1.1 Introduction and epidemiology

1.1.1 Definition

Cholera is an acute, highly transmissible, intestinal infection caused by toxigenic bacteria Vibrio cholerae O1 and O139. In its severe form, cholera is characterized by a sudden onset of acute voluminous watery diarrhoea that can rapidly lead to dehydration and death if left untreated.

1.1.2 Frequency and distribution

Cholera cases occur in all regions of the world, but many countries, including highly endemic countries, do not report cholera cases to the World Health Organization (WHO). However, it has been estimated that 1.3 to 4 million cholera cases and 21 000 to 143 000 deaths occur every year worldwide1.

In 2015, Africa accounted for 40% of all cholera cases reported to the WHO (compared with 93% to 98% between 2001 and 2009), Asia reported 38% and the Americas 21% (principally Haiti, the Dominican Republic, and Cuba)2. The reduced proportion of African cases since 2010 is a consequence of the dramatic appearance of cholera in the Caribbean region in that year. From the onset of the outbreak in October 2010 until the end of 2016, almost 800 000 cases and over 9400 deaths have been reported3.

Latin America was hit with several large epidemics in the 1990’s. Cases reported in Europe are almost all imported.

1.1.3 Aetiological agent

Characteristics

Vibrio cholerae is a gram-negative, curved rod-shaped, motile, non-invasive bacterium. It produces a toxin which is responsible for the voluminous diarrhoea characteristic of the illness.

Vibrio cholerae can survive one to two weeks in water, several days in moist alkaline food at ambient temperature, and longer when the food is refrigerated or frozen4.
On the other hand, Vibrio cholerae does not tolerate acid or dry conditions5. Boiling water assures complete killing.
Chlorine is effective against Vibrio cholerae under the following conditions: turbidity is sufficiently low, contact time is respected, and free residual chlorine level is achieved and maintained.

Nomenclature

Vibrio cholerae strains are classified in serogroups based on differences in the O-antigen. Although many serogroups can cause individual cases of mild gastroenteritis or extra-intestinal infections, only toxin-producing strains of serogroups O1 and O139 are responsible for cholera epidemics.

Serogroup O1 is divided into 2 biotypes: classical and El Tor.
• The classical biotype is thought to be responsible for the first 6 cholera pandemics (19th and 20th centuries).
• The El Tor biotype is responsible for the current 7th pandemic (since 1961).
Both biotypes are further divided into 3 serotypes: InabaOgawa, and the rare Hikojima.

Serogroup O139 emerged in 1992 in Bangladesh, most likely evolving from O1 El Tor. This strain has remained almost exclusively within south and south-eastern Asia.

1.1.4 Transmission

Reservoirs

Aquatic environment
Vibrios are natural inhabitants of marine and freshwater aquatic environments. They survive by associating with plants, zooplankton and crustaceans and can be found in shellfish and certain fish. They are able to enter into a quiescent survival state when environmental conditions are not favourable for growth and reproduction.

Humans
During periods of active transmission, humans are the principal reservoir for the pathogen. Transmission is maintained by passage from infected individuals to others through the faecal-oral route.
The faeces of a symptomatic individual contain 107 to 108 vibrios/ml; i.e. a quantity sufficient to cause infection1 6. As an individual may produce litres of diarrhoea while ill, the load of transmissible infectious material is enormous. The shedding of bacteria typically ends within 7 to 10 days. Chronic carriers are thought to be rare.
An asymptomatic infected individual can shed vibrios in the stool in low but potentially infectious concentrations (103 to 105/ml) for several days.

Modes of transmission

Cholera is most commonly acquired from drinking water in which Vibrio cholerae is found naturally or that has been contaminated by the faeces of an infected individual.

Transmission may also occur by eating food that has come into contact with human faeces. Food may be contaminated when prepared with contaminated water or kitchen utensils, or mixed with other contaminated food, or handled by infected persons in unhygienic conditions. Low temperatures favour the survival of Vibrio cholerae in food. Foods including cold rice, raw vegetables, ice cream and fruits, have been implicated in cholera outbreaks.

Less commonly, undercooked or uncooked molluscs, shellfish and crustaceans contaminated in their natural environment have been implicated in cholera outbreaks.

Direct transmission from person-to-person (i.e. vibrios ingested via faeces-contaminated hands) is generally thought to be less common7 but can occur, particularly within households.

1.1.5 Factors favouring infection

Pathogen factors

The classical O1 biotype produces a cholera toxin that is qualitatively and quantitatively different than that of El Tor O1 biotype, with a higher proportion of infected individuals developing symptoms and severe disease, while El Tor O1 biotype tolerates a wider range of environmental conditions and is thought to persist longer in the environment.

