Cholera is an acute diarrheal disease that can, in a matter of hours, result in profound, rapidly progressive dehydration and death. Accordingly, cholera gravis (the severe form) is a much-feared disease, particularly in its epidemic presentation. Fortunately, prompt aggressive fluid repletion and supportive care can obviate the high mortality that is historically associated with cholera. Although the term cholera has occasionally been applied to any severely dehydrating secretory diarrheal illness, whether infectious in etiology or not, it now refers to disease caused by V. cholerae serogroup O1 or O139—i.e., the serogroups with epidemic potential.
MICROBIOLOGY AND EPIDEMIOLOGY
The species V. cholerae is classified into >200 serogroups based on the carbohydrate determinants of their lipopolysaccharide (LPS) O antigens. Although some non-O1 V. cholerae serogroups (strains that do not agglutinate in antisera to the O1 group antigen) have occasionally caused sporadic outbreaks of diarrhea, serogroup O1 was, until the emergence of serogroup O139 in 1992 (see below), the exclusive cause of epidemic cholera. Two biotypes of V. cholerae O1, classical and El Tor, are distinguished. Each biotype is further subdivided into two serotypes, termed Inaba and Ogawa.
The natural habitat of V. cholerae is coastal salt water and brackish estuaries, where the organism lives in close relation to plankton. V. cholerae can also exist in freshwater in the presence of adequate nutrients and warmth. Humans become infected incidentally but, once infected, can act as vehicles for spread. Ingestion of water contaminated by human feces is the most common means of acquisition of V. cholerae. Consumption of contaminated food also can contribute to spread. There is no known animal reservoir. Although the infectious dose is relatively high, it is markedly reduced in hypochlorhydric persons, in those using antacids, and when gastric acidity is buffered by a meal. Cholera is predominantly a pediatric disease in endemic areas, but it affects adults and children equally when newly introduced into a population. In endemic areas, the burden of disease is often greatest during “cholera seasons” associated with high temperatures, heavy rainfall, and flooding, but cholera can occur year-round. For unexplained reasons, susceptibility to cholera is significantly influenced by ABO blood group status; persons with type O blood are at greatest risk of severe disease if infected, whereas those with type AB are at least risk.
Cholera is native to the Ganges delta on the Indian subcontinent. Since 1817, seven global pandemics have occurred. The current (seventh) pandemic—the first due to the El Tor biotype—began in Indonesia in 1961 and spread in serial waves throughout Asia as V. cholerae El Tor displaced the endemic classical biotype, which is thought to have caused the previous six pandemics. In the early 1970s, El Tor cholera erupted in Africa, causing major epidemics before becoming a persistent endemic problem. Currently, >40% of cholera cases reported annually to the World Health Organization (WHO) are from Africa, >35% are from Asia, and >20% are from the Americas (Fig. 163-1), but the true burden and distribution of cholera are unknown because the diagnosis is often syndromic and because many countries with endemic cholera do not report cholera to the WHO. It is possible that >2–3 million cases of cholera occur yearly (of which only ~200,000 are reported to the WHO) and that these cases result in >50,000–100,000 deaths annually (of which <2000 are reported to the WHO).
World distribution of cholera in 2013–2015. WHO, World Health Organization. (Courtesy of Drs. M. and R. Piarroux, Université de la Méditerranée, France, with permission; map generated with Philcarto [http://philcarto.free.fr].)
After a century without cholera in Latin America, the current cholera pandemic reached Central and South America in 1991. Following an initial explosive spread that affected millions, the burden of disease has markedly decreased in Latin America. In 2010, a severe cholera outbreak began in Haiti, a country with no recorded history of this disease. Several lines of evidence indicate that cholera was likely introduced into Haiti by United Nations security forces from Asia, raising the possibility that asymptomatic carriers of V. cholerae play an important role in transmitting cholera over long distances. To date, the outbreak has involved >800,000 individuals, resulting in thousands of deaths. The recent history of cholera has been punctuated by such severe outbreaks, especially among impoverished or displaced persons. These outbreaks are often precipitated by war or other circumstances that lead to the breakdown of public health measures. Such was the case in the camps for Rwandan refugees set up in 1994 around Goma, Zaire; in 2008–2009 in Zimbabwe; in 2015 in South Sudan and the Democratic Republic of the Congo; and in 2017 in Yemen.
