Cholera

Background

Cholera is an intestinal infection caused by Vibrio cholerae (see the images below). The hallmark of the disease is profuse secretory diarrhea. Cholera can be endemic, epidemic, or pandemic. Despite all the major advances in research, the condition still remains a challenge to the modern medical world. Although the disease may be asymptomatic or mild, severe cholera can cause dehydration and death within hours of onset.

View Image

Scanning electron microscope image of Vibrio cholerae bacteria, which infect the digestive system.

View Image

Electron microscopic image of Vibrio cholera.

See 11 Travel Diseases to Consider Before and After the Trip, a Critical Images slideshow, to help identify and manage infectious travel diseases.

Cholera is transmitted by the fecal-oral route. In the United States and other developed countries, because of advanced water and sanitation systems, cholera is not a major threat. Nevertheless, both clinicians and members of the general public, especially travelers, should be aware of how the disease is transmitted and what can be done to prevent it.^[1]

Definitive diagnosis is not a prerequisite for the treatment of patients with cholera. The priority in management of any watery diarrhea is replacing the lost fluid and electrolytes and providing an antimicrobial agent when indicated. (See Workup and Treatment.)

Historical background

Cholera is an ancient disease. Throughout history, populations all over the world have sporadically been affected by devastating outbreaks of cholera. Records from Hippocrates (460-377 BCE) and the Indian peninsula describe an illness that might have been cholera

The 19th century English physician John Snow provided the first demonstration that the transmission of cholera was significantly reduced when uncontaminated water was provided to the population. During a recurrent epidemic of cholera in London in 1854, Snow identified water from the Broad Street pump as the likely source of the disease; removal of the pump handle contained the epidemic.^[2]

Although not the first description, the discovery of the cholera organism is credited to German bacteriologist Robert Koch, who independently identified V cholerae in 1883 during an outbreak in Egypt. The genus name refers to the fact that the organism appears to vibrate when moving.

Since 1817, 7 cholera pandemics have occurred. The pandemics originated from cholera’s endemic reservoir in the Indian subcontinent. The first 6 occurred from 1817-1923 and were probably the result of V cholerae O1 of the classic biotype. Of these 6 pandemics, 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. The pandemic continues today. This seventh pandemic was the first recognized to be caused by the El Tor biotype of V cholerae O1. The pandemic originated from the Celebes Islands, Indonesia, and affected more countries and continents than the previous 6 pandemics.

A new strain of cholera, V cholerae serogroup O139 (Bengal) emerged in the fall of 1992 and caused outbreaks in Bangladesh and India in 1993. Disease from this strain has become endemic in at least 11 countries.

Cholera has been rare in industrialized nations for the past century; however, the disease is still common in other parts of the world, including the Indian subcontinent and sub-Saharan Africa. Epidemics occur after war, civil unrest, or natural disasters when water and food supplies become contaminated with V cholerae in areas with crowded living conditions and poor sanitation.

• References

Pathophysiology

V cholerae is a comma-shaped, gram-negative aerobic or facultatively anaerobic bacillus that varies in size from 1-3 µm in length by 0.5-0.8 µm in diameter (see the image below). Its antigenic structure consists of a flagellar H antigen and a somatic O antigen. The differentiation of the latter allows for separation into pathogenic and nonpathogenic strains. Although more than 200 serogroups of V cholerae have been identified, V cholerae O1 and V cholerae O139 are the principal ones associated with epidemic cholera.

View Image

This scanning electron micrograph (SEM) depicts a number of Vibrio cholerae bacteria of the serogroup 01; magnified 22371x. Image courtesy of CDC/Jani....

Currently, the El Tor biotype of V cholerae O1 is the predominant cholera pathogen. Organisms in both the classical and the El Tor biotypes are subdivided into serotypes according to the structure of the O antigen, as follows:

• Serotype Inaba - O antigens A and C
• Serotype Ogawa - O antigens A and B
• Serotype Hikojima - O antigens A, B, and C

The clinical and epidemiologic features of disease caused by V cholerae O139 are indistinguishable from those of disease caused by O1 strains. Both serogroups cause clinical disease by producing an enterotoxin that promotes the secretion of fluid and electrolytes into the lumen of 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 withstand gastric acidity.

The infectious dose of V cholerae required to cause clinical disease varies by the mode of administration. If V cholerae is ingested with water, the infectious dose is 10³ -10⁶ organisms. When ingested with food, fewer organisms (10² -10⁴) are required to produce disease.

The use of antacids, histamine receptor blockers, and proton pump inhibitors increases the risk of cholera infection and predisposes patients to more severe disease as a result of reduced gastric acidity. The same applies to patients with chronic gastritis secondary to Helicobacter pylori infection or those who have undergone a gastrectomy.

V cholerae O1 and V cholerae O139 cause clinical disease by producing an enterotoxin that promotes the secretion of fluid and electrolytes into the lumen of the small intestine. The enterotoxin is a protein molecule composed of 5 B subunits and 2 A subunits. The B subunits are responsible for binding to a ganglioside (monosialosyl ganglioside, GM1) receptor located on the surface of the cells that line the intestinal mucosa.

