Cholera

Infectious Disease MONDO:0015766 Pathograph 13 Bacterial Infection

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9
Pathophys.
14
Phenotypes
13
Pathograph
5
Treatments
5
References
2
Deep Research
⚙

Pathophysiology

9
Cholera Toxin Binding and Uptake
Cholera toxin B subunit (CTB) binds to GM1 ganglioside and alternative fucosylated glycan receptors (e.g., Lewis X) on the apical surface of intestinal epithelial cells, initiating receptor-mediated endocytosis and retrograde trafficking to the endoplasmic reticulum.
intestinal epithelial cell link
endocytosis link retrograde vesicle-mediated transport link
small intestine link
Downstream
ERAD-mediated CTA1 Translocation
ERAD-mediated CTA1 Translocation
The A1 enzymatic subunit of cholera toxin is unfolded by protein disulfide isomerase in the ER and hijacks the ER-associated degradation (ERAD) machinery to retro-translocate into the cytosol, where it refolds to become enzymatically active.
intestinal epithelial cell link
ERAD pathway link
small intestine link
Downstream
Gsα ADP-Ribosylation
Gsα ADP-Ribosylation
Cytosolic CTA1 catalyzes ADP-ribosylation of the Gsα subunit (GNAS) using NAD+ as substrate, locking adenylyl cyclase in a constitutively active state.
intestinal epithelial cell link
adenylate cyclase-activating G protein-coupled receptor signaling pathway link
small intestine link
Downstream
Increased cAMP
Cholera Toxin
Vibrio cholerae produces a toxin that activates adenylate cyclase in intestinal epithelial cells, leading to increased cyclic AMP (cAMP) levels.
intestinal epithelial cell link
small intestine link
Downstream
Increased cAMP
Show evidence (4 references)
PMID:8783505 SUPPORT
"Vibrio cholerae produce a variety of extracellular products that have deleterious effects on eukaryotic cells... CT acts by activation of adenylate cyclase-cAMP system located at the basolateral membrane of intestinal epithelial cells."
The statement is supported by the information that cholera toxin (CT) from Vibrio cholerae activates the adenylate cyclase-cAMP system in intestinal epithelial cells.
PMID:30624615 SUPPORT
"Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine monophosphate (cAMP)-mediated active Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR)."
The statement is supported as it describes CT inducing diarrhea through cAMP-mediated mechanisms.
PMID:4364505 SUPPORT
"Comparable results were also obtained when cholera toxin was used. The degree of enzyme stimulation was proportional to the concentration of enterotoxin."
This further confirms that cholera toxin stimulates adenylate cyclase activity in cells.
+ 1 more reference
Increased cAMP
Elevated cAMP levels cause cells to secrete large amounts of chloride ions into the intestinal lumen, followed by water and other electrolytes.
intestinal epithelial cell link
cAMP-mediated signaling link chloride transmembrane transport link
small intestine link
Downstream
Profuse Watery Diarrhea
Show evidence (3 references)
PMID:23651092 SUPPORT
"Increased intracellular cAMP in human intestinal epithelial cells accounts for pathogenesis of profuse diarrhea and severe fluid loss in cholera"
This reference directly supports the statement by confirming that elevated cAMP levels in intestinal epithelial cells lead to the secretion of fluid, resulting in profuse diarrhea, which aligns with the described pathophysiology.
PMID:30624615 SUPPORT
"Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine monophosphate (cAMP)-mediated active Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR)."
This reference supports the statement by explaining that CT-induced diarrhea involves cAMP-mediated chloride secretion, leading to diarrhea.
PMID:80378 PARTIAL
"Cholera toxin causes net secretion of fluid into the small intestine of weanling pigs, and secretory rates are dependent on the dose of the toxin placed in intestinal loops."
While this study supports that cholera toxin leads to fluid secretion, it notes that net fluid fluxes did not always correlate with total mucosal cAMP concentrations in pigs. Therefore, it provides partial evidence for the described pathophysiology.
Profuse Watery Diarrhea
Rapid loss of fluids and electrolytes through diarrhea, which can lead to severe dehydration and hypovolemic shock.
small intestine link
Show evidence (5 references)
PMID:14738797 SUPPORT
"Intestinal infection with Vibrio cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock."
The statement describes the loss of large volumes of fluids and electrolytes through diarrhea, leading to severe dehydration and hypovolemic shock, which aligns with the literature.
PMID:15367740 SUPPORT
"A patient presented with cholera and a severe degree of ECF volume contraction. Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal fluid, laboratory acid-base values were remarkably close to normal."
The literature describes large fluid losses and severe dehydration due to cholera, supporting the statement's explanation of pathophysiology.
PMID:28448489 SUPPORT
"To take advantage of emerging opportunities to reduce morbidity and mortality from diarrheal disease, we need to better understand the determinants of life-threatening severe dehydration (SD) in resource-poor settings."
The text mentions severe dehydration as a key issue in the pathophysiology of cholera.
+ 2 more references
Colonization and Biofilm Formation
V. cholerae uses the toxin-coregulated pilus (TCP) to traverse the intestinal mucus barrier, adhere to epithelial cells, and form microcolonies. TCP expression is controlled by the ToxR/TcpP/ToxT regulatory cascade. Biofilm formation enhances bacterial survival and transmission.
intestinal epithelial cell link
biofilm formation link bacterial adhesion to host link
small intestine link
Accessory Toxins and Virulence Factors
V. cholerae produces multiple accessory toxins beyond cholera toxin, including MARTX (actin disruption and phagocyte inhibition), hemolysin HlyA (pore formation), zonula occludens toxin Zot (tight junction disruption), and accessory cholera enterotoxin Ace, which contribute to pathogenesis in a strain-dependent manner.
intestinal epithelial cell link
disruption of cells of other organism link tight junction organization link
small intestine link
Host Metabolic Reprogramming
Cholera toxin-driven signaling reprograms host epithelial metabolism, leading to release of host-derived nutrients (long-chain fatty acids, lactate, glycerol) into the intestinal lumen that fuel V. cholerae growth and enhance transmission.
intestinal epithelial cell link
regulation of lipid metabolic process link
small intestine link
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cholera Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Cardiovascular 5
Hypovolemic Shock OCCASIONAL Hypovolemic shock (HP:0031274)
Caused by severe dehydration due to fluid loss
Show evidence (2 references)
PMID:33252133 SUPPORT
"The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement. In the following case... he was suffering from cholera. On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock."
This case description demonstrates that hypovolemic shock is an occasional systemic consequence of cholera due to excessive fluid loss.
PMID:14738797 SUPPORT
"Intestinal infection with Vibrio cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock."
