Rudolph's Pediatrics, 22nd Ed.

CHAPTER 260. Cholera

Chokechai Rongkavilit and Ashir Kumar

Cholera is a life-threatening disease characterized by enormous loss of fluid and electrolytes due to profuse diarrhea and vomiting. The first pandemic in 1817 spread outside the Indian subcontinent along trade routes as far as southern Russia. Unlike the previous pandemics, which were caused by classical V cholerae O1 biotype; the O1El Tor biotype, caused the seventh pandemic from India to South America. The most recent outbreak in 1992 in India, was caused by a new O139 or Bengal strain. Serogroups O139 and O1 now coexist and cause outbreaks in the Indian subcontinent. A detailed discussion of the history of cholera epidemics is available in the textbook DVD.

In the United States, one third of those infected acquired the infection overseas, one third acquired the infection by consumption of raw or undercooked domestic seafood, and one-third were residents of Guam with no identified sources. Shellfish harvested from the US gulf coast after Hurricane Katrina was the source of illness for certain cases of V cholerae O1 infection reported in 2005.10

MICROBIOLOGY AND PATHOPHYSIOLOGY

V cholerae is a gram-negative, highly mobile, curved bacillus. There are at least 200 serogroups based on somatic (O) antigens. V cholerae O1 are divided into three serotypes, Ogawa, Inaba, and Hikojima. V cholerae O1 are further divided into 2 biotypes, classical and El Tor. V cholerae O139 represents a mutation of O1 antigen in El Tor strain.1

Bacteria easily grow on chitinous shellfish which explains the infection following ingestion of seafood. Crabs harvested from the US gulf coast are a common source of cholera, especially during warmer months when environmental conditions favor the growth and survival of V cholerae in blackish and coastal water.1,12-14 The classic fecal–oral paradigm is a well-known means of transmission; however, contamination of a variety of foods by food handlers or contamination of fresh fruit and vegetables by cholera-contaminated water has also been attributed to the spread. Healthy individuals shedding the organism also contribute by contaminating food items as well as the environment. For developed countries, contaminated food, especially undercooked seafood, is the usual vehicle for transmission, and contaminated water is more common in less-developed countries.

Several genes are responsible for the virulence of V cholerae. Only epidemic strains of V cholerae O1 and V cholerae O139 possess the ctxA and ctxB genes that encode for enterotoxin subunits A and B.1,15Persons with blood type O are more susceptible to contract cholera as well as are likely to have a severe illness.16 Similarly, persons with low gastric acidity are more prone to disease. Because V cholerae are sensitive to acid, a large inoculum (> 108bacteria) is required to cause the disease. Considerably lower inoculum size (105 bacteria) may produce disease if given with antacids or in individuals with less gastric acidity. Once in the small intestine, the rapid penetration of the intestinal mucous coat is achieved through the organism’s motility, chemotaxis, and elaboration of mucinase, which enables the organism to penetrate the mucus barrier that covers the intestinal epithelium. The toxin coregulated pilus A gene, TcpA, governs effective colonization. V cholerae adheres to enterocytes without invading the mucosal barrier, and thus avoids peristaltic expulsion. Adherent bacteria multiply and elaborate an enterotoxin, also known as cholera toxin or choleragen. The toxin is composed of one A subunit, which is further divided into A1 and A2 and 5B subunits. A regulatory gene called ToxR coregulates ctxActxB, and TcpA genes. The zonula occludens toxin gene zot also plays a critical role in pathogenesis as it makes the tight cell junctions leaky.15

The B subunits of cholera toxin bind the toxin to GM1 ganglioside receptors on enterocytes, after which A1 subunit enters the cell. The A1 subunit irreversibly activates the adenylate cyclase system in the mucosa, leaving it in the “on” position, leading to increases in the intracellular concentration of cyclic AMP, which results in sodium and water loss. Thus, the active secretion of sodium and chloride into the gut lumen with water following it passively results in secretion of isotonic fluid into the small intestine surpassing the absorptive capacity of the colon. This results in volume depletion and shock. Loss of bicarbonate and potassium also occurs, and this leads to metabolic acidosis and hypokalemia.

CLINICAL FEATURES

The incubation period for cholera is short, ranging from 6 hours to 5 days. Clinical features range from asymptomatic infection to a severe fatal illness. Less than 5% of infected individuals develop the classic symptoms of cholera. Symptoms are generally abrupt and include watery diarrhea and vomiting. Anorexia and mild abdominal pain may precede the onset of diarrhea. Once the diarrhea becomes copious, the stools are pale gray in color with a faint fishy smell and contain mucous flecks giving them a classic “rice water” look.1,2,6 Because of the massive amount of fluid and electrolyte loss, severe dehydration and shock may develop within a few hours.

Children may also develop seizures, hypoglycemia, and may become unconscious. Hyponatremia and hypokalemia are more pronounced in children because of the greater loss of sodium and potassium in stools.7,8 Hypokalemia may cause severe muscle cramps, marked weakness, and hypotonia as well as ileus and cardiac arrhythmias. Acute renal failure from protracted hypotension may develop.