The A1 subunit of cholera toxin activates adenylate cyclase to cause a net increase in cyclic adenosine monophosphate (cAMP). The increased cAMP then carries on the downstream effects. cAMP blocks the absorption of sodium and chloride by the microvilli and promotes the secretion of chloride and water by the crypt cells.^{[3, 4]} The result is watery diarrhea with electrolyte concentrations isotonic to those of plasma.

Fluid loss originates in the duodenum and upper jejunum; the ileum is less affected. The colon is usually in a state of absorption because it is relatively insensitive to the toxin. However, the large volume of fluid produced in the upper intestine overwhelms the absorptive capacity of the lower bowel, resulting in severe diarrhea. Unless the lost fluid and electrolytes are replaced adequately, the infected person may develop shock from profound dehydration and acidosis from loss of bicarbonate.

The enterotoxin acts locally and does not invade the intestinal wall. As a result, few neutrophils are found in the stool.

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.

• References

Etiology

Cholera can be an endemic, epidemic, or a pandemic disease. Initiation and maintenance of epidemic and pandemic disease by V cholerae result from human infection and poor sanitation with assistance from human migration and seasonal warming of coastal waters.

Owing to the relatively large infectious dose, transmission occurs almost exclusively via contaminated water or food. V cholerae O1 has been shown to survive in crabs boiled for 8 minutes, but not in crabs boiled for 10 minutes. Transmission via direct person-to-person contact is rare.

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, humans 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 factors

Malnutrition increases susceptibility to cholera. Because gastric acid can quickly render an inoculum of V cholerae noninfectious before it reaches the site of colonization in the small bowel, hydrochlorhydria or achlorhydria of any cause (including Helicobacter pylori infection, gastric surgery, vagotomy, use of H2 blockers for ulcer disease) increases susceptibility.

The incidence of cholera appears to be twice as high in people with type O blood. The reason for this increased susceptibility is unknown.

Infection rates of household contacts of cholera patients range from 20-50%. Rates are lower in areas where infection is endemic and individuals, especially adults, may have preexisting vibriocidal antibodies from previous encounters with the organism. For the same reason, adults are symptomatic less frequently than children, and second infections rarely occur or are mild.

An attack of the classic biotype of V cholerae usually results in the generation of antibodies that protect against recurrent infection by either biotype. Those who have had El Tor cholera are not protected against further attacks. Attacks of V cholerae 01 do not lead to immunity against V cholerae 0139.

Asymptomatic carriers 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.

• References

Epidemiology

United States statistics

In the United States, cholera has virtually been eliminated because of improved hygiene and sanitation systems. Individuals living in the United States most often acquire cholera through travel to cholera-endemic areas or through consumption of undercooked seafood from the Gulf Coast or foreign waters. Between January 1, 1995, and December 31, 2000, 61 cases of cholera were reported in 18 states and 2 US territories. Thirty-seven were travel-associated cases; the other 24 cases were acquired in the United States.^[5]

A unique strain of V cholerae O1 (biotype El Tor, serotype Inaba), which 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. Of note, none of the toxigenic V cholerae strains associated with the US Gulf Coast (01, 0141, and 075) have caused more than sporadic cases and small outbreaks of diarrhea in the United States.^[6]

In October 2005, toxigenic V cholerae infection due to the consumption of contaminated and improperly cooked seafood was reported from Louisiana after Hurricanes Katrina and Rita.^[7]

The incidence of Vibrio infection in the United States continues to be low, with highest number documented in the age group older than 50 years, which has been around 0.50 cases per 100,000 population from 2003-2008. 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 statistics

The number of patients with cholera worldwide is uncertain because most cases go unreported. Likely contributory factors are as follows:

• Most cases occur in remote areas of developing countries where definitive diagnosis is not possible
• Reporting systems often are nonexistent in such areas
• The stigma of cholera, which has direct adverse effects on commercial trade and tourism, discourages reporting
• 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 surged again in 2005. From 2005 to 2008, 178,000-237,000 cases and 4000-6300 deaths were reported annually worldwide.^[8] However, the actual global burden is estimated to be 3-5 million cases and 100,000-130,000 deaths per year. The 2008 outbreak in Zimbabwe lasted longer than a year, with more than 98,000 cases and more than 4000 deaths.^[9] Outbreaks in Guinea and Yunnan province in China contributed to this increase.^{[10, 11]}

The V cholerae O139 serogroup (also known as Bengal), which emerged from Madras, India in October 1992, has spread throughout Bangladesh and India and into neighboring countries; thus far, 11 countries in Southeast Asia have reported isolation of this serogroup. Some experts regard this as an eighth pandemic.

In mid-October 2010, a cholera epidemic broke out in Haiti, which has been worsened by heavy rains in 2011. As of June 20, 2011, 363,117 cases of cholera and 5,506 deaths have been reported.^[12] The epidemic is the first in Haiti in at least a century, and the source may have been a United Nations peacekeeping team from Nepal that came to Haiti after the catastrophic earthquake that hit the Caribbean nation on January 12, 2010.^{[13, 14]}

Analyses performed by US and Haitian laboratories indicate that the strain involved in the outbreak is V cholerae El Tor O1 from the ongoing seventh pandemic predominant in South Asia . This may have consequences beyond Haiti, since this strain is more hardy and virulent, with an increased resistance to antibiotics.^[15]

Age-related differences in incidence

In nonendemic areas, the incidence of infection is similar in all age groups, although adults are less likely to become symptomatic 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.

