Cholera
From Wikipedia, the free encyclopedia
Cholera is an
infection in the small intestine caused by the bacterium Vibrio
cholerae. The main symptoms are watery diarrhea and vomiting.
Transmission occurs primarily by drinking water or eating food that has been
contaminated by the feces
(waste product) of an infected person, including one with no apparent symptoms.
The severity of the diarrhea and vomiting can lead to rapid dehydration
and electrolyte
imbalance, and death in some cases. The primary treatment is oral rehydration therapy, typically with oral rehydration solution, to replace
water and electrolytes. If this is not tolerated or does not provide
improvement fast enough, intravenous fluids can also be used. Antibacterial
drugs are beneficial in those with severe disease to shorten its duration and
severity. Worldwide, it affects 3–5 million people and causes 100,000–130,000
deaths a year as of 2010.
Cholera was one of the earliest infections to be studied by epidemiological
methods.
Signs and symptoms
The primary
symptoms of cholera are profuse, painless diarrhea and vomiting of
clear fluid.[1]
These symptoms usually start suddenly, one to five days after ingestion of the
bacteria.[1]
The diarrhea is frequently described as "rice water" in nature and
may have a fishy odor.[1]
An untreated person with cholera may produce 10 to 20 litres (3 to 5 US gal) of
diarrhea a day[1]
with fatal results. For every symptomatic person, 3 to 100 people get the
infection but remain asymptomatic.[2]
Cholera has been nicknamed the "blue death" due to a patient's skin
turning a bluish-gray hue from extreme loss of fluids.[3]
If the severe
diarrhea is not treated with intravenous rehydration, it can result in
life-threatening dehydration and electrolyte imbalances.[1]
The typical symptoms of dehydration include low blood
pressure, poor skin turgor (wrinkled hands), sunken eyes, and a rapid
pulse.[1]
Cause
Main article: Vibrio
cholerae
Transmission is
primarily by the fecal contamination of food and water caused by poor sanitation.[4]
This bacterium can, however, live naturally in any environment.[5]
Susceptibility
About 100
million bacteria must typically be ingested to cause cholera in a normal
healthy adult.[1]
This dose, however, is less in those with lowered gastric
acidity (for instance those using proton pump inhibitors).[1]
Children are also more susceptible, with two- to four-year-olds having the
highest rates of infection.[1]
Individuals' susceptibility to cholera is also affected by their blood type,
with those with type O blood being the most susceptible.[1][6]
Persons with lowered immunity, such as persons with AIDS or children who are
malnourished, are more likely to experience a severe case if they become
infected.[7]
However, it should be noted that any individual, even a healthy adult in middle
age, can experience a severe case, and each person's case should be measured by
the loss of fluids, preferably in consultation with a doctor or other health
worker.
The cystic
fibrosis genetic mutation in humans has been said to maintain a selective
advantage: heterozygous carriers of the mutation (who are thus not
affected by cystic fibrosis) are more resistant to V. cholerae
infections.[8]
In this model, the genetic deficiency in the cystic fibrosis
transmembrane conductance regulator channel proteins interferes with
bacteria binding to the gastrointestinal epithelium, thus reducing the
effects of an infection.
Transmission
Cholera is
typically transmitted by either contaminated food or water. In the developed
world, seafood is the usual cause, while in the developing world it is more
often water.[1]
Cholera has been found in only two other animal populations: shellfish and
plankton.[1]
People infected
with cholera often have diarrhea, and if this highly liquid stool, colloquially
referred to as "rice-water", contaminates water used by others,
disease transmission may occur.[9]
The source of the contamination is typically other cholera sufferers when their
untreated diarrheal discharge is allowed to get into waterways, groundwater
or drinking water supplies. Drinking any infected water and eating any foods
washed in the water, as well as shellfish living in the affected waterway, can
cause a person to contract an infection. Cholera is rarely spread directly from
person to person. Both toxic and nontoxic strains exist. Nontoxic strains can
acquire toxicity through a temperate bacteriophage.[10]
Coastal cholera outbreaks typically follow zooplankton
blooms, thus making cholera a zoonotic
disease.