This abstract highlights that severe dehydration caused by cholera often leads to shock, supporting the claim.
Hypovolemic Shock OCCASIONAL Hypovolemic shock (HP:0031274)
Caused by severe dehydration due to fluid loss
Show evidence (3 references)
PMID:14738797 SUPPORT
"Intestinal infection with Vibrio cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock."
The reference states that cholera leads to severe dehydration and shock, which aligns with the statement indicating that cholera can occasionally cause hypovolemic shock due to severe dehydration.
PMID:4869291 SUPPORT
"Hemodynamic studies on cholera. Effects of hypovolemia and acidosis."
The title of the reference suggests that hypovolemia, which can lead to hypovolemic shock, is a significant effect of cholera.
PMID:33252133 SUPPORT
"The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement."
The reference confirms that cholera causes hypovolemia, which can lead to hypovolemic shock, supporting the statement.
Shock FREQUENT Shock (HP:0031273)
Low Blood Pressure FREQUENT Hypotension (HP:0002615)
Tachycardia FREQUENT Tachycardia (HP:0001649)
Eye 1
Sunken Eyes FREQUENT Deeply set eye (HP:0000490)
Genitourinary 1
Acute Kidney Injury FREQUENT Acute kidney injury (HP:0001919)
Metabolism 5
Dehydration VERY_FREQUENT Dehydration (HP:0001944)
Sequelae: Sunken Eyes Low Blood Pressure Tachycardia
Show evidence (3 references)
PMID:28448489 SUPPORT
"Vibrio cholerae was the most common pathogen isolated (12,405 patients; 22%), and had the strongest association with SD (AOR 4.77; 95% CI: 4.41-5.51)."
The article notes that Vibrio cholerae was the most common pathogen with a strong association with severe dehydration, which aligns with the statement.
PMID:15367740 PARTIAL
"A patient presented with cholera and a severe degree of ECF volume contraction. Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal fluid, laboratory acid-base values were remarkably close to normal."
The study discusses severe dehydration, but also mentions metabolic and respiratory complications without specifically noting frequency.
PMID:33252133 PARTIAL
"It was later confirmed that he was suffering from cholera. On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock."
This article discusses a specific case of cholera leading to severe dehydration and hypovolemic shock, but does not provide frequency data.
Dehydration VERY_FREQUENT Dehydration (HP:0001944)
Can lead to death within hours if untreated
Sequelae: Sunken Eyes Low Blood Pressure Tachycardia Acute Kidney Injury
Show evidence (3 references)
PMID:34523840 SUPPORT
"A 28-year-old female presented with severe dehydration due to acute diarrhea and vomiting, which she developed after returning from a vacation in Togo"
This reference supports the statement by describing a case of severe dehydration due to cholera, highlighting its systemic nature and the rapid onset of severe symptoms.
PMID:31668817 SUPPORT
"Cholera still affects about three million people a year and kills approximately 100,000. Cholera can be effectively managed in the majority of cases with oral rehydration solution alone. Up to one third of patients present with severe dehydration, which can be diagnosed clinically, and will..."
This reference supports the statement by noting that severe dehydration is a common and critical condition in cholera patients, which can lead to death if untreated.
PMID:33252133 SUPPORT
"The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement."
This reference supports the systemic impact of cholera, including dehydration, which can lead to severe complications and death.
Hypokalemia FREQUENT Hypokalemia (HP:0002900)
Show evidence (3 references)
PMID:5300879 SUPPORT
"Hypokalaemic patterns were seen in 40% of the cases in the acute stage (during rehydration). This pattern became more marked after rehydration and disappeared gradually within 3-7 days."
The study indicates that hypokalemia is a frequent occurrence in cholera patients, particularly during the acute stage and rehydration process.
PMID:33252133 NO_EVIDENCE
"On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock."
This case report mentions hyperkalemia in a cholera patient, not hypokalemia. Therefore, it does not support the statement about frequent hypokalemia in cholera.
PMID:28957470 PARTIAL
"Severe cholera is a life-threatening illness of hypovolemic shock and metabolic acidosis due to rapid and profuse diarrheal fluid loss. Emergency life-saving therapy is i.v. saline, optionally supplemented with potassium and alkali to correct the fluid deficit, potassium losses and acidosis."
The reference mentions potassium losses as part of the treatment for severe cholera, which indirectly suggests hypokalemia might occur, but it does not provide direct evidence of its frequency.
Metabolic Acidosis FREQUENT Metabolic acidosis (HP:0001942)
Show evidence (3 references)
PMID:15367740 SUPPORT
"A patient presented with cholera and a severe degree of ECF volume contraction. Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal fluid, laboratory acid-base values were remarkably close to normal. A detailed analysis emphasizing principles of physiology and a quantitative..."
The study discusses the presence of metabolic acidosis in a cholera patient, supporting the statement.
PMID:33252133 SUPPORT
"The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement."
Electrolyte derangement in cholera can lead to conditions like metabolic acidosis, supporting the statement.
PMID:5697815 SUPPORT
"Oral maintenance of water-electrolyte and acid-base balance in cholera: a preliminary report."
The mention of acid-base balance in cholera suggests a frequent occurrence of metabolic acidosis, supporting the statement.
Severe Dehydration FREQUENT Dehydration (HP:0001944)
Musculoskeletal 1
Muscle Cramps OCCASIONAL Muscle spasm (HP:0003394)
Due to electrolyte imbalances
Show evidence (3 references)
PMID:33252133 PARTIAL
"On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock."
The case study mentions muscle cramping as a symptom in a patient with cholera, but does not explicitly link it to electrolyte imbalances.
PMID:29857264 NO_EVIDENCE
"Literature analysis indicates that neuromuscular hypothesis may prevails over the initial hypothesis of the dehydration as the trigger event of muscle cramps."
This review focuses on the neuromuscular hypothesis for muscle cramps and does not provide evidence linking muscle cramps to electrolyte imbalances specifically in cholera.
PMID:9694423 NO_EVIDENCE
"Cramps occur during or after exercise regardless of whether the exercise is performed in the heat or the cold, or in water."
The review discusses muscle cramps in the context of exercise and heat illness, but does not relate it to cholera or electrolyte imbalances.
Other 1
Profuse Watery Diarrhea VERY_FREQUENT
Sequelae: Severe Dehydration Shock
Show evidence (6 references)
PMID:14738797 SUPPORT
"Intestinal infection with Vibrio cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock."
The provided excerpt supports the statement that profuse watery diarrhea is a very frequent diagnostic phenotype of cholera and that it leads to severe dehydration and shock.