• References

Prognosis

Before the development of effective regimens for replacing fluids and electrolyte losses, the mortality in severe cholera was more than 50%. Mortality is higher in pregnant women and children. Mortality rates are lowest where intravenous therapy is available. Average case fatality rates for Europe and the Americas continue to hover around 1%. At the Treatment Center of the International Center for Diarrheal Disease Research, Bangladesh, less than 1% of patients with severe dehydration die.

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 4% in 1999) compared with the rest of the world. Low case fatality rates have been achieved in South America, presumably because of the availability of adequate treatment facilities and trained personnel.

• References

Patient Education

Education in environmental control is critical for the prevention of cholera. The source of V cholerae in nature is human excrement, and the most common vehicle of infection is water. Environmental control must focus on keeping these elements apart.

In the developed world, much has been done in public health planning and in the engineering of water conservation and sewage disposal. However, in developing countries, contamination of water by human excrement is a daily hazard. Members of these populations experience a constant cycle of infection, excretion, and reinfection. Education about the sterilization of water and hand-washing techniques is critical but difficult.

Contamination via food is also an important consideration. The source of this contamination is impure water used to wash or flush vegetables and fruit. Water contamination occurs via sewage or soil that is used to fertilize crops. In this situation, training food handlers is necessary.

• References

History

After a 24- to 48-hour incubation period, symptoms begin with the sudden onset of painless watery diarrhea that may quickly become voluminous and is often followed by vomiting. The patient may experience accompanying abdominal cramps, probably from distention of loops of small bowel as a result of the large volume of intestinal secretions. Fever is typically absent.

However, most Vibrio cholerae infections are asymptomatic, and mild to moderate diarrhea due to V cholerae infection may not be clinically distinguishable from other causes of gastroenteritis. An estimated 5% of infected patients will develop cholera gravis, ie, severe watery diarrhea, vomiting, and dehydration.

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 and is 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. Because of the large volume of diarrhea, patients with cholera have frequent and often uncontrolled bowel movements.

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).

Vomiting

Vomiting, although a prominent manifestation, may not always be present. Early in the course of the disease, vomiting is caused by decreased gastric and intestinal motility; later in the course of the disease it is more likely to result from acidemia.

Dehydration

If untreated, the diarrhea and vomiting lead to isotonic dehydration, which can lead to acute tubular necrosis and renal failure. In patients with severe disease, vascular collapse, shock, and death may ensue. 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.

• References

Physical Examination

Clinical signs of cholera parallel the level of volume contraction. The amount of fluid loss and the corresponding clinical signs of cholera are as follows:

• 3-5% loss of normal body weight - Excessive thirst
• 5-8% loss of normal body weight - Postural hypotension, tachycardia, weakness, fatigue, dry mucous membranes or dry mouth
• >10% loss of normal body weight - Oliguria; glassy or sunken eyes; sunken fontanelles in infants; weak, thready, or absent pulse; wrinkled "washerwoman" skin; somnolence; coma

• References

Assessment for Dehydration

The World Health Organization has classified dehydration in patients with diarrhea into the following 3 categories, to facilitate treatment (see Table 1):

• Severe
• Some (previously termed moderate, in the WHO criteria)
• None (previously termed mild, in the WHO criteria)

Children without clinically significant dehydration (< 5% loss of body weight) may have increased thirst without other signs of dehydration. In children with some (ie, moderate) dehydration, cardiac output and vascular resistance are normal, and changes in interstitial and intracellular volume are the primary manifestations of illness. Skin turgor is decreased, as manifested by prolonged skin tenting in response to a skin pinch (the most reliable sign of isotonic dehydration), and a normal pulse.

For the skin pinch, it is important to pinch longitudinally rather than horizontally and to maintain the pinch for a few seconds before releasing the skin. The skin pinch may be less useful in patients with marasmus (severe wasting), kwashiorkor (severe malnutrition with edema), or obesity.

In adults and children older than 5 years, other signs of severe dehydration include 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.

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.

Cholera causes bicarbonate loss in stools, accumulation of lactate because of diminished perfusion of peripheral tissues, and hyperphosphatemia. Acidemia results 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 3.0 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 ions are 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 tetanic contractions can occur.

Pediatric patients

In pediatric patients, the primary signs are similar to those in adults. However, children with severe cholera may present with signs that are rarely seen in adults. A child with cholera is usually very drowsy, and coma is not uncommon. In addition, pediatric patients may have convulsions that appear to be related, in part, to hypoglycemia because patients exhibit some response to intravenous dextrose. Another significant difference from the adult presentation is that children are often febrile.

Cholera sicca

Cholera sicca is an old term describing a rare, severe form of cholera that occurs in epidemic cholera. This form of cholera manifests as ileus and abdominal distention from massive outpouring of fluid and electrolytes into dilated intestinal loops. Mortality is high, with death resulting from toxemia before the onset of diarrhea and vomiting. The mortality in this condition is high. Because of the unusual presentation, failure to recognize the condition as a form of cholera is common.