Sporadic endemic infections due to V. cholerae O1 strains related to the seventh-pandemic strain have been recognized along the U.S. Gulf Coast of Louisiana and Texas. These infections are typically associated with the consumption of contaminated, locally harvested shellfish. Occasionally, cases in U.S. locations remote from the Gulf Coast have been linked to shipped-in Gulf Coast seafood.
In October 1992, a large-scale outbreak of clinical cholera caused by a new serogroup, O139, occurred in southeastern India. The organism appears to be a derivative of El Tor O1 but has a distinct LPS and an immunologically related O-antigen polysaccharide capsule. (O1 organisms are not encapsulated.) After an initial spread across 11 Asian countries, V. cholerae O139 has once again been almost entirely replaced by O1 strains. The clinical manifestations of disease caused by V. cholerae O139 are indistinguishable from those of O1 cholera. Immunity to one, however, is not protective against the other.
In the final analysis, cholera is a toxin-mediated disease. The watery diarrhea characteristic of cholera is due to the action of cholera toxin, a potent protein enterotoxin elaborated by the organism in the small intestine. The toxin-coregulated pilus (TCP), so named because its synthesis is regulated in parallel with that of cholera toxin, is essential for V. cholerae to survive and multiply in (colonize) the small intestine. Cholera toxin, TCP, and several other virulence factors are coordinately regulated by ToxR. This protein modulates the expression of genes coding for virulence factors in response to environmental signals via a cascade of regulatory proteins. Additional regulatory processes, including bacterial responses to the density of the bacterial population (in a phenomenon known as quorum sensing), modulate the virulence of V. cholerae.
Once established in the human small bowel, the organism produces cholera toxin, which consists of a monomeric enzymatic moiety (the A subunit) and a pentameric binding moiety (the B subunit). The B pentamer binds to GM1 ganglioside, a glycolipid on the surface of epithelial cells that serves as the toxin receptor and makes possible the delivery of the A subunit to its cytosolic target. The activated A subunit (A1) irreversibly transfers ADP-ribose from nicotinamide adenine dinucleotide to its specific target protein, the GTP-binding regulatory component of adenylate cyclase. The ADP-ribosylated G protein upregulates the activity of adenylate cyclase; the result is the intracellular accumulation of high levels of cyclic adenosine monophosphate (AMP). In intestinal epithelial cells, cyclic AMP inhibits the absorptive sodium-transport system in villus cells and activates the secretory chloride-transport system in crypt cells, and these events lead to the accumulation of sodium chloride in the intestinal lumen. Because water moves passively to maintain osmolality, isotonic fluid accumulates in the lumen. When the volume of that fluid exceeds the capacity of the rest of the gut to resorb it, watery diarrhea results. Unless the wasted fluid and electrolytes are adequately replaced, shock (due to profound dehydration) and acidosis (due to loss of bicarbonate) follow. Although perturbation of the adenylate cyclase pathway is the primary mechanism by which cholera toxin causes excess fluid secretion, cholera toxin also enhances intestinal secretion via prostaglandins and/or neural histamine receptors.
The V. cholerae genome comprises two circular chromosomes. Lateral gene transfer has played a key role in the evolution of epidemic V. cholerae. The genes encoding cholera toxin (ctxAB) are part of the genome of a bacteriophage, CTXΦ. The receptor for this phage on the V. cholerae surface is the intestinal colonization factor TCP. Because ctxAB is part of a mobile genetic element (CTXΦ), horizontal transfer of this bacteriophage may account for the emergence of new toxigenic V. cholerae serogroups. Many of the other genes important for V. cholerae pathogenicity, including the genes encoding the biosynthesis of TCP, those encoding accessory colonization factors, and those regulating virulence gene expression, are clustered together in the V. cholerae pathogenicity island. Similar clustering of virulence genes is found in other bacterial pathogens. It is believed that pathogenicity islands are acquired by horizontal gene transfer. V. cholerae O139 is probably derived from an El Tor O1 strain that acquired the genes for O139 O-antigen synthesis by horizontal gene transfer.