Mechanism
When consumed,
most bacteria do not survive the acidic conditions of the human stomach.[11]
The few surviving bacteria conserve their energy and stored
nutrients during the passage through the stomach by shutting down much
protein production. When the surviving bacteria exit the stomach and reach the small
intestine, they need to propel themselves through the thick mucus
that lines the small intestine to get to the intestinal walls where they can
thrive. V. cholerae bacteria start up production of the hollow
cylindrical protein flagellin to make flagella, the
cork-screw helical fibers they rotate to propel themselves through the mucus of
the small intestine.
Once the
cholera bacteria reach the intestinal wall they no longer need the flagella to
move. The bacteria stop producing the protein flagellin to conserve energy and
nutrients by changing the mix of proteins which they express in response to the
changed chemical surroundings. On reaching the intestinal wall, V. cholerae
start producing the toxic proteins that give the infected person a watery
diarrhea. This carries the multiplying new generations of V. cholerae
bacteria out into the drinking water of the next host if proper sanitation
measures are not in place.
The cholera
toxin (CTX or CT) is an oligomeric complex made up of six protein subunits: a single
copy of the A subunit (part A), and five copies of the B subunit (part B),
connected by a disulfide bond. The five B subunits form a
five-membered ring that binds to GM1 gangliosides on the surface of the intestinal epithelium
cells. The A1 portion of the A subunit is an enzyme that ADP-ribosylates
G proteins,
while the A2 chain fits into the central pore of the B subunit ring. Upon
binding, the complex is taken into the cell via receptor-mediated endocytosis.
Once inside the cell, the disulfide bond is reduced, and the A1 subunit is
freed to bind with a human partner protein called ADP-ribosylation factor 6 (Arf6).[12]
Binding exposes its active site, allowing it to permanently ribosylate the Gs
alpha subunit of the heterotrimeric G protein. This results in
constitutive cAMP production, which in turn leads
to secretion of H2O, Na+, K+, Cl−,
and HCO3− into the lumen of the small intestine and rapid
dehydration. The gene encoding the cholera toxin is introduced into V.
cholerae by horizontal gene transfer. Virulent strains of V. cholerae
carry a variant of temperate bacteriophage
called CTXf or CTXφ.
Microbiologists
have studied the genetic mechanisms by which the V. cholerae
bacteria turn off the production of some proteins and turn on the production of
other proteins as they respond to the series of chemical environments they
encounter, passing through the stomach, through the mucous layer of the small
intestine, and on to the intestinal wall.[13]
Of particular interest have been the genetic mechanisms by which cholera
bacteria turn on the protein production of the toxins that interact with host
cell mechanisms to pump chloride ions into the small intestine, creating an ionic pressure
which prevents sodium ions from entering the cell. The chloride and sodium ions
create a salt-water environment in the small intestines, which through osmosis
can pull up to six litres of water per day through the intestinal cells,
creating the massive amounts of diarrhea. The host can become rapidly
dehydrated if an appropriate mixture of dilute salt water and sugar is not
taken to replace the blood's water and salts lost in the diarrhea.
By inserting
separate, successive sections of V. cholerae DNA into the DNA of other
bacteria, such as E. coli that would not naturally produce the
protein toxins, researchers have investigated the mechanisms by which V.
cholerae responds to the changing chemical environments of the stomach,
mucous layers, and intestinal wall. Researchers have discovered a complex
cascade of regulatory proteins controls expression of V. cholerae virulence
determinants. In responding to the chemical environment at the intestinal wall,
the V. cholerae bacteria produce the TcpP/TcpH proteins, which, together
with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein.
ToxT then directly activates expression of virulence
genes that produce the toxins, causing diarrhea in the infected person and
allowing the bacteria to colonize the intestine.[13]
Current research aims at discovering "the signal that makes the cholera
bacteria stop swimming and start to colonize (that is, adhere to the cells of)
the small intestine."[13]
Genetic structure
Amplified
fragment length polymorphism fingerprinting of the pandemic isolates of V.
cholerae has revealed variation in the genetic structure. Two clusters have
been identified: Cluster I and Cluster II. For the most part, Cluster I
consists of strains from the 1960s and 1970s, while Cluster II largely contains
strains from the 1980s and 1990s, based on the change in the clone structure.