• References

Table: Assessment for Dehydration

Table 1. Assessment of the Patient With Diarrhea for Dehydration (based on WHO classification)

View Table

See Table

• References

Approach Considerations

Definitive diagnosis is not a prerequisite for the treatment of patients with cholera. The priority in management of any watery diarrhea is replacing the lost fluid and electrolytes and providing an antimicrobial agent when indicated.

According to World Health Organization (WHO) standard case definition, a case of cholera is suspected when the following conditions are met:

• In an area where the disease is not known to be present, a patient aged 5 years or older develops severe dehydration or dies from acute watery diarrhea
• In an area with a noted cholera epidemic, a patient aged 5 years or older develops acute watery diarrhea, with or without vomiting

In endemic areas, biochemical confirmation and characterization of the isolate are usually unnecessary. However, these tasks may be worthwhile in areas where Vibrio cholerae is an uncommon isolate. If identification of the organism is required, direct microscopic examination of stool (including dark-field examination) is indicated, along with Gram stain, culture, and serotype and biotype identification.

Polymerase chain reaction (PCR) tests for identifying V cholerae have been developed. These have a high degree of sensitivity and specificity. At present, however, such tests are used for screening of food samples.

• References

Stool Examination

Vibrio cholerae is a gram-negative curved bacillus that is motile by means of a single flagellum. Laboratory diagnosis is required not only for identification but also for epidemiological purposes (see the image below).

View Image

Electron microscopic image of Vibrio cholera.

Although observed as a gram-negative organism, the characteristic motility of Vibrio species cannot be identified on a Gram stain, but it is easily seen on direct dark-field examination of the stool.

• References

Stool Culture

V cholerae is not fastidious in nutritional requirements for growth. However, it does need an adequate buffering system if fermentable carbohydrate is present because viability is severely compromised if the pH is less than 6, often resulting in autosterilization of the culture. Many of the selective media used to differentiate enteric pathogens do not support the growth of V cholerae.

Routine differential media

Colonies are lactose-negative, like all other intestinal pathogens, but sucrose-positive. When plated onto triple-sugar iron agar to screen for Salmonella and Shigella species, the organism gives the nonpathogenic pattern of an acid (yellow) slant and acid butt because of fermentation of the sucrose contained in triple-sugar iron agar.

Unlike other Enterobacteriaceae, V cholerae is oxidase-positive; hence, in countries where selective media are not available and cholera is not endemic, V cholerae should be suspected if any motile, oxidase-positive, gram-negative rod isolated on routine differential media from the stool of a patient with diarrhea produces an acid reaction on triple sugar iron agar.

Alkaline enrichment media

As Vibrio has the ability to grow at a high pH or in bile salts, which inhibit many other Enterobacteriaceae, peptone water (pH 8.5-9) or selective media containing bile salts (eg, thiosulfate-citrate-bile-sucrose-agar [pH 8.6]) are recommended to facilitate isolation and lab diagnosis. On thiosulfate-citrate-bile-sucrose-agar, the sucrose-fermenting V cholera grow as large, smooth, round yellow colonies that stand out against the blue-green agar.

• References

Serotyping and Biotyping

Specific antisera can be used in immobilization tests. A positive immobilization test result (ie, cessation of motility of the organism) is produced only if the antiserum is specific for the Vibrio type present; the second antiserum serves as a negative control. Vibrio antisera may be unavailable in countries where cholera is not endemic. In endemic regions, this is an excellent quick method of identification, even in small laboratories.

Classic and El Tor biotypes also can be identified using the same method. This is useful for epidemiologic studies.

• References

Hematologic Tests

The major hematologic derangements in patients with cholera derive from the alterations in intravascular volume and electrolyte concentrations.

Hematocrit, serum-specific gravity, and serum protein are elevated in dehydrated patients because of resulting hemoconcentration. When patients are first observed, they generally have a leukocytosis without a left shift.

• References

Metabolic Panel

Serum sodium is usually 130-135 mmol/L, reflecting the substantial loss of sodium in the stool.

Serum potassium usually is normal in the acute phase of the illness, reflecting the exchange of intracellular potassium for extracellular hydrogen ion in an effort to correct the acidosis.

Hyperglycemia may be present, secondary to systemic release of epinephrine, glucagon, and cortisol due to hypovolemia.

Patients have elevated blood urea nitrogen and creatinine levels consistent with prerenal azotemia. The extent of elevation depends on the degree and duration of dehydration.

A reduced bicarbonate level (< 15 mmol/L) and an elevated anion gap occur as a result of increases in serum lactate, protein, and phosphate levels. The arterial pH is usually low (approximately 7.2). Calcium and magnesium levels are usually high as a result of hemoconcentration.

• References

Approach Considerations

Rehydration is the first priority in the treatment of cholera. Rehydration is accomplished in 2 phases: rehydration and maintenance.

