Version May 2024
INTRODUCTION — Cholera is a life-threatening diarrheal illness caused by cholera toxin-producing strains of Vibrio cholerae.
Issues related to the epidemiology, microbiology, clinical manifestations, and diagnosis of cholera will be reviewed here. Issues related to treatment and prevention of cholera are discussed separately. (See "Cholera: Treatment and prevention".)
Issues related to infections caused by non-O1/O139 V. cholerae strains are discussed separately. (See "Infections due to non-O1/O139 Vibrio cholerae".)
The general approaches to acute diarrhea among adults and children in resourced-limited settings are discussed elsewhere. (See "Approach to the adult with acute diarrhea in resource-limited settings" and "Approach to the child with acute diarrhea in resource-limited settings".)
MICROBIOLOGY
Etiologic agent — Vibrio cholerae is a highly diverse species with more than 200 serologic groups, including pathogenic and non-pathogenic variants. The disease cholera is caused by cholera toxin-producing (toxigenic) strains of V. cholerae, which are in serogroups O1 and O139 [1].
Toxigenic strains harbor the bacteriophage CTXΦ, which encodes cholera toxin [2]. V. cholerae can evolve rapidly through acquisition of mobile genetic elements. (See 'Mechanism of infection' below.)
V. cholerae has a distinctive appearance; it is a comma-shaped gram-negative rod; the organisms are highly motile and possess a single polar flagellum.
Classification — V. cholerae is classified based on differences in the structure of the O antigen of its lipopolysaccharide.
●Serogroup O1 – V. cholerae O1 is divided into two major serotypes, Inaba and Ogawa; these differ by the presence of a single methyl group on the Ogawa O-specific polysaccharide antigen [3].
V. cholerae O1 is also divided into two biotypes, El Tor and classical; these are differentiated by biochemical distinctions and susceptibility to specific bacteriophages. Previous V. cholerae pandemics were caused by the classical biotype, which is now thought to be extinct [4].
●Serogroup O139 – V. cholerae O139 emerged in 1992 and was an important cause of epidemic cholera for a decade, but is no longer a major cause of cholera [4,5].
PATHOGENESIS
Transmission — Vibrio cholerae is transmitted via the fecal-oral route; this includes transmission within households or between close contacts, as well as outbreaks related to contaminated food and water. In endemic regions, V. cholerae in the water are an important reservoir of the organism; V. cholerae can live on chitinous plankton [6].
The infectious dose of V. cholerae required to cause cholera is thought to be relatively high; an inoculum of 108 V. cholerae or higher resulted in severe infection among healthy volunteers [7,8].
Individuals with severe cholera excrete as many as 1010 to 1012 organisms per liter of stool. Recently shed organisms may be more infectious than organisms from the aquatic environment [9,10].
Issues related to preventing transmission are discussed separately. (See "Cholera: Treatment and prevention", section on 'Preventing transmission' and "Cholera: Treatment and prevention".)
Risk factors — Cholera is associated with people whose incomes are below federal poverty thresholds and lack of access to safe food, water, and adequate sanitation [11,12]. Large cholera epidemics often occur in populations impacted by natural disaster or human conflict [13].
In some foodborne cholera outbreaks, risk factors may include consumption of specific foods, including rice products or certain fruits or vegetables [14]. In areas where cholera occurs sporadically, most cases are associated with shellfish consumption.
Host-based factors influencing risk for V. cholerae infection include [15]:
●Blood group O has been associated with more severe illness [16-18].
●For patients with hypochlorhydria or partial gastrectomy, a lower infectious dose is needed to cause infection [19,20].
●Prior infection is protective against subsequent infection; however, protection is serogroup specific [21-23].
Breastfeeding of young infants has been shown to be protective against cholera [15,24].
Mechanism of infection — For infection to occur, V. cholerae must survive the acidic environment of the stomach, then attach to the small intestine and produce cholera toxin.
Cholera toxin is the main virulence factor of pathogenic V. cholerae strains; it activates an intracellular pathway resulting in massive fluid secretion into the small intestine, leading to large volumes of fluid loss with high concentrations of sodium, chloride, bicarbonate, and potassium [25].
EPIDEMIOLOGY
Global distribution — Each year, there are an estimated 3 million cases of diarrheal illness and approximately 100,000 deaths worldwide caused by Vibrio cholerae [26]. However, cholera is vastly underreported, and precise measurements of attributable morbidity and mortality are lacking.