This grouping of strains is best seen in the strains from the African
continent.[14]
Diagnosis
A rapid
dip-stick test is available to determine the presence of V. cholerae.[5]
In those samples that test positive, further testing should be done to
determine antibiotic resistance.[5]
In epidemic
situations, a clinical diagnosis may be made by taking a patient history and
doing a brief examination. Treatment is usually started without or before
confirmation by laboratory analysis.
Stool and swab
samples collected in the acute stage of the disease, before antibiotics have
been administered, are the most useful specimens for laboratory diagnosis. If
an epidemic of cholera is suspected, the most common causative agent is V.
cholerae O1. If V. cholerae serogroup O1 is
not isolated, the laboratory should test for V. cholerae O139. However,
if neither of these organisms is isolated, it is necessary to send stool
specimens to a reference laboratory. Infection with V. cholerae O139
should be reported and handled in the same manner as that caused by V.
cholerae O1. The associated diarrheal illness should be referred to as
cholera and must be reported in the United States.[15]
A number of
special media have been employed for the cultivation for cholera vibrios. They
are classified as follows:
Enrichment media
- Alkaline
peptone water at pH 8.6
- Monsur's
taurocholate tellurite peptone water at pH 9.2
Plating media
- Alkaline
bile salt agar (BSA): The colonies are very similar to those on nutrient agar.
- Monsur's
gelatin Tauro cholate trypticase tellurite agar (GTTA) medium: Cholera
vibrios produce small, translucent colonies with a greyish-black center.
- TCBS
medium: This is the mostly widely used medium; it contains thiosulphate,
citrate, bile salts and sucrose. Cholera vibrios produce flat,
2–3-mm-diameter, yellow-nucleated colonies.
Direct microscopy
of stool is not recommended, as it is unreliable. Microscopy is preferred only
after enrichment, as this process reveals the characteristic motility of Vibrio
and its inhibition by appropriate antisera.
Diagnosis can be confirmed, as well as serotyping done by agglutination with specific sera.
Prevention
Although
cholera may be life-threatening, prevention of the disease is normally
straightforward if proper sanitation practices are followed. In developed countries, due to nearly universal
advanced water treatment and sanitation practices, cholera
is no longer a major health threat. The last major outbreak of cholera in the
United States occurred in 1910–1911.[16][17]
Effective sanitation practices, if instituted and adhered to in time, are
usually sufficient to stop an epidemic. There are several points along the
cholera transmission path at which its spread may be halted:
- Sterilization:
Proper disposal and treatment of infected fecal waste water produced by
cholera victims and all contaminated materials (e.g. clothing, bedding,
etc.) are essential. All materials that come in contact with cholera
patients should be sanitized by washing in hot water, using chlorine bleach if
possible. Hands that touch cholera patients or their clothing, bedding,
etc., should be thoroughly cleaned and disinfected with chlorinated water
or other effective antimicrobial agents.
- Sewage:
antibacterial treatment of general sewage by
chlorine, ozone, ultraviolet light or other effective treatment before it
enters the waterways or underground water supplies helps prevent
undiagnosed patients from inadvertently spreading the disease.
- Sources:
Warnings about possible cholera contamination should be posted around
contaminated water sources with directions on how to decontaminate
the water (boiling, chlorination etc.) for possible use.
- Water
purification: All water used for drinking, washing, or cooking should be
sterilized by either boiling, chlorination, ozone water treatment,
ultraviolet light sterilization (e.g. by solar water disinfection), or
antimicrobial filtration in any area where cholera may be present.
Chlorination and boiling are often the least expensive and most effective
means of halting transmission. Cloth
filters or sari
filtration, though very basic, have significantly reduced the
occurrence of cholera when used in poor villages in Bangladesh
that rely on untreated surface water. Better antimicrobial filters, like
those present in advanced individual water treatment hiking kits, are most
effective. Public health education and adherence to appropriate sanitation
practices are of primary importance to help prevent and control
transmission of cholera and other diseases.