The goal of the rehydration phase is to restore normal hydration status, which should take no more than 4 hours. Set the rate of intravenous infusion in severely dehydrated patients at 50-100 mL/kg/hr. Lactated Ringer solution is preferred over isotonic sodium chloride solution because saline does not correct metabolic acidosis

The goal of the maintenance phase is to maintain normal hydration status by replacing ongoing losses. The oral route is preferred, and the use of oral rehydration solution (ORS) at a rate of 500-1000 mL/hr is recommended.

• References

Treatment Guidelines

The World Health Organization (WHO) guidelines for the management of cholera are practical, easily understood, and readily applied in clinical practice (see Table 7). These guidelines can be used for the treatment of any patient with diarrhea and dehydration. Diagnosis of cholera is not required to initiate hydration therapy.

• References

Cholera Cots

In areas where cholera is endemic, cholera cots have been used to assess the volume of ongoing stool losses. A cholera cot is a cot covered by a plastic sheet with a hole in the center to allow the stool to collect in a calibrated bucket underneath.

Use of such a cot allows minimally trained health workers to calculate fluid losses and replacement needs. The volume of stool is measured every 2-4 hours, and the volume of fluid administered is adjusted accordingly.

In the initial phase of therapy, urine losses account for only a small proportion of fluid losses, and the amount of fluid in the bucket is an adequate reflection of stool losses. With rehydration, urine should be collected separately, so that a vicious circle of increasing urine output and overhydration can be avoided.

• References

Rehydration

The WHO has provided recommendations for fluid replacement in patients with dehydration^[16] (see Table 2). The recommendations include recommendations for fluid replacement for severe hydration, some dehydration, and no dehydration.

Severe dehydration

Administer intravenous (IV) fluid immediately to replace fluid deficit. Use lactated Ringer solution or, if that is not available, isotonic sodium chloride solution. If the patient can drink, begin giving oral rehydration salt solution (ORS) by mouth while the drip is being set up; ORS can provide the potassium, bicarbonate, and glucose that saline solution lacks.

For patients older than 1 year, give 100 mL/kg IV in 3 hours—30 mL/kg as rapidly as possible (within 30 min) then 70 mL/kg in the next 2 hours. For patients younger than 1 year, administer 100 mL/kg IV in 6 hours—30 mL/kg in the first hour then 70 mL/kg in the next 5 hours.

Monitor the patient frequently. After the initial 30 mL/kg has been administered, the radial pulse should be strong and blood pressure should be normal. If the pulse is not yet strong, continue to give IV fluid rapidly. Administer ORS solution (about 5 mL/kg/h) as soon as the patient can drink, in addition to IV fluid.

Reassess the hydration status after 3 hours (infants after 6 h), using Table 1. In the rare case that the patient still exhibits signs of severe dehydration, repeat the IV therapy already given. If signs of some dehydration are present, continue as indicated below for some dehydration. If no signs of dehydration exist, maintain hydration by replacing ongoing fluid losses.

Routes for parenteral rehydration

Accessing a peripheral vein is relatively easy, despite the severe dehydration. If a peripheral vein is not readily accessible, scalp veins have been used for initial rehydration. As the vascular volume is reestablished, a larger needle or catheter can be introduced in a peripheral vein.

Intraosseous routes have been used successfully in young children when veins cannot be accessed. The intraperitoneal route has been tried, but is not recommended.

ORS solution can be administered via nasogastric tube if the patient has some signs of dehydration and cannot drink or if the patient has severe dehydration and IV therapy is not possible at the treatment facility.

Overhydration

A risk of overhydration exists with intravenous fluids; it usually first manifests as puffiness around the eyes. Continued excessive administration of intravenous fluids can lead to pulmonary edema and has been observed even in children with normal cardiovascular reserve. Thus, it is important to monitor patients who are receiving intravenous rehydration hourly. Serum-specific gravity is an additional measure of the adequacy of rehydration.

Some dehydration

Administer ORS solution according to the amount recommended in Table 3. WHO ORS contains the following:

• Sodium – 75 mmol/L
• Chloride – 65 mmol/L
• Potassium – 20 mmol/L
• Bicarbonate – 30 mmol/L
• Glucose – 111 mmol/L

A homemade equivalent is 6 teaspoons of sugar and one half teaspoon of salt in a liter of water; a half cup of orange juice or some mashed banana can provide potassium.^[17]

Use the patient's age only when weight is unknown. The approximate amount of ORS required (in mL) also can be calculated by multiplying the patient's weight (in kg) times 75.

If the patient passes watery stools or wants more ORS solution than shown, give more. Monitor the patient frequently to ensure that the ORS solution is taken satisfactorily and to identify patients with profuse ongoing diarrhea who require closer monitoring.

Reassess the patient after 4 hours, using Table 1. In the rare case where signs of severe dehydration have appeared, rehydrate for severe dehydration, as above. If some dehydration is still present, repeat the procedures for some dehydration and start to offer food and other fluids. If no signs of dehydration are present, maintain hydration by replacing ongoing fluid losses.

Most patients absorb enough ORS solution to achieve rehydration, even when they are vomiting. Vomiting usually subsides within 2-3 hours, as rehydration is achieved.

Urine output decreases as dehydration develops and may cease. It usually resumes within 6-8 hours after starting rehydration. Regular urinary output (ie, every 3-4 h) is a good sign that enough fluid is being given.