Cholera occurs primarily in settings where there is inadequate access to clean water and sanitation; it occurs endemically as well as epidemically (see 'Endemic versus epidemic infection' below):
●Cholera is endemic in approximately 50 countries (defined as having reported cholera cases in at least three of the five past years), mostly in Africa and Asia [26,27].
●Epidemics due to V. cholerae have occurred throughout Africa, Asia, the Middle East, South and Central America, and the Caribbean [28]. Epidemics can span a broad geographic area; as an example, the strain implicated in the 2010 outbreak in Haiti was subsequently associated with outbreaks in the neighboring countries of Dominican Republic, Cuba, and Mexico [29].
Cases in resource-abundant settings are generally imported from travel to endemic or epidemic settings [30].
Endemic versus epidemic infection — Patterns of cholera transmission and infection differ between endemic areas and areas experiencing epidemics.
In areas of high endemicity, the incidence of V. cholerae infection follows a seasonal distribution, with peaks before and after rainy seasons [28]. Superimposed epidemics may also occur; mathematical models suggest these epidemics are dependent on fluctuations in population-based immunity and climate [31]. In areas of high endemicity, the incidence of cholera is highest among children <5 years of age, likely reflecting lack of protective immunity [32].
In areas with limited population immunity, massive epidemics may occur, with similar attack rates among children and adults. As an example, during the 2010 cholera epidemic in Haiti, a V. cholerae O1 variant El Tor strain was introduced from South Asia [33,34]. Within two years, 604,634 cases of infection, 329,697 hospitalizations, and 7436 deaths from cholera were reported in Haiti [35]. A reactive vaccination campaign was credited with reducing cholera transmission in Haiti; no cases of cholera occurred between 2019 and 2022. However, the same V. cholerae strain reemerged in September 2022 [36]. During this reemergence, a higher burden of disease has been observed among young children, likely reflecting lack of protective immunity [37].
Even in endemic regions, breakdowns in safe water, hygiene, and health services can contribute to epidemic transmission of cholera. In Yemen, where public health and healthcare infrastructure have been devastated by years of warfare, two outbreaks occurred in short succession at the end of 2016 and the middle of 2017. During the second outbreak, approximately 500,000 cases and 2000 associated fatalities were recorded within four months [38].
Other major outbreaks have occurred in numerous countries. In 2022, 16 countries reported protracted cholera outbreaks [39]. Fatality rates in the setting of epidemic cholera are consistently >1 percent, particularly in rural areas and in the early stages of an epidemic [40]. As an example, in the 2008 to 2009 cholera outbreak in Zimbabwe which involved nearly 100,000 people, the case fatality rate was >4 percent [41].
Cholera pandemics — Over the last two centuries there have been seven pandemics of V. cholerae [28]. V. cholerae O1 El Tor is the cause of the current, seventh pandemic. This pandemic represents the expansion of a single bacterial lineage with a common ancestral clone dated to 1952 [4].
The current pandemic has been comprised of three independent waves of transmission; each has coincided with acquisition of new genetic material conferring enhanced environmental stability, drug resistance, or virulence to the previously circulating strains of V. cholerae [4]. Each wave of transmission originated in South Asia before spreading to distant locations throughout Asia, Africa, South America, and the Caribbean.
CLINICAL MANIFESTATIONS — Vibrio cholerae infection is associated with a spectrum of manifestations ranging from asymptomatic intestinal colonization to severe diarrhea [42].
Incubation period — The typical incubation period is one to two days [43-45]; however, it can range from several hours to as long as three to five days. Factors influencing the incubation period include host susceptibility and inoculum size.
Signs and symptoms — The clinical manifestations of cholera caused by V. cholerae O1 versus O139 are indistinguishable.
●Gastrointestinal symptoms – Vomiting may begin before or after onset of diarrhea. Patients may have abdominal cramping but usually do not have frank abdominal pain typically associated with dysentery. In early illness, cholera stools may contain fecal matter and bile [28]. Fever is uncommon; presence of fever should prompt evaluation for concurrent infection.
Severe cholera ("cholera gravis") is characterized by passage of profuse "rice-water" stool, a watery stool with flecks of mucous (picture 1). It typically has a fishy odor. The diarrhea is usually painless, without tenesmus.