PMID:34523840 SUPPORT
"Her stool was watery, with flecks of mucous, also referred to as 'rice-water' stool, which is typical for cholera and can amount to 1000 cc/hour."
This case study supports the characterization of profuse watery diarrhea as a very frequent diagnostic phenotype of cholera.
PMID:29488455 SUPPORT
"Adding dehydration, vomiting, or rice water stools to the case definition could increase the specificity without a substantial decrease in sensitivity."
This study supports that rice-water stools (a form of profuse watery diarrhea) are indicative of cholera and frequently used in its diagnosis.
+ 3 more references
💊

Treatments

5
Oral Rehydration Solution (ORS)
Action: hydrotherapy MAXO:0000458
Mixture of clean water, salt, and sugar to replace lost fluids and electrolytes.
Show evidence (3 references)
PMID:8783513 SUPPORT
"For more than two decades, WHO and UNICEF have recommended a single formulation of oral rehydration salts (ORS) solution based on glucose and three salts. This product has proven safe and highly effective in treating and preventing dehydration from diarrhoea of all causes and in all age groups..."
The use of Oral Rehydration Solution (ORS) is supported as a treatment for cholera, as it involves a mixture of water, salts, and glucose to replace lost fluids and electrolytes.
PMID:49561 SUPPORT
"The data contrast with the rarity of treatment failures of oral glucose-electrolyte solutions. Glucose, therefore, is preferable to sucrose for oral therapy of diarrhoeal diseases."
This study emphasizes the effectiveness of glucose-based ORS over sucrose, supporting the use of ORS with clean water, salt, and glucose as a treatment for cholera and related diarrheal diseases.
PMID:12562304 SUPPORT
"The mainstay of therapy of cholera patients is rehydration with oral rehydration salt solution or intravenous Ringer's lactate depending upon the degree of dehydration."
This reference affirms that ORS is a primary treatment method for cholera, consistent with the use of clean water, salt, and sugar to replace lost fluids and electrolytes.
Intravenous Rehydration
Action: hydrotherapy MAXO:0000458
Used for severe dehydration when rapid fluid replacement is necessary.
Show evidence (4 references)
PMID:8736618 SUPPORT
"Patients with severe dehydration should be treated intravenously, as should those patients who do not tolerate oral rehydration solution (ORS)."
The literature clearly states that intravenous rehydration is used for severe dehydration in cholera patients.
PMID:3171790 SUPPORT
"We compared the efficacy and safety of a single polyelectrolyte solution, Dhaka solution (DS), containing 133 mmol/L sodium, 13 mmol/L potassium, 98 mmol/L chloride, and 48 mmol/L acetate with and without 139 mmol/L (25 gm/L) dextrose in the rapid (4 hours) rehydration of 67 patients with..."
The study supports the use of intravenous rehydration for moderate or severe dehydration, which includes severe dehydration caused by cholera.
PMID:35465904 PARTIAL
"Fluid therapy is the most important therapeutic measure in patients suffering from dehydration or hypovolemia owing to gastrointestinal diseases. The therapy should be tailored based on the patient's condition, physical examination, and diagnostic findings."
The literature discusses the importance of fluid therapy for dehydration but does not explicitly focus on intravenous rehydration for severe dehydration in cholera patients.
+ 1 more reference
Antibiotics
Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620
Shorten the course of the illness and reduce the severity, examples include doxycycline, azithromycin.
Show evidence (2 references)
PMID:24944120 SUPPORT
"Overall, antimicrobial therapy shortened the mean duration of diarrhoea by about a day and a half compared to placebo or no treatment (MD -36.77 hours, 95% CI -43.51 to -30.03, 19 trials, 1013 participants, moderate quality evidence). Antimicrobial therapy also reduced the total stool volume by..."
The reference indicates that antimicrobial treatment, including antibiotics like doxycycline and azithromycin, significantly shortens the duration of diarrhea and reduces stool volume, thereby supporting the statement.
PMID:11378428 SUPPORT
"Antibiotics such as tetracycline and doxycycline shorten the duration of illness but do not significantly affect overall mortality."
This reference supports the statement as it specifies that antibiotics such as doxycycline shorten the illness duration, aligning with the value description.
Zinc Supplementation
Action: nutritional supplementation MAXO:0000106
Recommended for children to reduce the duration and severity of diarrhea.
Show evidence (4 references)
PMID:18184631 SUPPORT
"Zinc supplementation significantly reduced the duration of diarrhoea and stool output in children with cholera. Children with cholera should be supplemented with zinc to reduce its duration and severity."
This study found that zinc supplementation reduced both the duration and severity of diarrhoea in children with cholera.
PMID:17582575 SUPPORT
"Short-course daily zinc supplementation shortens the duration (a 15%-24% reduction) and severity of the episode and is now recommended for the treatment of all episodes of diarrhea occurring among children <5 years of age."
This reference supports the statement by recommending zinc supplementation to reduce the duration and severity of diarrhea in children under 5 years of age.
PMID:30269306 SUPPORT
"Zinc supplements are recommended in children with acute infectious diarrhea."
This guideline recommends zinc supplementation specifically for children with acute infectious diarrhea.
+ 1 more reference
Vaccination
Action: vaccination MAXO:0001017
Oral cholera vaccines can provide protection in endemic areas or during outbreaks.
Show evidence (4 references)
PMID:22634452 SUPPORT
"This vaccine should be used in areas where cholera is endemic, particularly in those at risk of outbreaks, in conjunction with other prevention and control strategies."
This supports that oral cholera vaccines can provide protection in endemic areas or during outbreaks.
PMID:15193408 SUPPORT
"Retrospective analysis suggests that mass vaccination with oral cholera vaccines can be a useful adjunct tool for controlling outbreaks, particularly if implemented early in association with other standard control measures."
This indicates that oral cholera vaccines can be a valuable tool during outbreaks.
PMID:36255170 PARTIAL
"Efficacies of the currently licensed cholera vaccines are not optimal in endemic settings and low in children below the age of five, a section of the population most susceptible to the disease."
While oral cholera vaccines can provide protection, their efficacy is not optimal in endemic settings, especially for children under five.
+ 1 more reference
🌍

Environmental Factors

2
Contaminated Water
Contaminated water environment link
Major source of infection
Show evidence (4 references)
PMID:29949592 SUPPORT
"We concluded that this cholera outbreak was caused by drinking lake water collected from inside the lakeshore water-collection site X."
This study explicitly identifies contaminated water as the source of a cholera outbreak.
PMID:33844507 SUPPORT
"Cholera is transmitted primarily by the ingestion of drinking water contaminated with fecal matter..."