Individuals infected with V. cholerae O1 or O139 exhibit a range of clinical manifestations. Some individuals are asymptomatic or have only mild diarrhea; others present with the sudden onset of explosive and life-threatening diarrhea (cholera gravis). The reasons for the range in signs and symptoms of disease are incompletely understood but include the level of preexisting immunity, blood type, and nutritional status. In a nonimmune individual, after a 24- to 48-h incubation period, cholera characteristically begins with the sudden onset of painless watery diarrhea that may quickly become voluminous. Patients often vomit. In severe cases, volume loss can exceed 250 mL/kg in the first 24 h. If fluids and electrolytes are not replaced, hypovolemic shock and death may ensue. Fever is usually absent. Muscle cramps due to electrolyte disturbances are common. The stool has a characteristic appearance: a nonbilious, gray, slightly cloudy fluid with flecks of mucus, no blood, and a somewhat fishy, inoffensive odor. It has been called “rice-water” stool because of its resemblance to the water in which rice has been washed (Fig. 163-2). Clinical symptoms parallel volume contraction: at losses of <5% of normal body weight, thirst develops; at 5–10%, postural hypotension, weakness, tachycardia, and decreased skin turgor are documented; and at >10%, oliguria, weak or absent pulses, sunken eyes (and, in infants, sunken fontanelles), wrinkled (“washerwoman”) skin, somnolence, and coma are characteristic. Complications derive exclusively from the effects of volume and electrolyte depletion and include renal failure due to acute tubular necrosis. Thus, if the patient is adequately treated with fluid and electrolytes, complications are averted and the process is self-limited, resolving in a few days.
Rice-water cholera stool. Note floating mucus and gray watery appearance. (Courtesy of Dr. A. S. G. Faruque, International Centre for Diarrhoeal Disease Research, Dhaka; with permission.)
Laboratory data usually reveal an elevated hematocrit (due to hemoconcentration) in nonanemic patients; mild neutrophilic leukocytosis; elevated levels of blood urea nitrogen and creatinine consistent with prerenal azotemia; normal sodium, potassium, and chloride levels; a markedly reduced bicarbonate level (<15 mmol/L); and an elevated anion gap (due to increases in serum lactate, protein, and phosphate). Arterial pH is usually low (~7.2).
Cholera should be suspected when a patient ≥5 years of age develops acute watery diarrhea in an area known to have cholera or develops severe dehydration or dies from acute watery diarrhea, even in an area where cholera is not known to be present. The clinical suspicion of cholera can be confirmed by the identification of V. cholerae in stool; however, the organism must be specifically sought. With experience, it can be detected directly by dark-field microscopy on a wet mount of fresh stool, and its serotype can be discerned by immobilization with specific antiserum. Laboratory isolation of the organism requires the use of a selective medium such as taurocholate–tellurite–gelatin (TTG) agar or thiosulfate–citrate–bile salts–sucrose (TCBS) agar. If a delay in sample processing is expected, Carey-Blair transport medium and/or alkaline-peptone water-enrichment medium may be used as well. In endemic areas, there is little need for biochemical confirmation and characterization, although these tasks may be worthwhile in places where V. cholerae is an uncommon isolate. Standard microbiologic biochemical testing for Enterobacteriaceae will suffice for identification of V. cholerae. All vibrios are oxidase-positive. A point-of-care antigen-detection cholera dipstick assay is now commercially available for use in the field or where laboratory facilities are lacking.
Death from cholera is due to hypovolemic shock; thus treatment of individuals with cholera first and foremost requires fluid resuscitation and management. In light of the level of dehydration (Table 163-1) and the patient’s age and weight, euvolemia should first be rapidly restored, and adequate hydration should then be maintained to replace ongoing fluid losses (Table 163-2). Administration of oral rehydration solution (ORS) takes advantage of the hexose-Na+ co-transport mechanism to move Na+ across the gut mucosa together with an actively transported molecule such as glucose (or galactose). Cl– and water follow. This transport mechanism remains intact even when cholera toxin is active. ORS may be made by adding safe water to prepackaged sachets containing salts and sugar or by adding 0.5 teaspoon (i.e., a small spoonful) of table salt and 6 level teaspoons (i.e., 6 small spoonfuls) of table sugar to 1 L of safe water. Potassium intake in bananas or green coconut water should be encouraged. A number of ORS formulations are available, and the WHO now recommends “low-osmolarity” ORS for treatment of individuals with dehydrating diarrhea of any cause (Table 163-3). If available, rice-based ORS is considered superior to standard ORS in the treatment of cholera. ORS can be administered via a nasogastric tube to individuals who cannot ingest fluid; however, optimal management of individuals with severe dehydration includes the administration of IV fluid and electrolytes. Because profound acidosis (pH <7.2) is common in this group, Ringer’s lactate is the best choice among commercial products (Table 163-4); it must be used with additional potassium supplements, preferably given by mouth. The total fluid deficit in severely dehydrated patients (>10% of body weight) can be replaced safely within the first 3–4 h of therapy, half within the first hour. Transient muscle cramps and tetany are common. Thereafter, oral therapy can usually be initiated, with the goal of maintaining fluid intake equal to fluid output. However, patients with continued large-volume diarrhea may require prolonged IV treatment to match gastrointestinal fluid losses. Severe hypokalemia can develop but will respond to potassium given either IV or orally. In the absence of adequate staff to monitor the patient’s progress, the oral route of rehydration and potassium replacement is safer than the IV route.