Since the early 1990’s, a variant strain of El Tor producing the classical cholera toxin has been circulating. This strain combining the “strengths” of both biotypes emerged on the Asian subcontinent and has spread to Africa and the Caribbean. Reviews of case data from outbreaks caused by this variant have shown a higher proportion of people with severe disease compared to the original El Tor strain8.

Host factors

Specific host factors
– Patients with O blood type2  have increased susceptibility to severe cholera infection9.
– Gastric acid acts as an important barrier against cholera infection. A decrease in gastric acidity due to pre-existing pathology or concurrent use of H2 receptor blockers or proton pump inhibitors increases susceptibility to infection.
Note: food also acts as an acid buffer and facilitates the passage of vibrios through the stomach.

Immune response induced by previous infection or vaccination
Introduction of vibrios into the intestinal tract stimulates both a local and systemic immune response. This provides natural immunity3  which is limited in duration (from 6 months to several years) depending on the individual immune response.
Oral cholera vaccine induces immunity in the same manner.

In endemic areas, attack rates in infants and children are higher compared to other age groups as they have not yet developed the immunity that comes with repeated exposure. Where cholera occurs infrequently or is unknown, all age groups are equally susceptible.

1.1.6 Factors triggering epidemics

Depending on context, cholera epidemics are triggered by a variety of factors.

Cholera endemic areas

The WHO defines a cholera endemic area as an area where bacteriologically confirmed cholera cases, resulting from local transmission, have been detected in the last 3 years10.
An area can be defined as any subnational administrative unit including state, district or smaller localities.
Note: any country that contains one or more subnational administrative units that are endemic, as defined above, is considered a cholera-endemic country.

In these areas, seasonal or sporadic epidemics (or “peaks” when cholera cases persist throughout the year) can occur with some degree of predictability if the initial source of Vibrio cholerae is the aquatic reservoir. Infections typically start after periods of increased sunlight and temperature coinciding with specific water characteristics (alkalinity, salinity, temperature). These conditions promote cholera-associated plant and zooplankton growth, generating sufficient concentrations of activated bacteria to serve as an infectious source. Persons infected from this environmental source introduce the pathogen into the population and an epidemic starts.
It has also been postulated that Vibrio cholerae can be maintained in an endemic zone between seasonal outbreaks by low level transmission from asymptomatic or mildly symptomatic carriers11.

Cholera non-endemic areas

Cholera epidemics may also occur where Vibrio cholerae is not endemic. Such epidemics are initiated by the introduction of the bacteria through human activity, including importation by individuals infected elsewhere.

Seasonal factors

In some regions, epidemics occur in dry seasons. In this context, the absence of water increases the likelihood that a single contaminated water source would contaminate many people.
Elsewhere, epidemics occur in rainy seasons, where run-off can disperse contaminated faeces left by open defecation into multiple water sources.

Poor, overcrowded living conditions

In addition, the likelihood of an epidemic after the introduction of Vibrio cholerae into a population is enhanced by conditions favouring wide-spread transmission, i.e. poor living conditions (inadequate sanitation, potable water supply and hygiene) and high population density.

1.1.7 Major cholera outbreak characteristics according to context


Rural settings

Urban settings
and slums

Closed situations
(refugee camps)

Population density

Low, scattered

High

High to very high

Population number

High

High

Small

Typical attack rate*

0.1 to 2%

1 to 5%

1 to 5%

Peak reached after

1 to 3 months

2 to 8 weeks

2 to 4 weeks

Epidemic duration

3 to 6 months

2 to 4 months

1 to 3 months

Case fatality ratio**

< 5%

2 to 5%

< 2%

   Attack rates (AR) can be higher in extreme cases (e.g. Goma, Haiti).
**  Expected case fatality ratio (CFR) when treatment is available.
Source: Review of MSF programs in cholera epidemics, 1990-1997 (Epicentre)

In sparsely populated rural areas, epidemic patterns are: low AR, long duration of outbreak, late appearance of the peak and high CFR.

In urban setting, slums and refugee camps, the AR is high because population density facilitates transmission. In refugee camps, the duration of the outbreak and time to peak is shorter because the population is fixed, generally smaller, and prevention measures are usually more easily implemented. Similarly, the CFR tends to be lower because access to care is easier for the vast majority of the population.



Footnotes
Ref Notes
1

The infectious dose (i.e. the number of bacteria that need to be ingested to cause disease), ranges from 103 to 108 cells depending on mode of transmission and pathogen and host factors.

2

Individuals with O blood type are more likely to have severe symptoms if infected with O1 El Tor and O139 cholera strains. This relationship does not hold for infections with classical O1 cholera.

3

There is no cross protection between O1 and O139 infections. Infections with El Tor Inaba strain provides cross protection for subsequent infection by the Ogawa strain but Ogawa provides significantly less protection against Inaba infection.