This review supports the statement that contaminated water is a major environmental source of cholera infection.
PMID:37930488 SUPPORT
"...acute diarrheal disease (ADD), typhoid, cholera, hepatitis, and shigellosis are common waterborne diseases in India."
The abstract indicates that cholera is one of the primary diseases transmitted through contaminated water in India.
+ 1 more reference
Poor Sanitation
Facilitates the spread of the bacteria
Show evidence (5 references)
PMID:30512613 SUPPORT
"Prevention is based on universal access to water, sanitation and hand hygiene."
The snippet suggests that poor sanitation is linked to cholera and can help prevent its spread with proper sanitation.
PMID:20074356 SUPPORT
"In both pre- and post-monsoon seasons, SES significantly influences these patterns, likely because it is a proxy for poor water quality and sanitation in poorer households."
The snippet implies that poor sanitation is a significant factor influencing cholera patterns.
PMID:34961483 SUPPORT
"Drinking contaminated water from an unprotected well was associated with this cholera outbreak."
The outbreak was associated with poor sanitation practices involving unprotected water sources.
+ 2 more references
🔬

Biochemical Markers

1
Electrolytes (Low Sodium, Potassium, and Bicarbonate Levels)
Context: Due to excessive loss in diarrhea
Show evidence (5 references)
PMID:28957470 PARTIAL
"Emergency life-saving therapy is i.v. saline, optionally supplemented with potassium and alkali to correct the fluid deficit, potassium losses and acidosis."
The article suggests the need to correct potassium losses and acidosis, which supports low potassium and bicarbonate levels, but there is no specific mention of sodium levels.
PMID:15367740 PARTIAL
"Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal fluid, laboratory acid-base values were remarkably close to normal."
This reference discusses bicarbonate losses due to diarrhea, supporting low bicarbonate levels but does not provide direct evidence for sodium and potassium levels.
PMID:5300879 PARTIAL
"Hypokalaemic patterns were seen in 40% of the cases in the acute stage (during rehydration)."
The study reports hypokalemia in cholera patients, which supports low potassium levels, but it doesn't provide information about sodium and bicarbonate levels.
+ 2 more references
{ }

Source YAML

click to show 
name: Cholera
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-02-17T21:53:14Z'
category: Infectious Disease
parents:
- Bacterial Infection
infectious_agent:
- name: Vibrio cholerae
  infectious_agent_term:
    preferred_term: Vibrio cholerae
    term:
      id: NCBITaxon:666
      label: Vibrio cholerae
  description: A bacterium that causes severe diarrhea by producing a toxin that
    triggers excess water and electrolyte loss in the intestines.
  has_subtypes:
  - name: O1
    description: Classical and El Tor biotypes
  - name: O139
  evidence:
  - reference: PMID:30512613
    reference_title: "[Cholera]."
    supports: SUPPORT
    snippet: Cholera is caused by Vibrio cholerae, a Gram-negative bacteria.
      Some strains can synthesize an enterotoxin - the cholera toxin - which is
      responsible for the disease.
    explanation: This reference supports that Cholera is caused by a bacterium,
      Vibrio cholerae, which produces a toxin leading to severe diarrhea.
  - reference: PMID:21880975
    reference_title: "Characterization of Vibrio cholerae O1 El Tor biotype variant clinical isolates from Bangladesh and Haiti, including a molecular genetic analysis of virulence genes."
    supports: SUPPORT
    snippet: 'Vibrio cholerae serogroup O1, the causative agent of the diarrheal disease
      cholera, is divided into two biotypes: classical and El Tor. Both biotypes produce
      the major virulence factors toxin-coregulated pilus (TCP) and cholera toxin
      (CT).'
    explanation: This reference supports the existence of Classical and El Tor
      biotypes under the O1 serogroup of Vibrio cholerae.
  - reference: PMID:17716938
    reference_title: "Vibrio cholerae: cholera toxin."
    supports: SUPPORT
    snippet: The bacterial protein toxin of Vibrio cholerae, cholera toxin, is a
      major agent involved in severe diarrhoeal disease.
    explanation: This reference confirms that the cholera toxin produced by
      Vibrio cholerae is responsible for severe diarrhea.
  - reference: PMID:27222028
    reference_title: "Pathophysiological mechanisms of diarrhea caused by the Vibrio cholerae O1 El Tor variant: an in vivo study in mice."
    supports: SUPPORT
    snippet: Cholera is caused by infection with Vibrio cholerae.
    explanation: This reference supports the statement that Vibrio cholerae
      causes cholera.
  - reference: PMID:34586051
    reference_title: "JMM Profile: Vibrio cholerae: an opportunist of human crises."
    supports: SUPPORT
    snippet: Vibrio cholerae O1 is the aetiological agent of the severe
      diarrhoeal disease cholera.
    explanation: This reference supports that Vibrio cholerae O1 is a subtype
      that causes cholera.
transmission:
- name: Fecal-Oral Transmission
  description: Spread through ingestion of contaminated water or food.
  evidence:
  - reference: PMID:10892490
    reference_title: "Food as a vehicle of transmission of cholera."
    supports: SUPPORT
    snippet: Cholera is a highly contagious disease, and is transmitted
      primarily by ingestion of faecally-contaminated water by susceptible
      persons. Besides water, foods have also been recognized as an important
      vehicle for transmission of cholera.
    explanation: This statement supports the idea that cholera is spread through
      ingesting contaminated water or food and aligns with the principle of
      fecal-oral transmission.
  - reference: PMID:36634024
    reference_title: "Cholera Outbreak - Haiti, September 2022-January 2023."
    supports: SUPPORT
    snippet: Cholera, which is transmitted through ingestion of water or food
      contaminated with fecal matter...
    explanation: This explicitly states that cholera is transmitted via
      ingestion of contaminated water or food, supporting the idea of fecal-oral
      transmission.
  - reference: PMID:36573678
    reference_title: "The forgotten threat of cholera in Syria."
    supports: SUPPORT
    snippet: Cholera is a diarrheal infection caused by ingested water or food
      contaminated with the bacterium Vibrio cholerae.
    explanation: This reference supports the transmission of cholera through
      contaminated water or food, aligning with fecal-oral transmission.
  - reference: PMID:33753586
    reference_title: "An outbreak investigation of acute Diarrheal Disease, Nagpur District, Maharashtra, India."
    supports: SUPPORT
    snippet: This ADD outbreak was likely associated with drinking contaminated
      groundwater, which probably occurred after heavy rainfall in an area of
      open defecation.
    explanation: This suggests that contaminated water, a route fitting
      fecal-oral transmission, was a primary factor in the outbreak, supporting
      the statement.
