eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Cholera

Author: Vidhu V Thaker, MB, BCh, MD, Instructor in Pediatrics, Albert Einstein College of Medicine; Consulting Staff, Department of Pediatrics, Jacobi Medical Center
Contributor Information and Disclosures

Updated: Dec 12, 2008

Introduction

Background

The appellation for cholera probably derives from the Greek word for the gutter of a roof, comparing the deluge of water following a rainstorm to that of the anus of an infected person. Cholera is an ancient disease caused by Vibrio cholerae O1 or, more recently, by V cholerae O139. The hallmark for the disease is profuse secretory diarrhea. Cholera can be spread as an endemic, epidemic, or pandemic disease. Despite all the major advances in research, the condition still remains a challenge to the modern medical world.

Throughout history, populations all over the world have sporadically been affected by devastating outbreaks of cholera. Records from Hippocrates (460-377 BC) and Galen (129-216 AD) describe an illness that might well have been cholera, and numerous hints indicate that a choleralike malady was also known in the plains of the Ganges River since antiquity.

The seventh pandemic of cholera, caused by V cholerae O1, biotype El Tor, began in 1961 and continues today. Reports also document endemics caused by biotype O139.

Cholera has been rare in industrialized nations for the last 100 years; however, the disease is still common in other parts of the world, including the Indian subcontinent and sub-Saharan Africa. The World Health Organization (WHO) has reported cholera outbreaks in West Africa as recent as September 2005.^1,2 In the United States, because of advanced water and sanitation systems, cholera is not a major threat; however, everyone, especially travelers, should be aware of how the disease is transmitted and what can be done to prevent it.

Although an ancient disease, the epidemic of cholera has been brought to the forefront due to the current outbreak in Zimbabwe started in August 2008.³

Pathophysiology

The species V cholerae has been classified according to the carbohydrate determinants of its somatic O antigens. Approximately 140 serotypes have been defined and are classified broadly as those that agglutinate in antisera to the O1 group antigen (V cholerae O1) or those that do not agglutinate in antisera to the O1 group antigen (non-O1 V cholerae).

V cholerae has 2 biotypes, classic and El Tor, which are defined on the basis of their biochemical and other laboratory parameters. Each biotype has been divided further into 2 serotypes, Inaba and Ogawa. V cholerae O1 was the cause of most pandemics until a new strain, termed V cholerae O139 (non-O1 type), was recognized as a cause of epidemic in southern India and parts of Bangladesh in 1992.

Cholera is a toxin-mediated disease. The clinical features and epidemiologic manifestations of disease caused by cholera O139 are indistinguishable from those caused by O1 strains. Cholera toxin (CTX) is a potent protein enterotoxin elaborated by the organism in the small intestine. To reach the small intestine, however, the organism has to negotiate the normal defense mechanisms of the GI tract. Because the organism is not acid-resistant, it depends on its large inoculum size to bypass gastric acidity. Using its own properties, such as motility, chemotaxis, and elaboration of hemagglutinin/protease, the organism transcends the mucous layer of the small intestine.

Hemagglutinin/protease is both an agglutinin and a zinc-dependent protease, which cleaves the mucin and fibronectin as well as a subunit of CTX. Hemagglutinin/protease also may serve to facilitate the spread and excretion of vibrios within the intestine in stools by detaching them from the intestinal walls. After the vibrios negotiate these 2 barriers, they adhere to the intestinal wall mediated by toxin-coregulated pilus (TCP). The synchronous working of TCP, CTX, and a few other virulence factors all are regulated by toxR gene product, which is designated as the "master switch."

Once established, the organisms produce CTX that consists of subunits A and B. The B subunit is the binding subunit, and the A subunit is the enzymatic subunit. These 2 working in harmony, transfer adenosine diphosphate (ADP) and activate it to cyclic adenosine monophosphate (cAMP), which inhibits the absorptive sodium transport and activates the excretory chloride transport in the intestinal crypt cells, eventually leading to an accumulation of sodium chloride in the intestinal lumen.

The high osmolality in the intestinal lumen is balanced by water secretion that eventually overwhelms the lumen absorptive capacity and leads to diarrhea. Unless the wasted fluid and electrolytes are replaced adequately, shock (caused by profound dehydration) and acidosis (caused by loss of bicarbonate) follow.