Surveillance
Surveillance
and prompt reporting allow for containing cholera epidemics rapidly. Cholera
exists as a seasonal disease in many endemic countries, occurring annually
mostly during rainy seasons. Surveillance systems can provide early alerts to
outbreaks, therefore leading to coordinated response and assist in preparation
of preparedness plans. Efficient surveillance systems can also improve the risk
assessment for potential cholera outbreaks. Understanding the seasonality and
location of outbreaks provide guidance for improving cholera control activities
for the most vulnerable.[18]
For prevention to be effective, it is important that cases are reported to
national health authorities.[1]
Vaccine
Main article: Cholera
vaccine
A number of
safe and effective oral vaccines for cholera are available.[19]
Dukoral, an
orally administered, inactivated whole cell vaccine, has an overall efficacy of
about 52% during the first year after being given and 62% in the second year,
with minimal side effects.[19]
It is available in over 60 countries. However, it is not currently recommended
by the Centers for Disease Control
and Prevention (CDC) for most people traveling from the United States to
endemic countries.[20]
One injectable vaccine was found to be effective for two to three years. The
protective efficacy was 28% lower in children less than 5 years old.[21]
However, as of 2010, it has limited availability.[4]
Work is under way to investigate the role of mass vaccination.[22]
The World Health Organization (WHO) recommends immunization of high risk
groups, such as children and people with HIV, in countries where
this disease is endemic.[4]
If people are immunized broadly, herd
immunity results, with a decrease in the amount of contamination in the
environment.[5]
Sari filtration
An effective
and relatively cheap method to prevent transmission of V. cholera is the
practice of folding a sari
(a long fabric garment) multiple times to create a simple filter for drinking
water.[23]
Folding saris four to eight times may create a simple filter to reduce the
amount of active V. cholera in the filtered water.[24]
The education of proper sari filter use is imperative, as there is a positive
correlation between sari misuse and the incidence of childhood diarrhea; soiled
saris worn by women are vectors of transmission of enteric pathogens to young
children.[25]
Educating at-risk populations about the proper use of the sari filter method
may decrease V. cholera-associated disease.
Treatment
Continued
eating speeds the recovery of normal intestinal function. The World Health
Organization recommends this generally for cases of diarrhea no matter what the
underlying cause.[26]
A CDC training manual specifically for cholera states: “Continue to breastfeed
your baby if the baby has watery diarrhea, even when traveling to get
treatment. Adults and older children should continue to eat frequently.”[27]
Fluids
In most cases,
cholera can be successfully treated with oral rehydration therapy (ORT), which is
highly effective, safe, and simple to administer.[5]
Rice-based solutions are preferred to glucose-based ones due to greater
efficiency.[5]
In severe cases with significant dehydration, intravenous
rehydration may be necessary. Ringer's
lactate is the preferred solution, often with added potassium.[1][26]
Large volumes and continued replacement until diarrhea has subsided may be
needed.[1]
Ten percent of a person's body weight in fluid may need to be given in the first
two to four hours.[1]
This method was first tried on a mass scale during the Bangladesh Liberation War, and was found
to have much success.[28]
If commercially
produced oral rehydration solutions are too expensive or difficult to obtain,
solutions can be made. One such recipe calls for 1 litre of boiled water, 1/2
teaspoon of salt, 6 teaspoons of sugar, and added mashed banana for potassium
and to improve taste.[29]
Electrolytes
As there
frequently is initially acidosis, the potassium
level may be normal, even though large losses have occurred.[1]
As the dehydration is corrected, potassium levels may decrease rapidly, and
thus need to be replaced.[1]
Antibiotics
Antibiotic
treatments for one to three days shorten the course of the disease and reduce
the severity of the symptoms.[1]
Use of antibiotics also reduces fluid requirements.[30]
People will recover without them, however, if sufficient hydration is
maintained.[5]
Doxycycline
is typically used first line, although some strains
of V. cholerae have shown resistance.[1]
Testing for resistance during an outbreak can help determine appropriate future
choices.[1]
Other antibiotics proven to be effective include cotrimoxazole,