Although not necessary for cure, the use of an antibiotic to which the organism is susceptible diminishes the duration and volume of fluid loss and hastens clearance of the organism from the stool. Adjunctive antibiotics should therefore be administered to patients with moderate or severe dehydration due to cholera. In many areas, macrolides such as erythromycin (adults, 250 mg orally four times a day for 3 days; children, 12.5 mg/kg per dose four times a day for 3 days) or azithromycin (adults, a single 1-g dose; children, a single 20-mg/kg dose) are the agents of choice. Increasing resistance to tetracyclines is widespread; however, in areas with confirmed susceptibility, tetracycline (nonpregnant adults, 500 mg orally four times a day for 3 days; children >8 years old, 12.5 mg/kg per dose four times a day for 3 days) or doxycycline (nonpregnant adults, a 300-mg single dose; children >8 years old, a single dose of 4–6 mg/kg) may be used. Similarly, increasing resistance to fluoroquinolones is being reported, but in areas with confirmed susceptibility, a fluoroquinolone such as ciprofloxacin may be used (adults, 500 mg twice a day for 3 days; children, 15 mg/kg twice a day for 3 days). Oral administration of supplemental zinc is associated with decreased volume and severity of diarrhea in young children, including in those with cholera. Children <6 months of age with cholera should be treated with 10 mg of zinc daily for 10 days; children from 6 to <60 months of age should be treated with 20 mg of oral zinc daily for 10 days.
TABLE 163-1Assessing the Degree of Dehydration in Patientswith Cholera ||Download (.pdf) TABLE 163-1 Assessing the Degree of Dehydration in Patientswith Cholera
|Degree of Dehydration ||Clinical Findings |
|None or mild, but diarrhea ||Thirst in some cases; <5% loss of total body weight |
|Moderate ||Thirst, postural hypotension, weakness, tachycardia, decreased skin turgor, dry mouth/tongue, no tears; 5–10% loss of total body weight |
|Severe ||Unconsciousness, lethargy, or “floppiness”; weak or absent pulse; inability to drink; sunken eyes (and, in infants, sunken fontanelles); >10% loss of total body weight |
TABLE 163-2Treatment of Cholera, Based on Degree of Dehydrationa ||Download (.pdf) TABLE 163-2 Treatment of Cholera, Based on Degree of Dehydrationa
|Degree of Dehydration, Patient’s Age (Weight) ||Treatmentb |
|None or Mild, but Diarrheac |
|<2 years ||1/4–1/2 cup (50–100 mL) of ORS, to a maximum of 0.5 L/d |
|2–9 years ||1/2–1 cup (100–200 mL) of ORS, to a maximum of 1 L/d |
|≥10 years ||As much ORS as desired, to a maximum of 2 L/d |
|<4 months (<5 kg) ||200–400 mL of ORS |
|4–11 months (5–<8 kg) ||400–600 mL of ORS |
|12–23 months (8–<11 kg) ||600–800 mL of ORS |
|2–4 years (11–<16 kg) ||800–1200 mL of ORS |
|5–14 years (16–<30 kg) ||1200–2200 mL of ORS |
|≥15 years (≥30 kg) ||2200–4000 mL of ORS |
|All ages and weights ||Undertake IV fluid replacement with Ringer’s lactate (or, if not available, normal saline). Give 100 mL/kg in the first 3-h period (or the first 6-h period for children <12 months old); start rapidly, then slow down. Give a total of 200 mL/kg in the first 24 h. Continue until the patient is awake, can ingest ORS, and no longer has a weak pulse. |
TABLE 163-3Composition of World Health Organization Reduced-Osmolarity Oral Rehydration Solution (ORS)a,b ||Download (.pdf) TABLE 163-3 Composition of World Health Organization Reduced-Osmolarity Oral Rehydration Solution (ORS)a,b
|Constituent ||Concentration, mmol/L |
|Na+ ||75 |
|K+ ||20 |
|Cl− ||65 |
|Citratec ||10 |
|Glucose ||75 |
|Total osmolarity ||245 |
TABLE 163-4Electrolyte Composition of Cholera Stool and of Intravenous Rehydration Solution ||Download (.pdf) TABLE 163-4 Electrolyte Composition of Cholera Stool and of Intravenous Rehydration Solution
|Substance ||Concentration, mmol/L |
|Na+ ||K+ ||Cl− ||Base |
|Stool || || || || |