The O139 Bengal strain of V cholerae has a very similar pathogenic mechanism except that it produces a novel O139 lipopolysaccharide (LPS) and an immunologically related O-antigen capsule. These 2 features enhance its virulence and increase its resistance to human serum in vitro and occasional development of O139 bacteremia.

Frequency

United States

In the United States, cholera has virtually been eliminated because of improved hygiene and sanitation systems.

A unique strain of V cholerae O1 that is related closely to, but distinguishable from, the strain of the seventh pandemic was recognized in Louisiana and along the Gulf of Mexico in 1973. Since then, this strain has become indigenous to the Gulf coast, although its environmental reservoirs and ecology remain unclear. With the current level of sanitation, epidemic spread of this organism is not expected.

Through 1991, 65 cases of diarrhea resulting from this endemic infection were reported to the Center for Disease Control (CDC).⁴ Most of these cases occurred in Louisiana. Through 1990, 42 cases of cholera occurred in travelers returning to the United States from abroad during the seventh pandemic. The frequency of cholera among international travelers returning to the United States has averaged 1 case per 500,000 population, with a range of 0.05-3.7 cases per 100,000 population, depending on the countries visited.

International

Periodic global or pandemic spread of cholera from its endemic reservoir in the Indian subcontinent was recognized as characteristic of cholera as early as 1831, when the second pandemic reached England.

Of the 6 pandemics that occurred in the 19th century, 5 affected Europe and 4 reached the United States, causing more than 150,000 deaths in 1832 and 50,000 deaths in 1866. The seventh pandemic of cholera, and the first in the 20th century, began in 1961; by 1991, it had affected 5 continents. This was the first pandemic recognized to be caused by the El Tor biotype of V cholerae O1. After its spread in Asia in the 1960s, V cholerae O1 El Tor entered Africa in the early 1970s, causing epidemic cholera and establishing itself as a significant endemic infection. Cholera epidemics now occur regularly in Africa.

The number of patients with cholera worldwide is uncertain because most cases go unreported. The likely contributory factors are that (1) most cases occur in remote areas of developing countries where definitive diagnosis is not possible, (2) reporting systems often are nonexistent in such areas, (3) the stigma of reporting cholera has direct consequences on commercial trade and tourism, and (4) many countries with endemic cholera do not report at all.

In 1990, fewer than 30,000 cases were reported to the WHO. Reported cases increased more than 10-fold with the beginning of the Latin American epidemic in 1991. In 1994, the number of cases (384,403) and countries (94) reporting cholera was the largest ever registered at the WHO. Even Europe experienced a 30-fold increase in cholera from 1993-1994, with reported cases increasing from 73 to 2,339 and deaths increasing from 2 cases to 47.

According to the WHO, the number of cases in 2005 surged to 131,943 with 2272 deaths from 52 countries, 30% increase from the previous year. Another unprecedented surge due to the ongoing outbreak in Zimbabwe is expected. By December 1, 2008 the ministry of health had reported 11,735 cases with 484 deaths since August 2008.³

Mortality/Morbidity

In 1950, during the sixth pandemic, case fatality rates were very high, and as many as 50-70% of patients died. With the replacement of classic cholera with El Tor, a less virulent strain, case fatality rates reduced dramatically during the 1960s. Fatality rates have declined further because of better treatment and, in particular, increasingly available oral rehydration therapy, which was introduced during the early 1970s but became widely available in many parts of the world in the 1980s.

For most patients, treatment with oral rehydration is sufficient; however, when safe water or oral rehydration salts are not available, case fatality rates can be very high. A case fatality rate of 25-50% was estimated among untreated patients in refugee camps in Goma. Where good treatment is readily accessible, the case fatality rate is less than 1%. In Africa, a marked decline in case fatality rates has occurred since 1970; however, Africa continues to have the highest reported case fatality rates (approximately 5% in 1998 and 4% in 1999) compared to the rest of the world.

Average case fatality rates for Europe and the Americas continue to hover around 1%. Because the fatality rates vary in different parts of the world, the global case fatality rates only partly reflect the trends in each region because the global rates also are affected by the global distribution of cases.