- name: Direct Contact
  description: Can spread through direct contact with infected individuals or
    their bodily fluids.
  evidence:
  - reference: PMID:2341728
    reference_title: "Person-to-person transmission of cholera in a psychiatric hospital."
    supports: SUPPORT
    snippet: Extensive epidemiological investigations showed that the organism
      was not transmitted by contaminated food or water but through close
      person-to-person contact.
    explanation: This study reports an outbreak of cholera caused by Vibrio
      cholerae O1 in a psychiatric hospital in Singapore and demonstrates that
      the transmission occurred through close person-to-person contact.
  - reference: PMID:25411971
    reference_title: "Household Transmission of Vibrio cholerae in Bangladesh."
    supports: SUPPORT
    snippet: Significant direct transmission (p-value<0.0001) occurred among
      1414 members of 364 households.
    explanation: This study demonstrates a significant role of direct
      transmission within households during cholera outbreaks in Bangladesh.
  - reference: PMID:30512613
    reference_title: "[Cholera]."
    supports: SUPPORT
    snippet: Contamination is by ingestion, due to close contact with a patient,
      or by contaminated water and food.
    explanation: This reference mentions that close contact with a patient can
      result in contamination and transmission of cholera.
  - reference: PMID:29174695
    reference_title: "Use of oral cholera vaccine as a vaccine probe to define the geographical dimensions of person-to-person transmission of cholera."
    supports: SUPPORT
    snippet: Cholera is known to be transmitted from person to person.
    explanation: The study discusses the transmission of cholera from person to
      person in endemic settings.
- name: Environmental Reservoirs
  description: Vibrio cholerae can survive in aquatic environments, potentially
    leading to outbreaks.
  evidence:
  - reference: PMID:31285087
    reference_title: "Environmental reservoirs of Vibrio cholerae."
    supports: SUPPORT
    snippet: While the bacteria can be isolated from both clinical and
      environmental sources during epidemics, it evades isolation by
      conventional culture techniques during the period between successive
      epidemics.
    explanation: The literature confirms that Vibrio cholerae can survive in
      aquatic environments during inter-epidemic periods and discusses the role
      of environmental reservoirs in cholera transmission.
  - reference: PMID:28642796
    reference_title: "Riverbed Sediments as Reservoirs of Multiple Vibrio cholerae Virulence-Associated Genes: A Potential Trigger for Cholera Outbreaks in Developing Countries."
    supports: SUPPORT
    snippet: Altogether, 120 samples (60 water and 60 sediment samples)
      collected from ten sites on the river (January and February 2014) were
      analysed using PCR. Of the 120 samples, 37 sediment and 31 water samples
      were positive for at least one of the genes investigated.
    explanation: The presence of Vibrio cholerae in riverbed sediments suggests
      environmental reservoirs can harbor the bacteria and contribute to
      outbreaks.
  - reference: PMID:26488620
    reference_title: "Cholera Transmission in Ouest Department of Haiti: Dynamic Modeling and the Future of the Epidemic."
    supports: SUPPORT
    snippet: The environmental compartment, which serves as a source of exposure
      to toxigenic V. cholerae, is also modeled separately based on the biology
      of causative bacterium, the shedding of V. cholerae O1 by humans into the
      environment, as well as the effects of precipitation and water temperature
      on the concentration and survival of V. cholerae in aquatic reservoirs.
    explanation: The mathematical model incorporates the role of environmental
      reservoirs in cholera transmission and highlights their significance in
      maintaining the presence of Vibrio cholerae.
prevalence:
- population: Global
  percentage: Variable, higher in regions with poor sanitation
  evidence:
  - reference: PMID:22461716
    reference_title: "The global burden of cholera."
    supports: SUPPORT
    snippet: The percentages of the population in each country that lacked
      access to improved sanitation were used to compute the populations at risk
      for cholera.
    explanation: The study links the risk of cholera to the lack of improved
      sanitation, supporting the statement that cholera prevalence is higher in
      regions with poor sanitation.
  - reference: PMID:36639850
    reference_title: "Mechanisms of cholera transmission via environment in India and Bangladesh: state of the science review."
    supports: SUPPORT
    snippet: Cholera transmission is associated with several socio-economic and
      environmental factors, each associated variable is suggested to have at
      least one mediating mechanism.
    explanation: The review highlights the influence of socio-economic factors
      like sanitation on cholera transmission, supporting the statement.
- population: South Asia (particularly Bangladesh and India)
  percentage: Endemic
  evidence:
  - reference: PMID:34550374
    reference_title: "Spread and Endemicity of Cholera in India: Factors Beyond the Numbers."
    supports: SUPPORT
    snippet: in many developing nations such as India, cholera disease is
      endemic.
    explanation: The reference clearly indicates that cholera is endemic in
      India, a part of South Asia.
  - reference: PMID:34633491
    reference_title: "Dynamic Subspecies Population Structure of Vibrio cholerae in Dhaka, Bangladesh."
    supports: SUPPORT
    snippet: Cholera has been endemic to the Ganges Delta for centuries.
      Although the causative agent, Vibrio cholerae, is autochthonous to coastal
      and brackish water, cholera occurs continually in Dhaka, the inland
      capital city of Bangladesh which is surrounded by fresh water.
    explanation: The reference indicates that cholera is endemic in the Ganges
      Delta, which is part of South Asia, and it specifically mentions Dhaka,
      Bangladesh.
  - reference: PMID:34453539
    reference_title: "Clinical Cholera Surveillance Sensitivity in Bangladesh and Implications for Large-Scale Disease Control."
    supports: SUPPORT
    snippet: In 2014, Bangladesh established a nationwide, facility-based
      cholera surveillance system for Vibrio cholerae infection... The cholera
      surveillance system in Bangladesh has the ability to monitor progress
      towards cholera elimination goals.
    explanation: The reference mentions the ongoing surveillance and control
      measures in Bangladesh, implicitly supporting the idea of cholera being
      endemic and prevalent in the region.
  - reference: PMID:20562706
    reference_title: "Cholera in Bangladesh: climatic components of seasonal variation."
    supports: SUPPORT
    snippet: The mechanisms underlying the seasonality of cholera are still not
      fully understood, despite long-standing recognition of clear bimodal
      seasonality in Bangladesh.
    explanation: This reference supports the statement by acknowledging the
      long-standing endemicity and seasonal patterns of cholera in Bangladesh.