| Adult ||135 ||15 ||100 ||45 |
| Child ||100 ||25 ||90 ||30 |
|Ringer’s lactate ||130 ||4a ||109 ||28 |
Provision of safe water and of facilities for sanitary disposal of feces, improved nutrition, and attention to food preparation and storage in the household can significantly reduce the incidence of cholera. In addition, precautions should be taken to prevent the spread of cholera via infected and potentially asymptomatic persons from endemic to nonendemic regions of the world (as was probably the case in the ongoing outbreak in Haiti; see “Microbiology and Epidemiology,” above).
Much effort has been devoted to the development of an effective cholera vaccine over the past few decades, with a particular focus on oral vaccine strains. In an attempt to maximize mucosal responses, two types of oral cholera vaccine have been developed: oral killed vaccines and live attenuated vaccines. Currently, three oral killed cholera vaccines have been prequalified by the WHO and are available internationally. BivWC (Shanchol™; Shantha Biotechnics, Hyderabad, India) contains several biotypes and serotypes of V. cholerae O1 and V. cholerae O139 without supplemental cholera toxin B subunit. A related vaccine is produced in South Korea (Euvichol™; Eubiologics, Seoul). WC-rBS (Dukoral®; Valneva, Lyon, France) contains several biotypes and serotypes of V. cholerae O1 supplemented with 1 mg of recombinant cholera toxin B subunit per dose. The vaccines are administered as a two- or three-dose regimen, with doses usually separated by 14 days. They provide ~60–85% protection for the first few months. Booster immunizations of WC-rBS are recommended after 2 years for individuals ≥6 years of age and after 6 months for children 2–5 years of age. For BivWC, which was developed more recently, no formal recommendation regarding booster immunizations exists. However, BivWC was associated with ~60% protection over 5 years among recipients of all ages in a study in Kolkata, India; the rate of protection among children ≤5 years of age approximated 40%. Models predict significant herd immunity when vaccination coverage rates exceed 50%. The killed vaccines have been safely administered among populations with high rates of HIV infection.
Oral live attenuated vaccines for V. cholerae O1 are also in development. These strains have in common their lack of the genes encoding cholera toxin. One such vaccine, CVD 103-HgR (Vaxchora™; PaxVax, Redwood City, CA), was approved in 2016 by the U.S. Food and Drug Administration for use in travelers to cholera-endemic regions. The vaccine was 90 and 80% efficacious against severe cholera after experimental infection of North American volunteers 10 days and 90 days after vaccination, respectively. Vaxchora is approved for use in adults 18–64 years of age; no recommendations concerning the timing or need for booster vaccinations are currently available. Other live attenuated vaccine candidate strains have been prepared from El Tor and O139 V. cholerae and have been tested in studies of volunteers. An advantage of live attenuated cholera vaccines is that they may induce protection after a single oral dose; evaluation of single-dose regimens of oral killed cholera vaccines is underway. Conjugate and subunit cholera vaccines are also being developed. Recognizing that it may be decades before safe water and adequate sanitation become a reality for those most at risk of cholera, the WHO has recommended incorporation of cholera vaccination into comprehensive control strategies and has established an international stockpile of oral killed cholera vaccine to assist in outbreak responses. One million doses of oral killed cholera vaccine were released from this stockpile for use in Haiti following Hurricane Matthew in 2016. Since its inception in 2017, more than 5 million doses of oral cholera vaccine have been released from the global stockpile.