Approximately 5 to 10 percent of patients develop severe hypovolemia [1]. In children with severe cholera, stool output is typically between 10 and 20 mL/kg per hour [46]. In adults with severe cholera, stool output can be as high as 1000 mL per hour. The total volume loss over the course of illness may be up to 100 percent of body weight [47]. Stool from patients with cholera contains a higher concentration of sodium than stool from patients with other causes of diarrheal illness (table 1).
●Manifestations of hypovolemia and electrolyte loss – Severe cholera is associated with rapid development of hypovolemic shock due to profound fluid and electrolyte losses, often within hours of the symptom onset. Among patients who died before presentation to a cholera treatment center during the early stages of the Haiti 2010 cholera epidemic, the median time between symptom onset and death was 12 hours [48].
Patients with severe hypovolemia may have sunken eyes, dry mouth, cold clammy skin, decreased skin turgor, and wrinkled hands and feet ("washer woman's hands") (table 2). Patients are frequently apathetic and lethargic. Kussmaul breathing (deep respirations reflecting compensatory hyperventilation) may occur due to acidosis from loss of stool bicarbonate as well as lactic acidosis from poor perfusion. Initially the pulse is rapid and thready; as the blood pressure drops, the pulse may become difficult to palpate. Muscle cramping and weakness due to loss of potassium and calcium are common.
Laboratory testing may demonstrate hypokalemia, hyponatremia or hypernatremia (although cholera is most often associated with isonatremic dehydration), hypocalcemia, hypoglycemia, and acidosis.
Renal failure with acute tubular necrosis may occur. In children, depletion of glycogen stores and inadequate gluconeogenesis can lead to symptoms of severe hypoglycemia or coma.
Complications
●The most important complication of cholera is hypovolemia and electrolyte loss, discussed above.
●Pneumonia (potentially from aspiration in the setting of vomiting) is an important complication of cholera among children. In one study including 33 patients who died of cholera, pneumonia accounted for two-thirds of deaths [49].
●Chronic enteropathy and malnutrition may develop among children <5 years of age [1].
●Pregnant patients with cholera are at increased risk of miscarriage, premature delivery, and stillbirth [50].
●"Cholera sicca" is an unusual form of the cholera in which fluid accumulates in the intestinal lumen; circulatory collapse and death can occur in the absence of diarrhea.
●Bacteremia due to V. cholera is rare.
DIAGNOSIS
When to suspect cholera — Cholera is a potential cause of severe watery diarrhea (with or without vomiting), especially in patients who develop rapid and severe volume depletion (table 2).
According to the World Health Organization (WHO) definition for cholera reporting, cholera should be suspected in the following circumstances [51-53]:
●In areas where a cholera outbreak has not been declared: any person age ≥2 years presenting with acute watery diarrhea (AWD; defined as ≥3 loose or watery, non-bloody stools within a 24-hours period) and severe dehydration or dying from AWD.
●Once a cholera outbreak has been declared: any person presenting with or dying from AWD.
In children, volume-depleting diarrhea may be attributable to several pathogens; in adults, volume-depleting diarrhea is usually attributable to Vibrio cholerae. (See "Approach to the child with acute diarrhea in resource-limited settings" and "Approach to the adult with acute diarrhea in resource-limited settings".)
In resource-abundant settings where cholera is rare, epidemiologic clues that might raise suspicion of V. cholerae in a patient with acute watery diarrhea include travel to an area where cholera is present or ingestion of undercooked or raw shellfish.
Clinical and diagnostic evaluation
●Clinical evaluation – Patients with suspected cholera should undergo careful assessment for signs and symptoms of volume depletion (table 2). (See "Approach to the adult with acute diarrhea in resource-limited settings", section on 'Clinical assessment' and "Approach to the child with acute diarrhea in resource-limited settings", section on 'Diagnostic evaluation'.)
These findings are important for guiding initial management. (See "Cholera: Treatment and prevention" and 'Transmission' above.)
●Establishing a diagnosis – In most cases, cholera is diagnosed presumptively in patients with severe acute watery diarrhea. However, there are no signs or symptoms that can unequivocally distinguish cholera from other infectious causes (table 3 and table 4).
The diagnosis of cholera can be confirmed by isolation of V. cholerae from stool cultures performed on specific selective media. In settings where stool culture is not readily available, rapid tests such as stool dipsticks or darkfield microscopy can support the diagnosis. (See 'Diagnostic tools' below.)
Routine laboratory testing is not required. In patients with ileus, confusion, seizure, or no urine output in response to fluid replacement, serum electrolyte, and glucose testing may be useful to guide further management.