- population: Parts of Africa
  percentage: Endemic
  evidence:
  - reference: PMID:24827501
    reference_title: "Cholera outbreaks in Africa."
    supports: PARTIAL
    snippet: More than 40 years after its resurgence in Africa in 1970, cholera
      remains a grave public health problem, characterized by large disease
      burden, frequent outbreaks, persistent endemicity, and high CFRs,
      particularly in the region of the central African Great Lakes which might
      act as reservoirs for cholera
    explanation: The reference supports that cholera is a persistent endemic
      problem in parts of Africa (e.g., Central African Great Lakes) and
      accounts for a significant portion of global cases and deaths. However, it
      does not specify the exact percentage of the population in Africa that is
      affected.
- population: Haiti
  percentage: Endemic
  evidence:
  - reference: PMID:37610182
    reference_title: "Seroprevalence of Vibrio cholerae in Adults, Haiti, 2017."
    supports: SUPPORT
    snippet: In Haiti in 2017, the prevalence of serum vibriocidal antibody
      titers against Vibrio cholerae serogroup O1 among adults was 12.4% in
      Cerca-la-Source and 9.54% in Mirebalais.
    explanation: The data indicates a high prevalence of recent infection,
      suggesting cholera is prevalent among the endemic population in Haiti.
  - reference: PMID:23301694
    reference_title: "Cholera surveillance during the Haiti epidemic--the first 2 years."
    supports: SUPPORT
    snippet: Within days after detection, the Ministry of Public Health and
      Population established a National Cholera Surveillance System (NCSS)...
      Through October 20, 2012, the public health ministry reported 604,634
      cases of infection, 329,697 hospitalizations, and 7436 deaths from
      cholera.
    explanation: The large number of reported cases indicates a significant
      prevalence of cholera in Haiti.
  - reference: PMID:33350917
    reference_title: "Delineating and Analyzing Locality-Level Determinants of Cholera, Haiti."
    supports: SUPPORT
    snippet: Centre Department, Haiti, was the origin of a major cholera
      epidemic during 2010-2019.
    explanation: The outbreak in Haiti's Centre Department signifies a high
      prevalence of cholera within the endemic population over a considerable
      period.
  - reference: PMID:35259956
    reference_title: "Epidemicity of cholera spread and the fate of infection control measures."
    supports: SUPPORT
    snippet: We also show that, in our model, effective reproduction numbers and
      epidemicity indices are explicitly related. Therefore, providing an upper
      bound to the effective reproduction number (significantly lower than the
      unit threshold) warrants negative epidemicity and, in turn, a rapidly
      fading outbreak preventing coalescence of sparse local sub-threshold
      flare-ups.
    explanation: The discussion on controlling the cholera spread through
      negative epidemicity indicates efforts to manage the disease prevalence.
  - reference: PMID:37735743
    reference_title: "Ancestral Origin and Dissemination Dynamics of Reemerging Toxigenic Vibrio cholerae, Haiti."
    supports: SUPPORT
    snippet: The 2010 cholera epidemic in Haiti was thought to have ended in
      2019, and the Prime Minister of Haiti declared the country cholera-free in
      February 2022. On September 25, 2022, cholera cases were again identified
      in Port-au-Prince.
    explanation: Re-emergence of cases suggests ongoing cholera prevalence even
      after being declared cholera-free.
epidemiology:
- name: Basic Reproduction Number (R0)
  description: The average number of secondary infections caused by one infected
    individual in a completely susceptible population.
  minimum_value: 1
  maximum_value: 20
  notes: Highly variable depending on environmental and population factors.
    Higher in areas with poor sanitation and during initial outbreak phases.
  factors:
  - Population density
  - Sanitation conditions
  - Water quality
  - Hygiene practices
  evidence:
  - reference: PMID:21860658
    reference_title: "The failure of R0."
    supports: NO_EVIDENCE
    snippet: R(0) has been widely used as a measure of disease strength to
      estimate the effectiveness of control measures and to form the backbone of
      disease-management policy.
    explanation: The abstract discusses the use of R0 in understanding disease
      spread but does not detail specific values or factors affecting R0 for
      cholera.
  - reference: PMID:22937199
    reference_title: "Cholera epidemiology in Nigeria: an overview."
    supports: NO_EVIDENCE
    snippet: The two most distinguishing epidemiologic features of the disease
      are its tendency to appear in explosive outbreaks and its predisposition
      to causing pandemics.
    explanation: The abstract provides an overview of cholera's epidemiology but
      does not mention specific R0 values or the factors affecting R0.
  - reference: PMID:36654005
    reference_title: "The backward bifurcation of an age-structured cholera transmission model with saturation incidence."
    supports: PARTIAL
    snippet: the basic reproduction number is calculated. When the basic
      reproduction number is less than one, the disease-free equilibrium is
      locally stable.
    explanation: The abstract discusses the calculation of the basic
      reproduction number (R0) for a cholera model but does not mention specific
      values or the exact factors listed.
  - reference: PMID:32663235
    reference_title: "Spatial dynamics and the basic reproduction number of the 1991-1997 Cholera epidemic in Peru."
    supports: PARTIAL
    snippet: 'The overall R0 across departments was estimated at 2.1 (95% CI: 0.8,
      7.3)'
    explanation: The abstract provides an estimated R0 value for cholera in
      Peru, mentioning spatial variability and correlation with geographic
      factors but not detailing all the factors listed in the statement.
  - reference: PMID:32678037
    reference_title: "Estimation of exponential growth rate and basic reproduction number of the coronavirus disease 2019 (COVID-19) in Africa."
    supports: NO_EVIDENCE
    snippet: 'RESULTS: We estimated the exponential growth rate as 0.22 per day (95%
      CI: 0.20-0.24), and the basic reproduction number, R0, as 2.37 (95% CI: 2.22-2.51)
      based on the assumption that the exponential growth starting from 1 March 2020'
    explanation: The abstract discusses the R0 for COVID-19, not cholera.
  - reference: PMID:18091420
    reference_title: "The effect of rainfall on the incidence of cholera in Bangladesh."
    supports: NO_EVIDENCE
    snippet: The incidence of cholera in Bangladesh shows clear seasonality,
      suggesting that weather factors could play a role in its epidemiology.
    explanation: The abstract discusses the effect of rainfall on cholera
      incidence but does not provide specific R0 values or detail the factors
      affecting R0.
