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Internal Medicine

Cholera

Cholera is an acute secretory diarrheal illness caused by the bacteria Vibrio cholerae.

Scanning electron microscope image of Vibrio cholerae bacteria, which infect the digestive system. | Zeiss DSM 962 SEM | T.J. Kirn, M.J. Lafferty, C.M.P Sandoe and R.K. Taylor, 2000, "Delineation of pilin domains required for bacterial association into microcolonies and intestinal colonization", Molecular Microbiology, Vol. 35(4):896-910

Cholera is an acute secretory diarrheal illness caused by the bacteria Vibrio cholerae.

Microbiology

Epidemiology:

There are about four million cases of cholera worldwide annually, with over 140,000 deaths attributed to the disease. Nearly 1.8 million people worldwide obtain their drinking water from sources contaminated with human feces that may act as a reservoir for the cholera bacteria. Outbreaks are known to occur, specifically in the developing world where sanitation and water filtration standards may not exist. Currently, cholera is known to be endemic in approximately 50 nations, mostly throughout Asia and Africa. The incidence is tied to a seasonal distribution, depending on the timing of the region’s rainy season. Epidemics can be more widespread, however, involving other parts of the world, including South and Central America. The introduction of the species to a new region with a collapse of hygiene and health services has been known to lead to the propagation of epidemics.
  • V. cholerae is found in food (classically shellfish) and poorly sanitized water.
  • Large dose is required to develop infectivity.
  • Spread: Fecal-oral route and is thus endemic to areas associated with inadequate food and water hygiene
  • Factors that increase susceptibility include:
    • Proton-pump inhibitors (PPIs) and antihistamine use
    • Type O blood
    • Poor sanitation
    • Overcrowding
    • Prior vagotomy
    • Helicobacter pylori infection
Life cycle of pathogenic Vibrio cholerae: Toxigenic strains of Vibrio cholerae persist in aquatic environments alongside non-toxigenic strains, aided by biofilm formation on biological surfaces and use of chitin as a carbon and nitrogen source. On ingestion of these aquatic-environment-adapted bacteria in contaminated food or water, toxigenic strains colonize the small intestine, multiply, secrete cholera toxin and are shed back into the environment by the host in secretory diarrhoea. The stool-shed pathogens are in a transient hyperinfectious state that serves to amplify the outbreak through transmission to subsequent hosts. | Nelson, E. J., Harris, J. B., Morris, J. G., Jr, Calderwood, S. B., & Camilli, A. (2009). Cholera transmission: the host, pathogen and bacteriophage dynamic. Nature reviews. Microbiology, 7(10), 693–702. https://doi.org/10.1038/nrmicro2204

Vibrio cholerae:

Facultative, gram-negative, comma-shaped, oxidase-positive rod that is prevalent in developing countries.

Cholera toxin-producing (toxigenic) strains:

  • O1 serogroup: Responsible for all recent outbreaks
    • The O1 serogroup is subdivided into two phenotypically distinct biotypes, El Tor and classical, the second of which is associated with earlier pandemics.
    • Both biotypes can be further subdivided into two serotypes, Inaba and Ogawa7. In the past 20 years, El Tor has replaced the classical biotype
  • O139 serogroup: First appeared in 1992, as a result of a multi-gene substitution in the O antigen-coding region of a progenitor O1 El Tor strain. Although the O139 serogroup caused devastating outbreaks in the 1990s especially in Asia, the El Tor strain remains the dominant strain globally
Phylogenetic relationship of Vibrio cholerae strains: On the basis of the antigenicity of the O antigen component of the outer membrane lipopolysaccharide, more than 200 serogroups (O1–O200) of Vibrio cholerae exist in aquatic environments. Only a subset of O1 and O139 serogroup strains are toxigenic (Tox+) and therefore capable of causing cholera when ingested; such strains are selected for in the host. Other strains are non-toxigenic (Tox−) and are selected against. Different O antigen types are indicated by the colour of the outer membrane and sheathed flagellum (the periplasmic space and the inner membrane are not shown). Capsules are present in a subset of strains. Different strain genotypes are indicated by the colour of the cytoplasm; note that Tox+ O1 and O139 have essentially the same genotype, with the exception of the O antigen genes. | Nelson, E. J., Harris, J. B., Morris, J. G., Jr, Calderwood, S. B., & Camilli, A. (2009). Cholera transmission: the host, pathogen and bacteriophage dynamic. Nature reviews. Microbiology, 7(10), 693–702. https://doi.org/10.1038/nrmicro2204

Virulence factors:

  • Cholera toxin (secreted AB-subunit toxin): The B subunit pentamer binds monosialotetrahexosylgangliosides on absorptive epithelial cells, triggering endocytosis of the enzymatic A subunit, whereupon it ADP ribosylates a subunit of the G protein that controls adenylyl cyclase activity.
  • Toxin co-regulated pilus (TCP): Self-binding pilus that tethers bacterial cells together, possibly to resist shearing forces in the host small intestine.
  • Lysogenic bacteriophage: Carries genes for cholera toxin and the SXT element that harbours antibiotic resistance genes
Cholera toxin mechanism of action. (1) Upon ingestion, Vibrio cholerae colonises the intestine and produces cholera toxin, consisting of the toxic A subunit and five B subunits, which are responsible for receptor binding. (2) Once bound to GM1 receptors, cholera toxin is endocytosed and trafficked to the endoplasmic reticulum where the A and B subunits disassociate. (3) The A subunit stimulates the adenylate cyclase complex, resulting in an increase in intracellular cAMP. (4) cAMP activates protein kinase A which, in turn, phosphorylates the CFTR chloride channel, resulting in an efflux of chloride ions from the cell and a reduction in uptake of sodium ions. The resulting osmotic gradient leads to an overall movement of water into the intestinal lumen, resulting in the secretory diarrhoea characteristic of cholera. (5) Cholera vaccines promote the generation of antibodies against cholera toxin, which block receptor binding, or against cholera vibrios, which immobilise the pathogen and prevent colonisation. A, cholera toxic A subunit; AC, adenylate cyclase; B, cholera toxic B subunit; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; Cl, chloride ion; GM1, monosialotetrahexosylganglioside receptor; Na, sodium ion; PKA, protein kinase A. | Gabutti, G., Rossanese, A., Tomasi, A., Giuffrida, S., Nicosia, V., Barriga, J., … Stefanati, A. (2020). Cholera, the Current Status of Cholera Vaccines and Recommendations for Travellers. Vaccines, 8(4), 606. doi:10.3390/vaccines8040606

Presentation

High-volume fluid loss with electrolyte derangements that can progress to hypovolemic shock and ultimately death characterizes this gastrointestinal disease. The infection is transmitted via the fecal-oral route and can vary in severity.

Clinical manifestations of cholera can range from asymptomatic to profuse diarrhea.

  • Common symptoms: Diarrhea, abdominal discomfort, and vomiting
  • Stools: Characteristic “rice water” consistency, which can be laced with bile and mucus
    • Adult output can reach as high as one liter per hour whereas, in children, it can reach up to 20 cc/kg/hr.
(A). “Rice water” stool in a patient with cholera. (B). Cholera cot used in management of patients with cholera to monitor ongoing volume losses in stool. (C). Patient with cholera before rehydration. (D). Patient with cholera eight hours after starting rehydration therapy. (A, C and D) | Chowdhury F, Khan AI, Faruque AS, Ryan ET. Severe, acute watery diarrhea in an adult. PLoS Negl Trop Dis. 2010;4(11):e898.

Cholera gravis (severe cholera):

Severe cholera can be distinguished clinically from other diarrheal illnesses due to the profound and rapid loss of fluid and electrolytes. The resulting hypovolemia results in the characteristic manifestations of fluid loss.
  • Hypovolemia: Dry oral mucosa, cool skin, and decreased skin turgor
  • Poor perfusion → Lactic acidosis (hyperventilation and Kussmaul breathing)
  • Electrolyte abnormalities (hypokalemia and hypocalcemia): Generalized muscle weakness and cramping
    • Non-anion gap metabolic acidosis

Diagnosis

The diagnosis of cholera can be based on clinical suspicion. The characteristic high volume diarrhea and travel to an endemic area can be sufficient for a diagnosis. As such, laboratory testing is often not required before initiating treatment. The diagnosis can be confirmed, however, by the isolation and culture of V. cholerae from stool isolates.

Differential diagnosis:

  • Escherichia coli infection
  • Salmonellosis
  • Shigellosis
  • Typhoid fever
  • Rotavirus infection

Management

Fluid resuscitation

The mainstay of treatment of cholera is prompt fluid resuscitation based on the degree of volume depletion. If an estimated 5% to 10% of body weight has been lost, oral rehydration solution should be used. Prompt treatment of severe cholera with fluids can reduce the mortality from over 10% to less than 0.5%.
  • Severe cases (hypovolemic shock or > 10% loss of body weight): IV fluids

Antibiotic therapy:

Once an appropriate volume status has been achieved, antibiotic therapy can be initiated.
  • Tetracyclines (M/C used class) or doxycycline
  • Alternative therapies: Macrolides (erythromycin/azithromycin), or fluoroquinolones (ciprofloxacin)

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