CholeraCholera

Rose Lee and Ricardo Lé

January 14, 2008

Rose Lee and Ricardo Lé

January 14, 2008

Cholera: The IllnessCholera: The Illness

Clinical Features

Acute diarrhoeal infectionDiarrhoea leads to death by

dehydration and kidney failure (stool output can reach 0.5-1L/hour) - hypotension, tachycardia, and vascular collapse

Clinical Features

Acute diarrhoeal infectionDiarrhoea leads to death by

dehydration and kidney failure (stool output can reach 0.5-1L/hour) - hypotension, tachycardia, and vascular collapse

Short incubation period (2 hours to 5 days)

75% of those infected do not develop symptoms

100-1000 organisms may cause disease, although a million are needed to consistently infect

Short incubation period (2 hours to 5 days)

75% of those infected do not develop symptoms

100-1000 organisms may cause disease, although a million are needed to consistently infect

TransmissionTransmission

Direct fecal-oral contamination or ingestion of contaminated water and food

Linked to inadequate environmental management (lack of safe water and sufficient sanitation)

Human-Human contact does not spread the bacterium

Direct fecal-oral contamination or ingestion of contaminated water and food

Linked to inadequate environmental management (lack of safe water and sufficient sanitation)

Human-Human contact does not spread the bacterium

TreatmentTreatment

Up to 80% of cases can be treated through oral rehydration salts

Severe cases require intravenous fluids (Ringer lactate)

Antibiotics can diminish duration of diarrhoea, reduce volume of rehydation fluids needed, and shorten duration of V.cholerae excretion

Up to 80% of cases can be treated through oral rehydration salts

Severe cases require intravenous fluids (Ringer lactate)

Antibiotics can diminish duration of diarrhoea, reduce volume of rehydation fluids needed, and shorten duration of V.cholerae excretion

Parenteral VaccineParenteral Vaccine

2 doses administered 2 weeks apart Efficacy of approximately 50% Protection hardly exceeds 6 months Does not prevent transmission of

infectious agent Not recommended for general public

health use

2 doses administered 2 weeks apart Efficacy of approximately 50% Protection hardly exceeds 6 months Does not prevent transmission of

infectious agent Not recommended for general public

health use

Killed WC/rBS VaccineKilled WC/rBS Vaccine

Killed whole-cell V.cholerae in combination with a recombinant B-subunit of cholera toxin

Safe in pregnancy and breastfeeding Efficacy of approximately 50% after 3

years Only significant side-effects are mild

gastrointestinal disturbances, and toleration is great for HIV-positive subjects

Killed whole-cell V.cholerae in combination with a recombinant B-subunit of cholera toxin

Safe in pregnancy and breastfeeding Efficacy of approximately 50% after 3

years Only significant side-effects are mild

gastrointestinal disturbances, and toleration is great for HIV-positive subjects

Live, attenuated CVD 103-HgR Vaccine

Live, attenuated CVD 103-HgR Vaccine

Protection as early as 1 week after vaccination, with >90% protection against moderate or severe cases

Protection lasts at least 6 months, further data is unknown

Unknown efficacy for children under 2

No adverse side-effects

Protection as early as 1 week after vaccination, with >90% protection against moderate or severe cases

Protection lasts at least 6 months, further data is unknown

Unknown efficacy for children under 2

No adverse side-effects

Major Issues in VaccinesMajor Issues in Vaccines

Preventative (other measures)Parenteral: low efficacy, short

durationWC/rBS: 2 doses (logistics)CVD 103-HgR: Long term results? Inefficient for O139 or children <2Need more tests and trials.

Preventative (other measures)Parenteral: low efficacy, short

durationWC/rBS: 2 doses (logistics)CVD 103-HgR: Long term results? Inefficient for O139 or children <2Need more tests and trials.

PreventionPrevention

Basic health education and hygieneMass chemoprophylaxisProvision of safe water and

sanitationComprehensive Multidisciplinary

Approach: water, sanitation, education, and communication

Basic health education and hygieneMass chemoprophylaxisProvision of safe water and

sanitationComprehensive Multidisciplinary

Approach: water, sanitation, education, and communication

Control of SpreadControl of Spread

Set up treatment centres for prompt treatment.

Sanitary measures.Comprehensive surveillance data

(adapt to each situation) for a comprehensive multidisciplinary approach.

Set up treatment centres for prompt treatment.

Sanitary measures.Comprehensive surveillance data

(adapt to each situation) for a comprehensive multidisciplinary approach.

Vibrio CholeraeVibrio Cholerae

The Organism

Type of BacteriumType of Bacterium

Gram negative (LPS cell wall)Type of GammaproteobacteriaDistinguishing factors: Oxidase-

positive, motile via polar flagellum, and both respiratory and fermentative metabolism.

Simple growth requirements

Gram negative (LPS cell wall)Type of GammaproteobacteriaDistinguishing factors: Oxidase-

positive, motile via polar flagellum, and both respiratory and fermentative metabolism.

Simple growth requirements

History of CholeraHistory of CholeraFirst observed in India then S. AsiaDiscovered conclusively in 1883 by

KochSpread to Europe and Americas from

1817. 6 epidemics by 1990s.7th epidemic in 1961 of El Tor biotypeSpread across Asia, Middle East,

Africa, and parts of Europe

First observed in India then S. AsiaDiscovered conclusively in 1883 by

KochSpread to Europe and Americas from

1817. 6 epidemics by 1990s.7th epidemic in 1961 of El Tor biotypeSpread across Asia, Middle East,

Africa, and parts of Europe

Some Definitions:

Strain: Subset of a bacteria differing from same species.

Biotype: Same genotype, but different phenotype.

Serotype: Closely related microorganisms distinguished by a characteristic set of antigens.