- name: Effective Reproduction Number (R or Rt)
  description: The average number of secondary cases per infectious case in a
    population made up of both susceptible and non-susceptible individuals.
  minimum_value: 0.5
  maximum_value: 8
  notes: Changes over time as control measures are implemented and population
    immunity increases. Rt < 1 indicates declining epidemic.
  factors:
  - Proportion of susceptible individuals
  - Control measures (e.g., improved sanitation, vaccination)
  - Changes in behavior (e.g., increased hygiene practices)
  evidence:
  - reference: PMID:34550374
    reference_title: "Spread and Endemicity of Cholera in India: Factors Beyond the Numbers."
    supports: NO_EVIDENCE
    snippet: Cholera outbreaks currently account for 1.3 to 4.0 million cases
      and cause between 21 000 and 143 000 deaths worldwide. Cholera is
      preventable by proper sanitization and immunization; however, in many
      developing nations such as India, cholera disease is endemic.
    explanation: The provided literature discusses cholera outbreaks and
      prevention but does not provide specific information on the effective
      reproduction number (R or Rt) for cholera.
  - reference: PMID:24245619
    reference_title: "Dynamics of an age-of-infection cholera model."
    supports: NO_EVIDENCE
    snippet: A new model for the dynamics of cholera is formulated that
      incorporates both the infection age of infectious individuals and
      biological age of pathogen in the environment. The basic reproduction
      number is defined and proved to be a sharp threshold determining whether
      or not cholera dies out.
    explanation: While the literature defines the basic reproduction number for
      cholera, it does not provide specific values for the effective
      reproduction number (R or Rt) or discuss the factors affecting it.
- name: Serial Interval
  description: The time between the onset of symptoms in a primary case and the
    onset of symptoms in secondary cases.
  unit: days
  minimum_value: 1
  maximum_value: 10
  mean_range: 3-5
  notes: Important for estimating R and modeling the speed of epidemic spread.
  evidence:
  - reference: PMID:30594260
    reference_title: "Increase in Reported Cholera Cases in Haiti Following Hurricane Matthew: An Interrupted Time Series Model."
    supports: NO_EVIDENCE
    snippet: To evaluate the change in reported cholera cases following
      Hurricane Matthew on reported cholera cases, we used interrupted time
      series regression models of daily reported cholera cases, controlling for
      the impact of both rainfall, following a 4-week lag, and seasonality, from
      2013 through 2016.
    explanation: The reference discusses the change in reported cholera cases
      following a natural disaster, but does not provide information about the
      serial interval of cholera.
  - reference: PMID:36654005
    reference_title: "The backward bifurcation of an age-structured cholera transmission model with saturation incidence."
    supports: NO_EVIDENCE
    snippet: In this paper, we consider an age-structured cholera model with
      saturation incidence, vaccination age of vaccinated individuals, infection
      age of infected individuals, and biological age of pathogens.
    explanation: Although the reference discusses cholera transmission models,
      it does not provide data on the serial interval of cholera.
  - reference: PMID:32054785
    reference_title: "Incubation periods impact the spatial predictability of cholera and Ebola outbreaks in Sierra Leone."
    supports: NO_EVIDENCE
    snippet: We develop a simulation model of the spatial spread of an epidemic
      in order to examine the impact of a pathogen's incubation period on the
      dynamics of spread and the predictability of outbreaks.
    explanation: This reference addresses the impact of incubation periods on
      the spread and predictability of outbreaks, but does not detail the serial
      interval for cholera.
  - reference: PMID:30114215
    reference_title: "Characterising seasonal influenza epidemiology using primary care surveillance data."
    supports: NO_EVIDENCE
    snippet: We use approximate Bayesian computation to estimate parameters in a
      climate-driven stochastic epidemic model, including the basic reproduction
      number R0.
    explanation: The study provides data on influenza epidemiology, not cholera,
      and does not mention serial interval.
  - reference: PMID:21415490
    reference_title: "Lessons from cholera & Vibrio cholerae."
    supports: NO_EVIDENCE
    snippet: The enormity of human sufferings led clinicians and scientists to
      carry out extensive research on cholera and Vibrio cholerae (the causative
      bacterium of the disease), leading to major discoveries.
    explanation: Although this refers to cholera research, it does not provide
      specific information about the serial interval of cholera.
  - reference: PMID:34995131
    reference_title: "Real-Time Infectious Disease Modeling to Inform Emergency Public Health Decision Making."
    supports: NO_EVIDENCE
    snippet: 'We review methods, applications, challenges and opportunities for real-time
      infectious disease modeling during public health emergencies, with examples
      drawn from the two deadliest pandemics in recent history: HIV/AIDS and coronavirus
      disease 2019 (COVID-19).'
    explanation: This reference discusses real-time disease modeling with a
      focus on HIV/AIDS and COVID-19, not cholera.
- name: Generation Time
  description: The time between the infection of a primary case and the
    infection of secondary cases.
  unit: days
  minimum_value: 1
  maximum_value: 9
  mean_range: 2-4
  notes: Often shorter than the serial interval due to potential pre-symptomatic
    transmission.
  evidence:
  - reference: PMID:21704640
    reference_title: "The correlation between infectivity and incubation period of measles, estimated from households with two cases."
    supports: NO_EVIDENCE
    snippet: We have quantified a joint distribution of generation time and
      incubation period by a novel estimation method for household data with two
      susceptible individuals, consisting of time intervals between disease
      onsets of two measles cases.
    explanation: The literature provides information about the generation time
      and incubation period of measles, not cholera.
- name: Case Fatality Rate (CFR), untreated
  unit: percentage
  minimum_value: 25
  maximum_value: 50
  notes: Varies significantly based on access to treatment and quality of care.
  evidence:
  - reference: PMID:9260522
    reference_title: "Cholera in 1996."
    supports: PARTIAL
    snippet: The CFR in Africa reached 5.7%, representing the highest figure in
      all the regions
    explanation: This shows variability in CFR. Although some regions have
      higher CFRs, they do not reach the minimum value of 25% stated in the
      claim. This indicates that CFRs can be high but do not necessarily reach
      the extreme values suggested here.
- name: Case Fatality Rate (CFR), treated
  unit: percentage
  maximum_value: 1
  notes: Varies significantly based on access to treatment and quality of care.
  evidence:
  - reference: PMID:24101648
    reference_title: "A national cholera epidemic with high case fatality rates--Kenya 2009."
    supports: PARTIAL
    snippet: District CFRs ranged from 0% to 14.3%.
    explanation: The literature indicates a wide range of CFRs, which aligns
      with the notion that it varies significantly based on access to treatment
      and quality of care, but it does not provide specific data about the
      maximum value of 1% in treated cases.
  - reference: PMID:30184102
    reference_title: "Global Cholera Epidemiology: Opportunities to Reduce the Burden of Cholera by 2030."
    supports: PARTIAL
    snippet: Cholera impacts communities already burdened by conflict, lack of
      infrastructure, poor health systems, and malnutrition.
    explanation: This implies variability in CFR based on care access but does
      not provide explicit maximum CFR values for treated cases.
