Reflections on Cholera:

Historical & Clinical Perspectives

Kate Venable MD, C.Trop Med
Internal Medicine/Pediatrics
Core Faculty, Global Health
University of Minnesota
Global Health Course May 2015
 Objectives
At the end of this presentation, participants
should be able to:
• identify the specific microbiologic features of
cholera which lead to epidemics/outbreaks
• describe the approach to cholera treatment
centers and containment of the disease
• explain the impact some social determinants
of health have on cholera's potential for
causing disease
• I have no financial disclosures
• I will discuss no off-label uses of medications
 What do you already know about
Cholera?
• Experiences?
• Patient care?
• Public health?
 Historical & Literary Perspectives
• "It was inevitable: the scent of bitter almonds always
reminded him of the fate of unrequited love.”
– Love in the Time of Cholera by Gabriel García Márquez, 1985
• “Cholera will not disappear nor cease to mean. A great
challenge will be to respond to the meanings it is given.”
– Cholera: The Biography by Christopher Hamlin, 2009
• Mary Lennox would never have left India for Mistlethwaite
Manor had not her parents, her ayah, and most of the
servants died of cholera in the first pages of …
– The Secret Garden by Frances Hodgson Burnett
 Art & Cholera
Alfred Rethel:
Death as the Cutthroat.
– painting inspired by
an account of 1832
Cholera Epidemic in
Paris
• J. Roze
• Le Cholera a Paris
– Also from 1830s
Paris epidemic
 The Seven Cholera Pandemics
• 1816-1826: First Cholera Pandemic.
– Bengal, India, spread to Caspian Sea
• 1829-1851: Second Cholera Pandemic
– Reached Europe – London, Paris (100K deaths in
all of France) then Russia, Quebec, New York,
Pacific US
• 1852-1860: Third Cholera Pandemic
– Mostly in Russia, >1 million deaths
• 1863-1875: Fourth Cholera Pandemic
– Mostly Europe, Africa
 The Seven Cholera Pandemics
• 1881-1896: Fifth Cholera Pandemic
– 1892 in Hamburg, Germany (8K deaths), led to upheaval
regarding government attention to water supply. Last major
European cholera outbreak.
• 1899-1923: Sixth Cholera Pandemic
– Mostly in Russia, badly affected; Europe improved water supply
thus less affected
• To this point, cause has been “Classical O1” biotype
• 1961-1970s: Seventh Cholera Pandemic – “El Tor” begins
– Began in Indonesia, called “El Tor” after the strain/biotype,
India, Russia, elsewhere.
– Eventually reached Latin America in 1991 impacting Peru &
other countries w/ >1 Million cases
– And many believe this hasn’t really ended…
 7th Pandemic’s Ongoing Havoc…
• January 1991- Sept 1994: Outbreak in S.America
– Due to ship-discharged water
– Caused by an O1, El Tor biotype mostly similar to 7th Pandemic
• 1992 – new strain appeared, a non-O1, non-agglutinable
Vibrio called “O139 Bengal”
– As it was identified in Bangledesh/India epidemic
• 1997 – most countries in E.Africa, 80% of cases worldwide
found there.
– Outbreak in TZ studied: RFs were bathing in the river, eating
dried fish, and living >10 minutes walking distance from the
closest water source
• 2000-2010: Major cholera epidemics in Zimbabwe, Kenya,
Nigeria, Afghanistan, Iraq, Somalia, Angola, Guinea-Bissau,
Sudan, South Africa, Malawi, Liberia, India and Vietnam
• 2010 October – Haiti and DR, following January earthquake
in Haiti
Map here
 Global & Public Health Perspectives
• Endemic to >50 countries
• Affects 2–5 million persons each year, and kills 100,000/yr
• Three major epidemiologic patterns:
– heavily endemic
– neoepidemic (newly invaded, cholera-receptive areas)
– occasional limited outbreaks in developed countries with good
sanitation
• Patterns depend on:
– Sanitation and water supply/infrastructure (AKA Social Determinants
of Health)
– Prior infections/immune status (antigenic experience)
– Features of the Vibrios – strain/biotype, acid tolerance, etc.