No signs of dehydration

Patients who have no signs of dehydration when first observed can be treated at home. Give these patients ORS packets to take home, enough for 2 days. Demonstrate how to prepare and give the solution. The caretaker should give the patient the amount of ORS solution shown in Table 4.

Instruct the patient or the caretaker to return if any of the following signs develop:

• Increased number of watery stools
• Eating or drinking poorly
• Marked thirst
• Repeated vomiting
• Any signs indicating other problems (eg, fever, blood in stool)

• References

Maintenance of Hydration

Maintain hydration of patients presenting with severe or some dehydration. Replace ongoing fluid losses until diarrhea stops.

When a patient who has been rehydrated with IV fluid or ORS solution is reassessed and has no signs of dehydration, continue to administer ORS solution to maintain normal hydration. The aim is to replace stool losses as they occur with an equivalent amount of ORS solution. See Table 5 .

The amount of ORS solution required to maintain hydration varies greatly among patients, depending on the volume of stool passed. It is highest in the first 24 hours of treatment and is especially large in patients who present with severe dehydration. In the first 24 hours, the average requirement of ORS solution in such patients is 200 mL/kg, but some patients may need as much as 350 mL/kg.

Continue to reassess the patient for signs of dehydration at least every 4 hours to ensure that enough ORS solution is being taken. Patients with profuse ongoing diarrhea require more frequent monitoring. If signs of some dehydration are detected, the patient should be rehydrated as described earlier, before continuing with treatment to maintain hydration.

A few patients, whose ongoing stool output is very large, may have difficulty in drinking the volume of ORS needed to maintain hydration. If these patients become tired, vomit frequently, or develop abdominal distension, ORS solution should be stopped and hydration should be maintained intravenously with lactated Ringer solution or isotonic sodium chloride solution, administering 50 mL/kg in 3 hours. After this is done, resuming treatment with ORS solution is usually possible.

Keep the patient under observation, if possible, until diarrhea stops or is infrequent and of small volume. This is especially important for any patient presenting with severe dehydration. If a patient must be discharged from the hospital before diarrhea has stopped, show the caretaker how to prepare and give ORS solution, and instruct the caretaker to continue to give ORS solution, as above. Also instruct the caretaker to return the patient to the hospital if any signs of danger appear.

• References

Antibiotic Treatment

An effective antibiotic can reduce the volume of diarrhea in patients with severe cholera and shorten the period during which V cholerae O1 is excreted. In addition, it usually stops the diarrhea within 48 hours, thus shortening the period of hospitalization. Whenever possible, antibiotic therapy should be guided by susceptibility reports.

Antibiotic treatment is indicated for severely dehydrated patients who are older than 2 years. Begin antibiotic therapy after the patient has been rehydrated (usually in 4-6 h) and vomiting has stopped. No advantage exists to using injectable antibiotics, which are expensive. No other drugs should be used in the treatment of cholera. Antimicrobial agents typically are administered for 3-5 days (see Table 6). However, single-dose therapy with tetracycline, doxycycline, furazolidone, or ciprofloxacin has been shown effective in reducing the duration and volume of diarrhea. Because single dose doxycycline has been shown to be as effective as multiple doses of tetracycline, this has become the preferred regimen.

• References

Fluid Replacement for Dehydration

Table 2. Fluid Replacement for Dehydration

View Table

See Table

• References

Oral Rehydration During First 4 Hours

Table 3. Approximate Amount of Oral Rehydration Solution to Administer in the First 4 Hours

View Table

See Table

• References

Oral Rehydration for Home Administration

Table 4. Estimate of Oral Rehydration Solution Packets to Be Administered at Home

View Table

See Table

• References

Oral Replacement Solution for Hydration Maintenance

Table 5. Oral Replacement Solution for Maintenance of Hydration

View Table

See Table

• References

Antimicrobial Therapy for Cholera

Table 6. Antimicrobial Therapy Used in the Treatment of Cholera*

View Table

See Table

• References

WHO Guidelines for Cholera Management

Table 7. WHO Guidelines for Cholera Management

View Table

See Table

• References

Diet

Resume feeding with a normal diet when vomiting has stopped. Continue breastfeeding infants and young children.

Malnutrition after infection is not a major problem, as it is after infection with Shigella species or rotavirus diarrhea. The catabolic cost of the infection is relatively low, anorexia is neither profound nor persistent, and intestinal enzyme activity remains intact after infection; hence, intestinal absorption of nutrients is near normal.

There is no reason to withhold food from cholera patients.

• References

Deterrence/Prevention

The current response to cholera outbreaks tends to be reactive, in the form of an emergency response. Although this approach prevents many deaths, it fails to prevent cases of cholera.

Rapid identification of cases in children and adults and prompt treatment will limit further spread of the disease. Water can be made safer to drink by boiling or adding chlorine, although both methods are expensive and difficult to implement during epidemics.

Sensitive surveillance and prompt reporting contribute to the rapid containment of cholera epidemics. In many endemic countries, cholera is a seasonal disease, occurring every year usually during the rainy season. Surveillance systems can provide an early alert to outbreaks, which should lead to a coordinated response and assist in the preparation of preparedness plans.

