CHOLERA

CHOLERA

Cholera can kill within hours of the onset of symptoms, and even today the impact of an outbreak of cholera can be catastrophic in locations in which the water and sanitation infrastructure are weak, especially in crisis or war situations. The 21st century has already seen large-scale cholera epidemics in Haiti, Zimbabwe, and Pakistan, as well as many smaller outbreaks in countries and areas in which cholera is endemic. When cholera is untreated, mortality can be as high as 60% to 70%, but even in epidemics, with appropriate management and well-run diarrhea treatment centers, mortality can be reduced to well below 1%.

Oral rehydration therapy (ORT) is now the mainstay of treatment (Table 1). Developed in the 1960s in Dhaka, Bangladesh, ORT was used to great effect during the Bangladesh Liberation War of 1971. Cholera broke out in the refugee camps outside Calcutta, and the medical services ran out of intravenous fluid. ORT was not accepted as routine therapy by the medical profession at that time. The courageous decision to treat people with ORT saved thousands of lives and convinced the world of the effectiveness of ORT in the management of cholera.

Table 1

Composition (mEq/L) of Common Solutions Used for Rehydration

Reprinted with permission from Harris JB, Pietroni M: Approach to the child with acute diarrhea in developing countries. UpToDate. Available at http://www.uptodate.com/contents/approach-to-the-child-with-acute-diarrhea-in-developing- countries (accessed August 11, 2016).

Abbreviations: D5 = 5% dextrose; ORS = oral rehydration solution; ReSoMal = reduced osmolarity ORS for malnourished  children.

*  Also contains Mg 6 mmol/L, Zn 300 μmol/L, Cu 45  μmol/L.

Pathophysiology

Cholera is caused by a gram-negative, comma-shaped bacterium called Vibrio cholerae. Clinical disease is caused by two serogroups: V. cholerae O1 (which has two biotypes: classical and El Tor) and V. cholerae O139. Humans are the only known natural host, and asymptomatic human carriage is rare. V. cholerae is rapidly killed by boiling water, but it can lie dormant for months in blue-green algae, crustaceans, and copepods in brackish water, especially in estuaries. The Ganges delta provides an ideal habitat and is believed to be the place cholera first emerged.

Human infection is caused by ingestion of contaminated food or drink or from poor hand hygiene in epidemic situations. Relative or absolute achlorhydria facilitates passage through the stomach.

Proliferation occurs in the small intestine, where a number of toxins are released. This results in massive secretion of isotonic fluid into the gut. The fluid passes out of the anus full of vibrios to perpetuate the cycle of transmission. Killing the host does not appear to interrupt this cycle!

The cholera toxin is secreted only by the O1 and O139 serogroups. It has two subunits: A (active) and B (binding). Subunit B binds to receptors in the small intestine and subunit A activates adenylate cyclase. This causes the active secretion of a number of ions into the gut, which drags water by osmosis and also blocks the reabsorption of sodium from the gut. The net result is a massive loss of water, sodium chloride, and bicarbonate. This cannot be replaced by drinking a sodium solution because sodium reabsorption is blocked. However, the addition of glucose to a solution of sodium activates a sodium– glucose co-transporter; sodium is absorbed and water follows by osmosis. This is the basis of oral rehydration therapy for diarrhea today.

Clinical Presentation and Diagnosis

Cholera manifests as an acute watery diarrhea without blood in the stool or (usually) abdominal cramps. The majority of cases are clinically indistinguishable from other causes of watery diarrhea and require only oral rehydration fluid as treatment. However, some progress to classic or severe cholera.

The classic picture is of the rapid onset of profuse watery diarrhea (rice-water stool) and vomiting, which is painless and can result in circulatory collapse within hours without effective treatment. The history is usually less than 24 hours, although it may be longer if the patient is taking oral rehydration solution. Abdominal cramps can occur. Fever is absent. Patients usually remain alert, but severe electrolyte abnormalities such as hypoglycemia and hyponatremia can cause a reduced level of consciousness or convulsions, especially in children. Acidosis is often severe and commonly results in tachypnea, which is commonly misdiagnosed as pneumonia. Patients should be reassessed for the presence or absence of pneumonia 1 to 2 hours after adequate rehydration. The diagnosis of cholera can be confirmed by the presence of rapidly motile vibrios detected by dark-field microscopy or by stool or rectal swab culture. However, the classic history, appearance of the stool, and rapid presentation mean that the diagnosis is usually clinical.