• Cholera vibrios can persist for some time in shellfish, algae or
plankton in coastal regions of infected
• Untreated cholera is fatal in ≈25% of cases, but with aggressive
volume and electrolyte replacement, the number of persons who
die of cholera is limited to <1%.
 Cholera’s
Family Tree
 Global & Public Health Perspectives
• El Tor biotype:
– Largely replaced the “Classical” Biotype of prior
pandemics
– More prolonged outbreaks w/ multiple waves
– Has ability to cause mild disease or short-term
asymptomatic passage once established in a
population (unlike prior Classical pattern)
– During the past 2 decades, evolution to become
hybrid, keeping its El Tor biotype characteristics but
incorporating classical biotype cholera toxin
– all eight combinations of biotype, serotype, and toxin
status exist

Ryan, E. Haiti in the Context of the Current Global Cholera Pandemic. Emerging Infectious Diseases •
www.cdc.gov/eid • Vol. 17, No. 11, November 2011
 Microbiology
• Vibrio cholerae
• Gram Negative, Highly
motile, Curved rods w/
Single polar flagellum
• John Snow MD identified
link between drinking
water and cholera disease
(1854)
• 1855 Filippo Pacini -
isolated bacillus
• 1885 - Robert Koch –
microscopic identification
 Micro Characteristics
• An effective selective medium is thiosulfate-
citrate-bile salts-sucrose (TCBS) agar, on which
the sucrose-fermenting cholera vibrios
produce a distinctive yellow colony.
• In adequate media, they grow rapidly with a
generation time of less than 30 minutes.
• Can grow aerobically or anaerobically, quite
tolerant of alkaline conditions
• Vibrios are sensitive to low pH and die rapidly
in solutions < pH 6
Cholera Transmission
 Mode of Transmission & Disease
• Fecal-oral transmission
• Humans are only reservoir*
• V. cholerae resides in aquatic sources such as brackish
water and estuaries, often associated with algae blooms.
• Most die in the stomach but… Surviving virulent organisms
may adhere to and colonize the small bowel
• Secrete the potent cholera enterotoxin (CT, also called
“choleragen”)
• CT binds to the plasma membrane of intestinal epithelial
cells and causes a rise in cyclic adenosine 5-
monophosphate (cAMP) production
• Resulting high intracellular cAMP level causes massive
secretion of electrolytes and water into the intestinal
lumen.
 Pathophysiology
• Exclusively a disease of small bowel
• Adherence to microvilli by several
mechanisms
– Motility
– Mucinolytic enzymes
– Cholera toxin elaboration
 Host Immune Response
• Non-specific defenses:
– Gastric acid
– Intestinal mucus secretion & intestinal motility
• Specific defenses:
– Disease results in effective specific immunity with
secretory IgA; IgG vs Vibrios
– Breastfeeding in endemic areas
• Vaccine has been practically ineffective
 Clinical Features
• 6-48 hrs of incubation, symptoms in 1-3 days
• Impressive, abrupt onset of watery diarrhea &
vomiting… “rice water diarrhea”
• V.Cholerae binds to bowel wall – causes secretion
of Cl and prevents Na abs, hence extremely
watery diarrhea.
• Studies in adult American volunteers have shown
that 5µg of CT, administered orally with
bicarbonate, causes 1 to 6 L of diarrhea; 25µg
causes > 20 L !!