Age

In nonendemic areas, incidence of infection is similar in all age groups, although adults are less likely to become asymptomatic than children. The exception is breastfed children, who are protected against severe disease because of less exposure and because of the antibodies to cholera they obtain in breast milk.

Clinical

History

• Diarrhea
  • Profuse watery diarrhea is a hallmark of cholera. Cholera should be suspected when a patient older than 5 years develops severe dehydration from acute, severe, watery diarrhea (usually without vomiting) or in any patient older than 2 years who has acute watery diarrhea in an area where an outbreak of cholera has occurred.
  • Stool volume during cholera is more than that of any other infectious diarrhea. Patients with severe disease may have a stool volume of more than 250 mL/kg body weight in a 24-hour period.
  • The stool may contain fecal material early in the course of clinical illness. The characteristic cholera stool is an opaque white liquid that is not malodorous and often is described as having a rice water appearance (ie, in color and consistency, it resembles water that has been used to wash or cook rice).
  • V cholerae does not elicit an inflammatory response, and cholera stool contains few leukocytes and no erythrocytes.
  • Because of the large volume of diarrhea, patients with cholera have frequent and often uncontrolled bowel movements.
  • Patients experience abdominal cramps, probably caused by distention of loops of small bowel as a result of the large volume of intestinal secretions.
• Vomiting
  • Vomiting is a prominent manifestation of illness. It occurs early in the course of the disease when the vomiting is caused by decreased gastric and intestinal motility and later in the course of the disease when acidemia is more likely.
  • If untreated, the diarrhea and vomiting lead to isotonic dehydration and, in patients with severe disease, vascular collapse, shock, and death.
  • Dehydration can develop with remarkable rapidity, within hours after the onset of symptoms. This contrasts with disease produced by infection from any other enteropathogen.
  • Because the dehydration is isotonic, water loss is proportional between 3 body compartments, intracellular, intravascular, and interstitial.

Physical

• Dehydration
  • Dehydration has been classified into the following 3 categories to facilitate patient treatment: severe, some (previously termed moderate in the WHO criteria for the classification of dehydration), and none (previously termed mild by the WHO). Table 1 shows the clinical findings associated with the classification.  Table 1. Assessment of the Patient With Diarrhea for Dehydration

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    Table

    Condition	Eyes	Tears	Mouth and Tongue	Thirst	Skin Pinch	Decision
    Well, alert	Normal	Present	Moist	Drinks normally, not thirsty	Goes back quickly	Patient has no signs of dehydration.
    *Restless, irritable	Sunken	Absent	Dry	*Thirsty, drinks eagerly	*Goes back slowly	If the patient has 2 or more signs, including at least 1 * sign, some dehydration is present.
    *Lethargic or unconscious, floppy	Very sunken and dry	Absent	Very dry	*Goes back very slowly	*Goes back very slowly	If the patient has 2 or more signs, including at least 1 * sign, severe dehydration is present.

    Condition	Eyes	Tears	Mouth and Tongue	Thirst	Skin Pinch	Decision
    Well, alert	Normal	Present	Moist	Drinks normally, not thirsty	Goes back quickly	Patient has no signs of dehydration.
    *Restless, irritable	Sunken	Absent	Dry	*Thirsty, drinks eagerly	*Goes back slowly	If the patient has 2 or more signs, including at least 1 * sign, some dehydration is present.
    *Lethargic or unconscious, floppy	Very sunken and dry	Absent	Very dry	*Goes back very slowly	*Goes back very slowly	If the patient has 2 or more signs, including at least 1 * sign, severe dehydration is present.