Some Definitions:

Strain: Subset of a bacteria differing from same species.

Biotype: Same genotype, but different phenotype.

Serotype: Closely related microorganisms distinguished by a characteristic set of antigens.

Many strains of Vibio cholerae.

O antigens distinguish 139 serotypes: O1 (3 biotypes—each has “classical” or El Tor phenotype), O139 Bengal.

O139 is a new serological strain with unique O-antigen (no residual immunity from O1)

Many strains of Vibio cholerae.

O antigens distinguish 139 serotypes: O1 (3 biotypes—each has “classical” or El Tor phenotype), O139 Bengal.

O139 is a new serological strain with unique O-antigen (no residual immunity from O1)

DifferencesDifferences

El Tor strain is more virulent (replacing classical): Lower ratio of cases to carriers Longer duration of carriage after Survives longer in extraintestinal env

O139 Bengal (derived from El Tor)

Different antigenic structure on LPS Distinct polysaccharide capsule Possess all El Tor virulence

El Tor strain is more virulent (replacing classical): Lower ratio of cases to carriers Longer duration of carriage after Survives longer in extraintestinal env

O139 Bengal (derived from El Tor)

Different antigenic structure on LPS Distinct polysaccharide capsule Possess all El Tor virulence

Virulence FactorsVirulence Factors

Cholera toxinTcp pili

Aggregation, adhesion

Flagellum withstand propulsive gut

Resistant to bile salts in intestines If escapes low pH of stomach, easy to survive in

intestines

Cholera toxinTcp pili

Aggregation, adhesion

Flagellum withstand propulsive gut

Resistant to bile salts in intestines If escapes low pH of stomach, easy to survive in

intestines

Cholera toxinCholera toxin

Potent exotoxin multimeric protein complex of five binding

subunits (B) and one enzymatic (A) subunit.

B subunits bind to intestinal epithelia cell and A1 subunit enter cell and activates adenylate cyclase enzyme.

Potent exotoxin multimeric protein complex of five binding

subunits (B) and one enzymatic (A) subunit.

B subunits bind to intestinal epithelia cell and A1 subunit enter cell and activates adenylate cyclase enzyme.

A1 catalyzes ADP-Ribose attachment to Gs Gi cannot hydrolyze GTP to inactivate adenylate cyclase.

cAMP produced at high rate. Triggers Cl- into intestines. H2O, Na+, bicarbonate, and other electrolytes follow

A1 catalyzes ADP-Ribose attachment to Gs Gi cannot hydrolyze GTP to inactivate adenylate cyclase.

cAMP produced at high rate. Triggers Cl- into intestines. H2O, Na+, bicarbonate, and other electrolytes follow

ColonizationColonization

AdhesinsTcp pili, hemagglutinin, acf gene

productsNeuraminidaseMotilityChemotaxisToxin production

AdhesinsTcp pili, hemagglutinin, acf gene

productsNeuraminidaseMotilityChemotaxisToxin production

RegulationRegulation

Enterotoxin is a product of ctx genes regulated by transcription

Environmental signals-Temperature, pH, osmolarity, amino acids

ToxR regulatory protein activated-Induces positive control, binds to DNA

Genes for attachment and toxin production transcribed

Enterotoxin is a product of ctx genes regulated by transcription

Environmental signals-Temperature, pH, osmolarity, amino acids

ToxR regulatory protein activated-Induces positive control, binds to DNA

Genes for attachment and toxin production transcribed

EcologyEcology

Can exist in dormant stateConversion to infectious state:

-increase Temp, pH, nutrients.-decrease salinity

Can shift to “rugose form”: exopolysaccharide production for cell aggregation, resists chlorine

Can exist in dormant stateConversion to infectious state:

-increase Temp, pH, nutrients.-decrease salinity

Can shift to “rugose form”: exopolysaccharide production for cell aggregation, resists chlorine

On our mission we came across a village in rural Bangladesh. It is very small but very crowded with poor water sanitation and irrigation systems.

Its position is dangerously close to the urban slums that have had cholera outbreaks within the past few months. Luckily, there has been no reported cases of cholera so far within the last 6 months… but now we have some decisions to make.

On our mission we came across a village in rural Bangladesh. It is very small but very crowded with poor water sanitation and irrigation systems.

Its position is dangerously close to the urban slums that have had cholera outbreaks within the past few months. Luckily, there has been no reported cases of cholera so far within the last 6 months… but now we have some decisions to make.

Discussion Question 1Discussion Question 1

What is our plan of action in regards to this village?

- Where should the emphasis be placed on protecting a population before an outbreak occurs? Vaccination or sanitation?

- What are the pros and cons of each?

What is our plan of action in regards to this village?

- Where should the emphasis be placed on protecting a population before an outbreak occurs? Vaccination or sanitation?

- What are the pros and cons of each?

Discussion Question 2Discussion Question 2

Unfortunately, while the members were debating, an outbreak occurred in this village. What is the plan now?

-What is the best hybrid solution for controlling a cholera outbreak? You have short time and limited resources.

Unfortunately, while the members were debating, an outbreak occurred in this village. What is the plan now?

-What is the best hybrid solution for controlling a cholera outbreak? You have short time and limited resources.

Discussion Question 3Discussion Question 3

The outbreak has been controlled for the moment. What should be the long-term plan for this population?

The outbreak has been controlled for the moment. What should be the long-term plan for this population?

Discussion Question 4Discussion Question 4

What are your sentiments and policies regarding cholera around the world? How do you feel about the importance each of these as aspects?

Scientific Lab Research Field Work Infrastructure of Sanitation Education

What are your sentiments and policies regarding cholera around the world? How do you feel about the importance each of these as aspects?

Scientific Lab Research Field Work Infrastructure of Sanitation Education