Treatment

A clinical syndrome of acute watery diarrhea (three or more watery stools in the last 24 hours) of short duration (24–48 hours) with or without vomiting associated with dehydration in anyone older than 2 years in an endemic or epidemic situation should be treated as cholera. Children younger than 2 years may be managed in the same way, but other diagnoses such as rotavirus should be considered. The mainstay of management (whatever the causative organism) is appropriate early rehydration, and time should not be wasted worrying about investigations or which antibiotic to use (Figure 1).

FIGURE 1    Quick identification of cholera cases can be made using  a standard case definition. During an outbreak, cholera should be suspected in any patient who is older than 2 years, is attending  a health facility, and has a history of acute watery diarrhea (passage of at least three stools in the last 24 hours) of a short duration (less than 24 hours), with or without vomiting, and with signs of dehydration. (Flow chart modified from International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) internal treatment protocol.) Abbreviation: ORS = oral rehydration solution.

The initial assessment should be brief but must:

•   Confirm the diagnosis of acute watery diarrhea

•   Assess the level of dehydration

•   Assess the presence or absence of malnutrition

•   Recognize any other comorbidities

Accurate assessment and rapid, appropriate treatment of dehydration is critical to the management of cholera. A simple scoring system based on five clinical signs is sufficient and can accurately predict patients with 5% to 10% (some) dehydration and greater than 10% (severe) dehydration. Common mistakes include overreliance on individual clinical signs and giving too little intravenous fluid during the initial phase and too much during the recovery phase. Patients with less than 5% (no) dehydration and 5% to 10% (some) dehydration can be managed with oral rehydration alone (Box 1) unless there is a reduced level of consciousness or inability to take fluids by mouth. Those with 5% to 10% (some) dehydration must be reassessed every 1 to 2 hours to make sure that hydration is improving.

Box 1  
Fluids for Patients without Signs of Dehydration
Acceptable

Oral rehydration solution (optimal for both repletion and maintenance)

Salted drinks (salted rice water or salted yogurt drink)

Broth or soup (salted vegetable or meat soup)

Water

Rice water

Coconut water (unsweetened)

Weak tea (unsweetened)

Fresh fruit juice (unsweetened)

Unacceptable

Carbonated beverages

Sweetened juices

Coffee

Medicinal teas or infusions

Fluids containing salt should be encouraged. Unacceptable fluids include carbonated beverages and sweetened juices; the sugar in these fluids may worsen diarrhea. Coffee and medicinal teas or infusions are also unacceptable since they can have diuretic and purgative effects.

Reprinted with permission from Harris JB, Pietroni M: Approach to the child with acute diarrhea in developing countries. UpToDate. Available at http://www.uptodate.com/contents/approach-to-the-child-with-acute-diarrhea-in-developing- countries (accessed August 11, 2016).

Patients with severe dehydration require an immediate intravenous fluid bolus of 100 mL/kg given over 3 hours with one third in the first 30 minutes (double the duration in children who are younger than 1 year and have malnutrition). If possible, the intravenous fluid should contain sodium, potassium, and bicarbonate—Ringer’s lactate or cholera saline—but normal saline with 5 to 10 mmol/L of potassium may also be used. Oral rehydration should start at the same time.

Once the intravenous fluid bolus has finished, further intravenous fluids are usually not required.

Patients are best managed using a cholera cot, especially in an epidemic situation. The cholera cot is a bed (or sometimes a chair) covered with a nonabsorbent sheet with a hole that allows the passage of stool and urine directly to a bucket under the bed (Figure 2). The sheets and bucket should be replaced three times a day and between patients. They may be washed, sterilized, and reused. Patients do not need to use a toilet (which can be several times an hour), linen is not soiled, and body fluids are prevented from running on the floor. This system enables adequate infection control to be maintained with limited resources.