A multisectoral and coordinated approach is paramount to efficiently control a cholera outbreak. Key sectors to be involved are health, water and sanitation, fishery and agriculture, and education.

Cholera is usually transmitted through fecally contaminated water or food. Outbreaks can occur sporadically in any part of the world where water supply, sanitation, food safety, and hygiene are inadequate. WHO recommends improvements in water supply and sanitation as the most sustainable approach for protecting against cholera and other waterborne epidemic diarrheal diseases. However, such an approach is unrealistic for the many impoverished populations most affected by cholera.

Outbreaks can be mitigated and case-fatality rates can be reduced by means of several other measures, many of which are suitable for community participation. Human behaviors related to personal hygiene and food preparation contribute greatly to the occurrence and severity of outbreaks. Education on specific hygiene practices is important in the prevention of cholera.

• References

Vaccines

Difficulties in implementing public health and personal preventive practices have stimulated the century-long search for vaccines. Experience with the parenteral vaccine has been disappointing. Because of a better understanding of the immune response to natural infection, researchers now know that the oral route of administration is better.

Cholera vaccination is no longer officially required for any international traveler, and the International Certificate of Vaccination no longer provides a special section for recording cholera immunization. The risk of an international traveler from a developed country contracting cholera is small (1 case in 500,000 travelers). WHO has identified 3 oral vaccines. These are available in some countries but are used mainly by travelers.

One vaccine consists of a monovalent killed whole-cell V cholerae O1 with purified recombinant B-subunit of cholera toxoid (WC/rBS). Clinical trials have been performed in Bangladesh, Peru, and Sweden. Efficacy trials have shown that this vaccine is safe and confers 85-90% protection during 6 months in all age groups after administration of 2 doses, 1 week apart. In Bangladesh, protection declined rapidly after 6 months in young children but was still about 60% in older children and adults after 2 years. 

This vaccine is available in more than 60 countries for adults and children older than 2 years. It was approved for use in the United States in 2006.

Shanchol and ORCVAX are bivalent vaccines that are based on serogroups O1 and O139; however, they do not contain the bacterial toxin B subunit. ORCVAX was originally formulated in Vietnam in 1997 and was modified in 2004. Over 20 million doses have been administered to adults and children in endemic areas of Vietnam. Shanchol is a similar formulation available in India. Shanchol is administered in 2 liquid doses 14 days apart in adults and children older than 1 year. A booster dose is recommended after 2 years.^[18]

CVD 103-HgR is a cholera vaccine developed by the Swiss Serum and Vaccine Institute in Berne, Switzerland. This vaccine, although not recognized by the WHO, is available in Europe, Latin America, and, since 1997, Canada. The vaccine is composed of attenuated V cholerae O1 prepared by recombinant DNA. It has been tested in industrialized countries and in developing countries that have endemic, epidemic, and little or no cholera.^[19]

The vaccine is highly protective against moderate and severe cholera, and it is very well tolerated and extremely immunogenic. In addition, the rate and extent of vaccine excretion is minimal.

In June, 2016, the FDA approved the CVD 103-HgR cholera vaccine (Vaxchora, PaxVax, Inc) for the prevention of cholera caused by serogroup 01. Also, in June, 2016 the Advisory Committee on Immunization Practices (ACIP) of the CDC voted unanimously to recommend the CVD 103-HgR cholera vaccine (Vaxchora, PaxVax, Inc) for adults aged 18 to 64 years who are traveling to an area of active toxigenic Vibrio cholerae O1 transmission and who have an increased risk for exposure or poor clinical outcome if infected.^{[20, 21]}

The Advisory Committee on Immunization Practices for Use of Cholera Vaccine recommend^{[22, 23]} :

• Adults between the ages of 18 and 64 yr are recommended to receive one dose of the lyophilized CVD 103-HgR (Vaxchora, PaxVax) cholera vaccine before travel to areas with active cholera transmission.
• Vaccine recipients should not have received oral or parenteral antibiotics in the 14 days before vaccine administration.
• Recipients should wait at least 10 days after vaccine administration to take chloroquine.

According to a 2011 Cochrane review on oral cholera vaccines, currently available vaccines are safe and provide 50-60% efficacy in preventing episodes of cholera in the first 2 years after the primary vaccination schedule. A booster dose may be required after 3 years.^[24] At this time, no countries use these vaccines in routine immunization. A randomized trial by Qadri et al reported that a single dose of the inactivated whole-cell oral cholera vaccine offered 2 years of protection to adults and children over 5.^[30]  Another study by Azman et al reported that vaccination campaigns that use a single dose of oral cholera vaccine may be able to prevent more deaths than the standard two-dose campaign when vaccine supplies are limited.^{[28, 29]}

Another study by Qadri et al assessed the feasibility and protective effect of delivering the vaccine Shanchol through routine government services in urban Bangladesh and evaluated the benefit of adding behavioral interventions to encourage safe drinking water and hand washing along with the vaccination.  The study analyzed 267,270 people, 94,675 assigned to vaccination only, 92,539 assigned to vaccination and behavioral change, and 80,056 assigned to non-intervention. The study found that vaccine coverage was 65% in the vaccination only group and 66% in the vaccination and behavioral change group. Overall protective effectiveness was 37% in the vaccination group and 45% in the vaccination and behavioral change group.^{[25, 26]}

