactory (40mL/hr), and stool volume is low (400mL/hr).
Modified with permission from Seas C, DuPont HL, Valdez LM, etal. Practical guidelines for the
treatment of cholera. Drugs. 1996;51:966-973.

protection against cholera (80%) by this vaccine, especially against severe

dehydration (90%). Additionally, reanalysis of data on this vaccine in field
trials has shown that it may also confer herd protection in the unvaccinated
population. A large field trial of the live attenuated vaccine showed no protective efficacy. Indications for use of the currently available cholera vaccines
include travel to endemic areas and situations in which high attack rates of
cholera are expected, such as after environmental disasters, in refugee camps,
and in urban slums in highly endemic areas. New oral vaccines including both
killed and live Vibrio are being evaluated in endemic areas, with promising
preliminary reports.

PROGNOSIS

Patients with severe cholera left untreated or improperly treated carry a poor
prognosis, with mortality rates higher than 50%. However, case-fatality rates
during epidemics may be reduced to values below 1% even in disaster situations, provided that adequate access to health care centers and proper management of patients can be ensured. In contrast, figures higher than 10% have
been reported in epidemic settings when patients had no access to health care
or received improper treatment.

OTHER VIBRIO INFECTIONS

Noncholera vibrios have worldwide distribution and coexist in environments

in which V. cholerae lives. They cause a spectrum of clinical syndromes,
including acute diarrhea, soft tissue infections, and sepsis, especially in immunocompromised hosts. In the United States, 549 patients with disease attributable to non-cholerae Vibrio were reported in 2007 to the Cholera and Other
Vibrio Illness Surveillance System. Complete information was available for
199 patients; 39% were hospitalized and 7% died. The most frequently
reported species were Vibrio parahaemolyticus, Vibrio vulnificus, and nontoxigenic Vibrio cholerae. Vibrio illnesses in the United States are seasonal and
peak during the summer (Fig. 310-2). The incubation period for noncholeragenic Vibrio infection is usually 12 to 72 hours but can be as long as 1 week.
Nontoxigenic V. cholerae causes gastroenteritis, but unlike toxigenic V. cholerae O1 or O139, nontoxigenic V. cholerae does not cause epidemics. Illness
ranges in severity from mild diarrhea to severe watery diarrhea. Fever and
bloody diarrhea are unusual, but immunocompromised persons and those
with liver disease can experience more severe illness, including fever, chills,
and septic shock.
V. parahaemolyticus lives in marine environments and is a source of intestinal illness associated with the ingestion of contaminated shellfish. Certain
serovars have shown pandemic spread (O3:K6 and O4:K68). It is not well
known how this Vibrio causes infection in humans, but the clinical illness may
mimic cholera, although the vast majority of cases are milder and self-limited
forms of acute watery diarrhea. Acute dysentery is reported rarely.
In the United States, V. parahaemolyticus and V. vulnificus, as well as other
noncholeragenic vibrios, caused skin and soft tissue infections in victims and
responders affected by the Gulf Coast hurricane disasters in fall 2005. V.
parahaemolyticus wound infections are generally less severe than those caused
by V. vulnificus. However, in persons with liver disease or those who are
immunocompromised, fatal infections can occur.
V. vulnificus is associated with wound infections in persons in contact
with contaminated water, as well as with primary sepsis in immunocompromised hosts. Wound infections follow trauma and are characterized by rapid

100

Number

80

United States
Gulf Coast States*

60
40
20
0

Jan Feb Mar Apr May June July Aug Sept Oct Nov Dec
*Alabama, Florida, Louisiana, Mississippi, and Texas

FIGURE 310-2. Cases of noncholeragenic Vibrio infection, 2000 to 2004, United States.
(From Centers for Disease Control and Prevention [CDC]. Vibrio illnesses after Hurricane
Katrinamultiple states, August-September 2005. MMWR Morb Mortal Wkly Rep.
2005;54(37):928-931.)

progression of skin and soft tissue involvement, with necrosis and bulla formation occurring in more severe cases. Fever, chills, and sepsis syndrome
may ensue rapidly. Primary sepsis with bacteremia and metastatic lesions on
the skin, characterized by disseminated erythematous lesions that may evolve
to necrotic lesions, is a distinctive clinical manifestation in patients with
chronic liver illnesses, alcoholics, and patients with blood disorders such as
thalassemia. A history of seafood ingestion, usually oysters, is typical. Patients
are acutely ill with high fever and need to be managed aggressively with fluid
resuscitation, surgical dbridement, general supportive care, and antibiotic
coverage. An intravenous combination of cefotaxime, 2g four times a day,
plus doxycycline, 100mg two times a day, is recommended. This combination is synergistic in vitro. Alternative antimicrobials are ceftazidime and
ciprofloxacin.

1. Sur D, Lopez AL, Kanungo S, et al. Efficacy and safety of a modified killed-whole-cell oral cholera
vaccine in India: an interim analysis of a cluster-randomised, double-blind, placebo-controlled trial.
Lancet. 2009;374:1694-1702.
2. Saha D, Karim MM, Khan WA, et al. Single-dose azithromycin for the treatment of cholera in adults.
N Engl J Med. 2006;354:2452-2462.
3. Roy SK, Hossain MJ, Khatun W, et al. Zinc supplementation in children with cholera in Bangladesh:
randomised controlled trial. BMJ. 2008;336:266-268.
4. Jeuland M, Whittington D. Cost-benefit comparisons of investments in improved water supply and
cholera vaccination programs. Vaccine. 2009;27:3109-3120.

SUGGESTED READINGS
Centers for Disease Control and Prevention (CDC). Update on choleraHaiti, Dominican
Republic, and Florida, 2010. MMWR Morb Mortal Wkly Rep. 2010;59:1637-1641. Review of over
120,000 cases.
Reyburn R, Deen JL, Grais RF, et al. The case for reactive mass oral cholera vaccinations. PLoS Negl Trop
Dis. 2011;5:e952. The reactive vaccination approach can prevent cholera cases in outbreak settings.
Tena D, Arias M, Alvarez BT, et al. Fulminant necrotizing fasciitis due to Vibrio parahaemolyticus. J Med
Microbiol. 2010;59:235-238. Systematic review of sepsis caused by V. parahaemolyticus.
Weil AA, Khan AI, Chowdhury F, et al. Clinical outcomes in household contacts with cholera in Bangladesh. Clin Infect Dis. 2009;49:1473-1479. About 50% of contacts developed diarrhea.