Diagnostic tools
Stool culture — A definitive diagnosis of cholera is based on culture of the organism from a clinical sample (such as stool or rectal swab). V. cholerae can be isolated from stool using selective media such as thiosulfate citrate bile sucrose agar or taurocholate tellurite gelatin agar. Once cultured, V. cholerae can be identified by biochemical tests; serogroup and serotype can be assigned by testing with specific antibodies [54].
During transport to a central laboratory from field settings, V. cholerae can persist in a number of standard transport media including Cary-Blair media. In addition, recovery of viable V. cholerae can be enhanced by enrichment in alkaline peptone water [54].
In settings where cholera is a sporadic illness, the microbiology laboratory should be notified of suspicion for cholera so that appropriate selective media can be used; these media are not used routinely for stool culture.
Rapid tests and other tools
●Antigen detection – Several rapid antigen detection-based tests are commercially available for diagnosis of cholera [55]. Antibody-based immunochromatographic dipstick assays (for stool or rectal swab) include Crystal VC (which detects presence of O1 or O139 antigen) and Cholkit (which detects the O1 antigen only).
In one meta-analysis including 20 studies and 8 different commercial rapid tests, the combined sensitivity was 90 percent (95% CI, 86-93) and the specificity was 86 percent (95% CI, 81-90), relative to bacterial culture (the diagnostic gold standard); there was variation across individual studies [55].
●Molecular tests – Molecular testing for V. cholerae is feasible; however, thus far practical use has been limited to epidemiologic research and surveillance [56].
●Darkfield microscopy − Darkfield microscopy of rice-water stools (at 400x magnification) can be used to evaluate for the presence of highly motile Vibrios, whose shooting star-like motion can be inhibited by the subsequent addition of specific antibodies [57]. Darkfield microscopy is highly specific for V. cholerae but lacks sufficient sensitivity to be used for routine diagnosis.
DIFFERENTIAL DIAGNOSIS — A variety of pathogens can cause acute watery diarrhea (table 3 and table 4).
In resource-limited settings, rotavirus and cryptosporidium are frequent pathogens among infants and young children, whereas enterotoxigenic Escherichia coli predominates among older children and adults.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults" and "Society guideline links: Travel medicine".)
SUMMARY AND RECOMMENDATIONS
●Microbiology – Cholera is a life-threatening diarrheal illness caused by cholera toxin-producing strains of Vibrio cholerae (serogroups O1 and O139). (See 'Microbiology' above.)
●Transmission – V. cholerae is transmitted via the fecal-oral route; this includes transmission within households or between close contacts, as well as outbreaks related to contaminated food and water. (See 'Transmission' above.)
●Epidemiology – Each year, there are an estimated 3 million cases of diarrheal illness and approximately 100,000 deaths worldwide caused by V. cholerae; however, cholera is vastly underreported. Cholera occurs primarily in settings where there is inadequate access to clean water and sanitation; it occurs endemically as well as epidemically. (See 'Endemic versus epidemic infection' above.)
●Clinical manifestations – V. cholerae infection is associated with a spectrum of manifestations ranging from asymptomatic intestinal colonization to severe diarrhea.
•Incubation period – The typical incubation period is one to two days.
•Gastrointestinal symptoms
-Vomiting may begin before or after onset of diarrhea. Patients may have abdominal cramping but usually do not have frank abdominal pain. Fever is uncommon.
-Severe cholera ("cholera gravis") is characterized by passage of profuse "rice-water" stool, a watery stool with flecks of mucous (picture 1). It typically has a fishy odor. The diarrhea is usually painless, without tenesmus.
-Severe cholera is associated with rapid development of hypovolemic shock due to profound fluid and electrolyte losses, often within hours of the symptom onset. Manifestations of hypovolemia are summarized in the table (table 2).
●Diagnosis
•When to suspect cholera – Cholera is a potential cause of severe watery diarrhea (with or without vomiting), especially in patients who develop rapid and severe volume depletion (table 2).
•Diagnostic evaluation
-In most cases, cholera is diagnosed presumptively; however, there are no signs or symptoms that can unequivocally distinguish cholera from other infectious causes.
-The diagnosis of cholera can be confirmed by isolation of V. cholerae from stool cultures performed on selective media. In settings where stool culture is not readily available, rapid tests such as stool dipsticks or darkfield microscopy can support the diagnosis.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