A study by Matias et al found that immunization with the bivalent oral cholera vaccine (Shanchol) induced antibody secreting cell responses among a cohort of healthy adults in Haiti after a single dose, however, the second dose of vaccine resulted in a minimal response.^[27]

• References

Medication Summary

Antimicrobial therapy for cholera is an adjunct to fluid therapy and is not an essential therapeutic component. However, an effective antibiotic can reduce the volume of diarrhea in patients with severe cholera and shorten the period during which Vibrio cholerae O1 is excreted. In addition, it usually stops the diarrhea within 48 hours, thus shortening the period of hospitalization. No other drugs besides antibiotics should be used in the treatment of cholera.

The choice of antibiotics is determined by the susceptibility patterns of the local strains of V cholerae O1 or O139.

If antimicrobial therapy is to be initiated, it should be given when the patient is first seen and cholera is suspected. Little reason exists to wait for culture and susceptibility reports.

Furazolidone has been the agent routinely used in the treatment of cholera in children; however, resistance has been reported, and ampicillin, erythromycin, and fluoroquinolones are potentially effective alternatives. The use of quinolones is contraindicated in children with cholera.

Travelers to cholera-affected regions should receive a cholera vaccine. The cholera vaccine Vaxchora is the only one approved by the FDA for cholera prevention. It is a live, weakened vaccine administered as a single, oral liquid dose of about three fluid ounces at least 10 days before travel to a cholera-affected region. The only other existing cholera-prevention vaccines require 2 doses, according to the Centers for Disease Control and Prevention (CDC). A single-dose vaccine is especially beneficial to a person who needs to travel to a cholera-affected region on short notice.^[20]

• References

Doxycycline (Adoxa, Vibramycin, Doxy)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

• References

Tetracycline

• Dosing, Interactions, etc.

Clinical Context:  Tetracycline inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s). This agent treats gram-positive and gram-negative organisms and mycoplasmal, chlamydial, and rickettsial infections.

• References

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra DS)

• Dosing, Interactions, etc.

Clinical Context:  This combination agent inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Trimethoprim is a dihydrofolate reductase inhibitor that prevents tetrahydrofolic acid production in bacteria. It is active in vitro against a broad range of gram-positive and gram-negative bacteria, including uropathogens (eg, Enterobacteriaceae and Staphylococcus saprophyticus). Resistance is usually mediated by decreased cell permeability or alterations in amount or structure of dihydrofolate reductase. It demonstrates synergy with sulfonamides, potentiating inhibition of bacterial tetrahydrofolate production.

• References

Ciprofloxacin (Cipro, Proquin XR)

• Dosing, Interactions, etc.

Clinical Context:  Ciprofloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), S epidermidis, and most gram-negative organisms. It does not have activity against anaerobes. This agent inhibits bacterial DNA synthesis and, consequently, growth.

• References

Ampicillin

• Dosing, Interactions, etc.

Clinical Context:  Ampicillin has bactericidal activity against susceptible organisms.

• References

Erythromycin (E.E.S., Erythrocin, Ery-Tab)

• Dosing, Interactions, etc.

Clinical Context:  Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer RNA (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. Erythromycin is used for treatment of staphylococcal and streptococcal infections. In children, age, weight, and severity of infection determine proper dose. When twice-daily dosing is desired, half the total daily dose may be taken q12h. For more severe infections, double the dose.

• References

Azithromycin (Zithromax, Zmax)

• Dosing, Interactions, etc.

Clinical Context:  This agent acts by binding to the 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.

It concentrates in phagocytes and fibroblasts, as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. This agent is used to treat mild-to-moderate microbial infections.

• References

Norfloxacin (Noroxin)

• Dosing, Interactions, etc.

Clinical Context:  Norfloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms. It does not have activity against anaerobes. It inhibits bacterial DNA synthesis and growth.

• References

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Although not necessarily curative, treatment with an antibiotic to which the organism is susceptible diminishes the duration and volume of the fluid loss and hastens clearance of the organism from stool. Pharmacotherapy plays a secondary role in the management of cholera; fluid replacement is primary.

Emerging drug resistance in certain parts of the world is a concern, as some V cholerae strains contain plasmids that confer resistance to many antibiotics. In areas of known tetracycline resistance, therapeutic options include ciprofloxacin and erythromycin. Strains resistant to ciprofloxacin have been reported from Calcutta, India.

Chemoprophylaxis of household contacts is not necessary.

• References

Cholera vaccine (Vaxchora)

• Dosing, Interactions, etc.

Clinical Context:  Contains live attenuated cholera bacteria that replicate in the gastrointestinal tract of the recipient to provide immunity. It is indicated for active immunization against disease caused by Vibrio cholerae serogroup O1 in adults aged 18-64 y traveling to cholera-affected areas.

• References

Class Summary

In June, 2016, the first U.S. cholera vaccine was approved by the FDA.^[20]

• References