FIGURE 2    Cholera cot.

After an initial assessment has been made and fluids started, a fuller clinical assessment can take place. Patients with significant comorbidities can require individually tailored treatment plans.

Antibiotics reduce the length of stay and fluid requirement in patients with severe dehydration due to cholera (Box 2). A single dose is sufficient, but this should be repeated if the dose is vomited back.

The choice of antibiotic should be guided by local sensitivities where these are available. If not, a single dose of azithromycin (Zithromax)1 1 g in adults and 20 mg/day for 10 days in children 6 months to 5 years old, 10 mg/day for 10 days in children under 6 months. All children between 6 months and 5 years of age should receive zinc1 20 mg/day for 10 days because this reduces subsequent mortality and further episodes of diarrhea.

Box 2  
Antibiotics in Cholera
Antibiotics should be given to all patients with severe dehydration. Choice of antibiotic depends on local sensitivity pattern.

First-Line Drug (If Susceptibility Report Is Not Available)

Adults

Azithromycin (Zithromax)1 1 g (500 mg × 2) PO as a single dose after correcting severe dehydration

Children

Azithromycin 20 mg/kg PO as a single dose after correction of dehydration and cessation of vomiting (if any)

Second-Line Drug (Not Recommended for Children < 5 Years or Pregnant Women)

Adults

Ciprofloxacin (Cipro)1 1 g (500 mg × 2) PO as a single dose after correction of severe dehydration

Children

Ciprofloxacin 20 mg/kg PO as a single dose after correction of dehydration and cessation of vomiting (if any)

Third-Line Drugs

Doxycycline (Vibramycin) 300 mg as a single dose after food (not in children or pregnant women)

1 Not FDA approved for this  indication.

Recovery from cholera is rapid, and mortality is extremely low if the dehydration is treated appropriately. The Cholera Hospital run by the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), in Dhaka treats around 120,000 patients a year. The average length of stay is 16 hours, and the mortality rate is zero.

Prevention

Because the transmission of cholera is feco-oral, cholera can be prevented by good hand hygiene and by providing safe drinking water and appropriate sanitation. Standard food and hygiene precautions should be followed by people travelling in endemic areas (e.g., eat only boiled or fried foods; drink only boiled or bottled water). The FDA recently approved a single-dose live oral cholera vaccine, called Vaxchora in the United States. Vaxchora is indicated for adults 18–64 years old who are traveling to an area of active cholera. Two other oral inactivated cholera vaccines, Dukoral and ShanChol, are not available in the U.S. These two cholera vaccines provide around 60% to 80% efficacy for 6 months. They are not recommended for the occasional traveler or tourist but may be given to people working in high-risk situations, such as aid workers in a cholera outbreak. The World Health Organization recommends the use of oral cholera vaccine in endemic areas as part of disease control programmes and maintains a global cholera vaccine stockpile for use in epidemic situations.

References

1.     Alam N.H., Ashraf H. Treatment of infectious diarrhea in children. Paediatr Drugs. 2003;5:151–165.

2.    Harris J.B., Pietroni M. Approach to the child with acute diarrhea in developing countries. UpToDate. 2012. Available at http://www.uptodate.com/contents/approach-to-the-child- with-acute-diarrhea-in-developing-countries ; 2012 [accessed 14.05.12].

3.     Roy S.K., Tomkins A.M., Akramuzzaman S.M., et al. Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhea. Arch Dis Child. 1997;77:196–200.

4.    Saha D., Karim M.M., Khan W.A., et al. Single-dose azithromycin for the treatment of cholera in adults. N Engl J Med. 2006;354:2452–2462.

5.     World Health Organization. The treatment of diarrhoea, a manual for physicians and other senior health workers. 4th revision. WHO/FCH/CAH/05.1 Geneva: World Health Organization; 2005. http://whqlibdoc.who.int/publications/2005/9241593180.pdf [accessed August 11, 2016].

1  Not FDA approved for this  indication.

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