erythromycin,
tetracycline,
chloramphenicol,
and furazolidone.[31]
Fluoroquinolones,
such as norfloxacin,
also may be used, but resistance has been reported.[32]
In many areas
of the world, antibiotic resistance is increasing. In Bangladesh,
for example, most cases are resistant to tetracycline, trimethoprim-sulfamethoxazole, and
erythromycin.[5]
Rapid diagnostic assay methods are available for the identification of multiple
drug-resistant cases.[33]
New generation antimicrobials have been discovered which are effective against
in in vitro studies.[34]
Prognosis
If people with
cholera are treated quickly and properly, the mortality rate is less than 1%;
however, with untreated cholera, the mortality rate rises to 50–60%.[1][35]
For certain genetic strains of cholera, such as the one present during the 2010
epidemic in Haiti and the 2004 outbreak in India, death can occur within two
hours of becoming ill.[36]
Cholera affects
an estimated 3–5 million people worldwide, and causes
100,000–130,000 deaths a year as of 2010.[4]
This occurs mainly in the developing
world.[37]
In the early 1980s, death rates are believed to have been greater than 3
million a year.[1]
It is difficult to calculate exact numbers of cases, as many go unreported due
to concerns that an outbreak may have a negative impact on the tourism of a
country.[5]
Cholera remains both epidemic and endemic in many areas of the world.[1]
Although much
is known about the mechanisms behind the spread of cholera, this has not led to
a full understanding of what makes cholera outbreaks happen some places and not
others. Lack of treatment of human feces and lack of treatment of drinking water greatly
facilitate its spread, but bodies of water can serve as a reservoir,
and seafood shipped long distances can spread the disease. Cholera was not
known in the Americas
for most of the 20th century, but it reappeared towards the end of that
century.[38]
History
The word
cholera is from Greek: χολέρα kholera from χολή kholē "bile". Cholera likely
has its origins in the Indian Subcontinent; it has been prevalent in
the Ganges
delta since ancient times.[1]
The disease first spread by trade routes (land and sea) to Russia in 1817,
then to the rest of Europe,
and from Europe to North America.[1]
Seven cholera pandemics
have occurred in the past 200 years, with the seventh originating in Indonesia in
1961.[39]
The first cholera pandemic occurred in the
Bengal region of India starting in 1817 through 1824. The disease dispersed
from India to Southeast Asia, China, Japan, the Middle East, and southern
Russia. The second pandemic lasted from 1827 to 1835
and affected the United States and Europe. The third pandemic erupted in 1839, persisted
until 1856, extended to North Africa, and reached South America, for the first
time specifically infringing upon Brazil. Cholera hit the sub-Saharan African
region during the fourth pandemic from 1863 to 1875. The fifth and sixth pandemics raged from 1881–1896 and
1899-1923. These epidemics were less fatal due to a greater understanding of
the cholera bacteria. Egypt, the Arabian peninsula, Persia, India, and the
Philippines were hit hardest during these epidemics, while other areas, like
Germany in 1892 and Naples from 1910–1911, experienced severe outbreaks. The
final pandemic originated in 1961 in Indonesia
and is marked by the emergence of a new strain, nicknamed El Tor, which still
persists today in developing countries.[40]
From a local
disease, cholera became one of the most widespread and deadly diseases of the
19th century, killing an estimated tens of millions of people.[41]
In Russia
alone, between 1847 and 1851, more than one million people perished of the
disease.[42]
It killed 150,000 Americans during the second pandemic.[43]
Between 1900 and 1920, perhaps eight million people died of cholera in India.[44]
Cholera became
the first reportable disease in the United States due to
the significant effects it had on health.[1]
John Snow, in England, was the
first to identify the importance of contaminated water in its cause in 1854.[1]
Cholera is now no longer considered a pressing health threat in Europe and
North America due to filtering and chlorination of water supplies, but still
heavily affects populations in developing countries.
In the past,
people traveling in ships would hang a yellow quarantine
flag if one or more of the crew members suffered from cholera. Passengers from
boats with a yellow flag hung would not be allowed to disembark at any harbor
for an extended period, typically 30 to 40 days.[45]
In modern international maritime signal flags,
the quarantine flag is yellow and black.