  • In adults and children older than 5 years, other signs for severe dehydration include absent radial pulse and low blood pressure.
  • The skin pinch may be less useful in patients with marasmus (severe wasting), kwashiorkor (severe malnutrition with edema), or obesity.
  • Tears are relevant signs only for infants and young children.
  • Patients with severe dehydration have a characteristic clinical appearance that is attributable to the loss of approximately 15% of total body water (approximately 10% of total body weight).
  • Intracellular and intravascular dehydration is manifested in decreases skin turgor, sunken eyes, and wrinkled ("washer woman") hands.
  • Decreased intravascular volume is manifested by tachycardia, absent or barely palpable peripheral pulses, and hypotension.
  • Tachypnea and hypercapnia also are part of the clinical picture and are attributable to the metabolic acidosis that invariably is present in patients with cholera who are dehydrated.
  • Children with some (moderate) dehydration have lost approximately 7-10% of body water (approximately 5% of body weight). In these patients, cardiac output and vascular resistance are normal, and changes in interstitial and intracellular volume are the primary manifestations of illness. Children have decreased skin turgor, as manifested by prolonged skin tenting in response to a skin pinch (the most reliable sign of isotonic dehydration), and a normal pulse.
  • Children without clinically significant dehydration (<5% loss of body weight) may have increased thirst without other signs of dehydration.
• Metabolic and systemic manifestations
  • After dehydration, hypoglycemia is the most common lethal complication of cholera in children. Hypoglycemia is a result of diminished food intake during the acute illness, exhaustion of glycogen stores, and defective gluconeogenesis secondary to insufficient stores of gluconeogenic substrates in fat and muscle.
  • Acidosis in cholera is a result of bicarbonate loss in stools, accumulation of lactate because of diminished perfusion of peripheral tissues, and hyperphosphatemia.
  • Acidemia occurs when respiratory compensation is unable to sustain a normal blood pH.
  • Hypokalemia results from potassium loss in the stool, with a mean potassium concentration of approximately 30 mmol/L. Because of the existing acidosis, however, children often have normal serum potassium concentrations when first observed, despite severe total body potassium depletion. Hypokalemia develops only after the acidosis is corrected and intracellular hydrogen ion is exchanged for extracellular potassium. Hypokalemia is most severe in children with preexisting malnutrition who have diminished body stores of potassium and may be manifested as paralytic ileus.
  • Rehydration therapy with bicarbonate-containing fluids can also produce hypocalcemia by decreasing the proportion of serum calcium that is ionized.
  • Chvostek and Trousseau signs are often present, and spontaneous titanic contractions can occur.

Causes

Cholera can be an endemic, epidemic, or a pandemic disease. Initiation and maintenance of epidemic and pandemic disease by V cholerae require human infection and poor sanitation with assistance from human migration and seasonal warming of coastal waters. Certain environmental and host factors appear to play a role in the spread of V cholerae.

• Environmental factors
  • V cholerae is a saltwater organism, and its primary habitat is the marine ecosystem where it lives in association with plankton.
  • Cholera has 2 main reservoirs, man and water. V cholerae is rarely isolated from animals, and animals do not play a role in transmission of disease.
  • Primary infection in humans is incidentally acquired. Risk of primary infection is facilitated by seasonal increases in the number of organisms, possibly associated with changes in water temperature and algal blooms.
  • Secondary transmission occurs through fecal-oral spread of the organism through person-to-person contact or through contaminated water and food. Such secondary spread commonly occurs in households but can also occur in clinics or hospitals where patients with cholera are treated.
  • Infection rates predictably are highest in communities in which water is not potable and personal and community hygiene standards are low.
• Host susceptibility factors that may affect the course of infection with V cholerae O1
  • Malnutrition
  • Hydrochlorhydria or achlorhydria of any cause (including Helicobacter pylori infection, gastric surgery, vagotomy, use of H2 blockers for ulcer disease): The reason it is easily discernible is that gastric acid can quickly render an inoculum of V cholerae noninfectious before it reaches the site of colonization in the small bowel.
  • O blood group: The role played by O blood group is less certain. The cause is unknown, but incidence of infection appears to be twice as high in this population.
  • Previous exposure and acquired immunity: Infection rates of household contacts of cholera patients range from 20-50%. Rates are lower in areas where infection is endemic and if there are preexisting vibriocidal antibodies from previous encounters with the organism, especially in adults. For the same reason, adults are symptomatic less frequently than children, and second infections rarely occur or are mild.
  • Asymptomatic carriers: This may have a role in transfer of disease in areas where the disease is not endemic. Although carriage usually is short-lived, a few individuals may excrete the organisms for a prolonged period.

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