DIAGNOSIS

A rapid monoclonal antibody-based coagglutination test for direct detection of V cholerae O1 in fecal specimens is available. The test is sensitive and specific, does not require culture. Actively motile Vibrio with the characteristic “shooting star” movement are seen in stool by dark-field or phase microscopy. Adding specific antisera for V cholerae to the sample will extinguish the movement. Carry-Blair transport medium should be used for transportation of the specimen to the laboratory. The sample should be cultured in thiosulfate-citrate-bile salt sucrose agar. The subsequent identification of the organism is established by agglutination test with O1 or O139 specific antisera. Molecular methods including polymerase chain reaction assay and DNA probes are also available but are not widely used and are not practicable in many areas where cholera is common.

Table 260-1. Oral Cholera Vaccines

TREATMENT

The fatality rate for severe cholera can be as high as 50%. The primary therapy is replacement of fluid and electrolyte losses.1,6,12 Antibiotic therapy is of secondary importance. The principles of rehydration therapy are rapid replacement of fluid deficits, correction of metabolic acidosis, correction of hypokalemia, and replacement of continuing fluid losses as outlined in Chapter 385.

Antibiotic treatment for 2 to 3 days will shorten the clinical course from 4 to 5 days to 2 to 3 days, reduce the volume requirement for rehydration, and decrease the period of bacterial excretion. Tetracycline, 50 mg/kg per day given every 6 hours, or a single-dose doxycycline is the antibiotic of choice. V cholerae is also generally sensitive to trimethoprim-sulfamethoxazole, erythromycin, azithromycin, ciprofloxacin, furazolidone, chloramphenicol, and the aminoglycosides. The rapid emergence of multidrug-resistant isolates all over the world is of grave concern.12 In an antibiotic susceptibility of El Tor biotype from India, only 46% of isolates were susceptible to tetracycline, 54% to chloramphenicol, 24% to furazolidone, 30% to trimethoprim-sulfamethoxazole, and 80% to cefotaxime. The recently identified V cholerae O139 is susceptible to tetracycline but has been reported to be resistant to trimethoprim-sulfamethoxazole and furazolidone; the mechanism of resistance is due to the novel conjugative, self-transmissible, chromosomally integrating SXT element (a colinstin) that confers resistance to sulfamethoxazole, trimethoprim, chloramphenicol, and low levels of streptomycin. Quinolones generally have excellent activity against V cholerae, but fluoroquinolone-resistant strains have been reported from India. Therefore, during an outbreak, samples from representative patients should be tested for antibiotic susceptibility in order to select the most appropriate antibiotic on the basis of current sensitivity patterns. Antibiotics should not be given to asymptomatic contacts because that could increase the risk of development of resistance and is not cost-effective.

PREVENTION

Sanitation, a safe water supply, and good personal hygiene are of primary importance in controlling cholera. Clinical cholera confers effective and long-lasting immunity. Two oral cholera vaccines have been licensed for commercial use in many countries except the United States  (Table 260-1).

The rCTB-WC vaccine does not contain the A subunit toxin and, therefore, no pathogenic toxin is present. A large randomized, double-blinded, placebo controlled trial in Peru evaluated the rCTB-WC vaccine given as 2 doses following by a booster dose at 10 months.17 Protection starts 10 days after the second dose. The overall protective efficacy after 3 doses was 61%. The efficacy against severe cholera requiring hospitalization was 82%. The vaccine efficacy was 52% for children 2 to 5 years old, 46% for those 6 to 15 years old, and 72% for those older than 15 years. In a report of mass vaccination using a 2-dose regimen of rCTB-WC vaccine before cholera outbreak in Mozambique, receipt of 1 or more doses of the vaccine was associated with 78% to 84% protection.19 The vaccine was found to be equally effective in children younger than 5 years of age and in older persons. The rCTB-WC vaccine has been shown to confer moderate immunity up to 3 years in adults. Young children, however, develop immunity that lasts less than 1 year. Therefore, the booster interval is shorter for children. This vaccine is currently recommended for use in refugee settings at risk of cholera.

The live attenuated V cholerae O1 strain vaccine (Orochol) is derived from wild-type classical V cholerae O1 with 94% of the gene encoding the A subunit deleted (strain CVD 103-HgR). It has been shown to be immunogenic and safe; it is minimally excreted in the feces of the vaccinated children.20 Several research trials of adults, children, and infants have demonstrated the safety and immunogenicity of a single dose of CVD 103-HgR vaccine. A single dose provides complete protection against moderate or severe cholera caused by either El Tor or classical V cholerae O1 within 8 days of vaccination. Although protection was observed in a challenge study,21 a large field trial undertaken in Indonesia failed to demonstrate convincing protection.22 The production of this vaccine, although licensed, was stopped in 2004.