Historically
many different claimed remedies have existed in folklore. In the 1854–1855
outbreak in Naples homeopathic Camphor was used according to Hahnemann.[46]
While T. J. Ritter's "Mother's Remedies" book lists tomato syrup as a
home remedy from northern America. While elecampagne
was recommended in the United Kingdom according to William Thomas Fernie [47]
Cholera morbus
The term cholera
morbus was used in the 19th and early 20th centuries to describe both
nonepidemic cholera and other gastrointestinal diseases (sometimes epidemic)
that resembled cholera. The term is not in current use, but is found in many
older references.[48]
The other diseases are now known collectively as gastroenteritis.
Research
The
Russian-born bacteriologist Waldemar
Haffkine developed the first cholera vaccine around 1900. The bacterium had
been originally isolated 45 years earlier (1855) by Italian anatomist Filippo
Pacini, but its exact nature and his results were not widely known.
One of the
major contributions to fighting cholera was made by the physician and pioneer
medical scientist John Snow (1813–1858), who in 1854 found a link
between cholera and contaminated drinking water.[49]
Dr. Snow proposed a microbial origin for epidemic cholera in 1849. In his major
"state of the art" review of 1855, he proposed a substantially
complete and correct model for the etiology of the
disease. In two pioneering epidemiological field studies, he was able to
demonstrate human sewage
contamination was the most probable disease vector in two major epidemics in
London in 1854.[50]
His model was not immediately accepted, but it was seen to be the more
plausible, as medical microbiology developed over the next 30 years or so.
Cities in
developed nations made massive investment in clean water supply and
well-separated sewage treatment infrastructures between the mid-1850s and the
1900s. This eliminated the threat of cholera epidemics from the major developed
cities in the world. In 1883, Robert Koch identified V. cholerae with a
microscope as the bacillus causing the disease.[51]
Robert Allan Phillips, working at the US Naval Medical Research Unit Two in
Southeast Asia, evaluated the pathophysiology of the disease using modern
laboratory chemistry techniques and developed a protocol for rehydration. His
research lead the Lasker Foundation to award him its prize in 1967.[citation needed]
Cholera has
been a laboratory for the study of evolution of virulence. The province of
Bengal in British
India was partitioned into West Bengal
and East
Pakistan in 1947. Prior to partition, both regions had cholera pathogens
with similar characteristics. After 1947, India made more progress on public
health than East Pakistan (now Bangladesh). As a consequence,[clarification needed] the
strains of the pathogen that succeeded in India had a greater incentive in the
longevity of the host. They have become less virulent than the strains
prevailing in Bangladesh. These draw upon the resources of the host population
and rapidly kill many victims.
More recently,
in 2002, Alam, et al., studied stool samples from patients at the International
Centre for Diarrhoeal Disease in Dhaka,
Bangladesh. From the various experiments they conducted, the researchers
found a correlation between the passage of V. cholerae through the human
digestive system and an increased infectivity state. Furthermore, the
researchers found the bacterium creates a hyperinfected state where genes that control
biosynthesis of amino acids, iron uptake systems, and formation of periplasmic nitrate
reductase complexes were induced just before defecation. These induced
characteristics allow the cholera vibrios to survive in the "rice
water" stools, an environment of limited oxygen and iron, of patients with
a cholera infection.[52]
Notable cases
- Tchaikovsky's death has traditionally
been attributed to cholera, most probably contracted through drinking
contaminated water several days earlier.[53]
Since the water was not boiled and cholera was affecting Saint Petersburg, such a connection is quite
plausible ...."[54]
Tchaikovsky's mother died of cholera,[55]
and his father became sick with cholera at this time but made a full
recovery.[56]
Some scholars, however, including English musicologist and Tchaikovsky
authority David Brown and biographer Anthony
Holden, have theorized that his death was a suicide.[57]
- After the
2010 earthquake, an outbreak swept over Haiti,
traced to a United Nations base. This marks the worst
cholera outbreak in recent history, as well as the best documented cholera
outbreak in modern public health.
Other famous
people believed to have died of cholera include:
- Sadi Carnot, Physicist, a founder
of thermodynamics (d. 1832)[58]
- Charles X, King of France (d. 1836)[59]
- James
K. Polk, eleventh president of the United States (d. 1849)[60]
- Carl von Clausewitz, Prussian soldier and
German military theorist (d. 1831)[61]
The entire article can be found at: http://en.wikipedia.org/wiki/Cholera
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