• Patients can be severely dehydrated within hours
 Clinical Features
• Of total persons w/ infection,
75% asymptomatic
• Majority of the 25%
symptomatic – mild illness
– 2% of infected = severe cholera
(“cholera gravis”)
– 5% will have moderate illness &
seek medical attn
Triage and Disposition
 Diagnosis & Management
• Clinical diagnosis in most cases (w/ appropriate
conditions, RFs, exposures)
• Lab diagnosis:
– Wet mount of liquid stool viewed under microscope
– Rapid: Crystal VC® dipstick (+/- sens, spec)
– Stool culture (G.S.), slide agglutination, others
• Management is largely supportive:
– REHYDRATION – ORS, LR, massive quantities
– Abx (see next slide)
– Zinc in peds (2008 study)
CDC.gov
 A plug for ORS Solution
• Oral Rehydration Salts = NaCl, 3.5 g [OR
KCl,1.5 g OR NaHCO3, 2.5 g] + glucose, 20.0 g +
1 L of water
• Lifesaving
• Under-utilized
 Haiti Outbreak October 2010
• No cholera in Haiti prior to 2010 **
• Occurred post earthquake (Jan 12, 2010)
• On October 19, 2010, MSPP was notified of a sudden increase in
patients with acute watery diarrhea and dehydration in the
Artibonite and Plateau Centrale Departments
• V. cholerae serogroup O1, biotype Ogawa, confirmed in Haitian lab
on October 21, 2010
• Traced to UN workers who were from Nepal and did not have
appropriate sanitation, contaminated the water supply.
• CDC-MSPP investigation interviewed 27 pts at 5 hospitals to try and
trace the source – Artibonite River
• By November 19, cholera was laboratory confirmed in all 10
administrative departments and Port- au-Prince, as well as in the
Dominican Republic and Florida
 Public Health Response to Cholera
• First Steps:
– Confirm cases – clinical & microbiologic
– Identify source of water contamination if possible
– Mobilize resources/CHWs/health care facilities
• Immediate priorities:
– 1) prevent deaths in health facilities by distributing treatment supplies and
providing clinical training;
– 2) prevent deaths in communities by supplying oral rehydration solution (ORS)
sachets to homes and urging ill persons to seek care quickly;
– 3) prevent disease spread by promoting point-of-use water treatment and safe
storage in the home, handwashing, and proper sewage disposal;
– 4) conduct field investigations to define risk factors and guide prevention
strategies; and
– 5) establish a national cholera surveillance system to monitor spread of disease.
• Public Health Messaging:
– 1) drink only treated water;
– 2) cook food thoroughly (especially seafood)
– 3) wash hands
– 4) seek care immediately for diarrheal illness
– 5) and give ORS to anyone with diarrhea.
CTC general layout
Bleach used on shoes, floors, etc
Standard Cots/Buckets
CTC at Cite Soliel
 Cholera & the Social
Determinants of Health
Cholera has been said to be a disease of
“impoverishment, displacement and unrest”
What are your thoughts on this statement?
“Although cholera spreads through global interactions, it paradoxically
predominantly affects those most estranged from the benefits of
globalization. In the long term, economic investment and civil stability
will lead to the demise of cholera, but with ≈1 billion persons currently
lacking safe water, and 2.6 billion currently lacking adequate
sanitation, our current war with cholera will go on for decades…”

Ryan, E. Haiti in the Context of the Current Global Cholera Pandemic. Emerging Infectious
Diseases • www.cdc.gov/eid • Vol. 17, No. 11, November 2011
 Objectives
At the end of this presentation, participants
should be able to:
• identify the specific microbiologic features of
cholera which lead to epidemics/outbreaks
• describe the approach to cholera treatment
centers and containment of the disease
• explain the impact some social determinants
of health have on cholera's potential for
causing disease
 Review & Questions
• What are some of the virulence factors which
cause cholera to be so rapidly infective?
– Action on small bowel (mucinolytic enzymes, motility,
adherence features), relatively small infective dose
• What are the first steps in response to a
suspected cholera outbreak?
– Indentify case definition, confirm, mobilize
• How do SDH influence the potential for cholera to
cause an outbreak/epidemic?
– Poor sanitation, limited health access/infrastructure
challenges, rapid spread of disease
 References/Sources
• Medical Microbiology, 4th Edition. Chapter
24Cholera, Vibrio cholerae O1 and O139, and
Other Pathogenic Vibrios
• CDD.gov
• WHO.org
• Google images