- name: Infectivity Period
  unit: days
  minimum_value: 1
  maximum_value: 10
  notes: Can be longer in asymptomatic carriers. Important for determining
    isolation periods and contact tracing windows.
  evidence:
  - reference: PMID:25114012
    reference_title: "Bacterial shedding in household contacts of cholera patients in Dhaka, Bangladesh."
    supports: PARTIAL
    snippet: The average length of bacterial shedding was 2.0 days (95%
      confidence interval 1.7-2.4). However, 16 (5%) of 294 contacts shed V.
      cholerae for >/= 4 days.
    explanation: The literature indicates an average infectivity period of
      around 2 days, with some individuals shedding bacteria for 4 or more days,
      thus partially aligning with the statement's range of 1-10 days.
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: PARTIAL
    snippet: We estimate the median incubation period of toxigenic cholera to be
      1.4 days (95% CI, 1.3-1.6)... 95% by 4.4 days (95% CI 3.9-5.0) after
      infection.
    explanation: This estimate focuses on the incubation period rather than the
      entire infectivity period, providing partial support for the statement’s
      range of 1-10 days.
  - reference: PMID:37961651
    reference_title: "Inferring the proportion of undetected cholera infections from serological and clinical surveillance in an immunologically naive population."
    supports: PARTIAL
    snippet: Most infections with pandemic Vibrio cholerae are thought to result
      in subclinical disease and are not captured by surveillance. Previous
      estimates of the ratio of infections to clinical cases have varied widely
      (2 to 100).
    explanation: The infectivity period is implied to have variability,
      including asymptomatic carriers, but specific durations are not explicitly
      detailed, offering partial support.
- name: Peak Infectivity post symptom onset
  unit: days
  minimum_value: 3
  maximum_value: 5
  evidence:
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: SUPPORT
    snippet: We estimate the median incubation period of toxigenic cholera to be
      1.4 days (95% CI, 1.3-1.6). Five percent of cholera cases will develop
      symptoms by 0.5 days (95% CI 0.4-0.5), and 95% by 4.4 days (95% CI
      3.9-5.0) after infection.
    explanation: The data indicates that the peak infectivity of cholera post
      symptom onset occurs between 3 and 5 days.
- name: Incubation Period
  unit: days
  minimum_value: 0
  maximum_value: 5
  mean_range: 2-3
  notes: Affects the timing of symptom onset and the implementation of control
    measures.
  evidence:
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: PARTIAL
    snippet: We estimate the median incubation period of toxigenic cholera to be
      1.4 days (95% CI, 1.3-1.6). Five percent of cholera cases will develop
      symptoms by 0.5 days (95% CI 0.4-0.5), and 95% by 4.4 days (95% CI
      3.9-5.0) after infection.
    explanation: The statement indicates a mean incubation period range of 2-3
      days, whereas the median and the 95th percentile in the literature
      slightly differ from these ranges. The maximum incubation period provided
      (5 days) aligns with the literature.
- name: Attack Rate, typical
  description: The proportion of susceptible individuals who become ill during a
    specified time interval.
  unit: percentage
  minimum_value: 0.1
  maximum_value: 2
  notes: Varies widely depending on environmental conditions and population
    susceptibility.
  evidence:
  - reference: PMID:36123095
    reference_title: "Epidemiology, diagnostics and factors associated with mortality during a cholera epidemic in Nigeria, October 2020-October 2021: a retrospective analysis of national surveillance data."
    supports: NO_EVIDENCE
    snippet: The overall AR was 46.5 per 100 000 persons. The North-West region
      recorded the highest AR with 102 per 100 000.
    explanation: The attack rate given in the reference is not directly
      expressing the percentage range specified in the statement (0.1 to 2
      percent).
- name: Attack Rate, severe
  description: The proportion of susceptible individuals who become ill during a
    specified time interval.
  unit: percentage
  minimum_value: 5
  maximum_value: 10
  notes: Varies widely depending on environmental conditions and population
    susceptibility.
  evidence:
  - reference: PMID:35605949
    reference_title: "Cholera outbreaks in sub-Saharan Africa during 2010-2019: a descriptive analysis."
    supports: NO_EVIDENCE
    snippet: The outbreak periods accounted for 1.8 billion person-months (2% of
      the total during this period) from January 2010 to January 2020. Among 692
      outbreaks reported from second-level administrative units (e.g.,
      districts), the median attack rate was 0.8 per 1000 people (interquartile
      range (IQR), 0.3-2.4 per 1000), the median epidemic duration was 13 weeks
      (IQR, 8-19), and the median early outbreak reproductive number was 1.8
      (range, 1.1-3.5). Larger attack rates were associated with longer times to
      outbreak peak, longer epidemic durations, and lower case fatality risks.
    explanation: The literature provides the median attack rate in per 1000
      people, not percentages, and does not specify a range of 5%-10%. It
      mentions attack rates in terms of per thousand people which is not
      directly related to the percentages specified in the statement.
  - reference: PMID:37961651
    reference_title: "Inferring the proportion of undetected cholera infections from serological and clinical surveillance in an immunologically naive population."
    supports: NO_EVIDENCE
    snippet: Understanding cholera epidemiology and immunity relies on the
      ability to translate between numbers of clinical cases and the underlying
      number of infections in the population. We estimated the infection
      incidence during the first months of an outbreak in a cholera-naive
      population using a Bayesian vibriocidal antibody titer decay model
      combining measurements from a representative serosurvey and clinical
      surveillance data.
    explanation: This reference discusses the ratio of infections to clinical
      cases rather than specifying the attack rate range in percentages as
      stated in the claim.
- name: Asymptomatic Ratio
  description: The proportion of infected individuals who do not display
    symptoms.
  unit: percentage
  minimum_value: 10
  maximum_value: 80
  notes: Highly variable and challenging to measure accurately. Critical for
    understanding true disease spread and implementing control measures.
  evidence:
  - reference: PMID:18704085
    reference_title: "Inapparent infections and cholera dynamics."
    supports: SUPPORT
    snippet: Here we show that a model incorporating high asymptomatic ratio ...
      We find that the asymptomatic ratio in cholera is far higher than had been
      previously supposed.
    explanation: The study highlights that the asymptomatic ratio in cholera is
      much higher than previous estimates and provides evidence that it is
      critical for understanding cholera transmission dynamics.
  - reference: PMID:32529415
    reference_title: "Parameter and State Estimation in a Cholera Model with Threshold Immunology: A Case Study of Senegal."
    supports: SUPPORT
    snippet: They indicate the existence of bacteria and asymptomatic
      individuals in the population of Senegal at any single time.
    explanation: The study suggests the presence of a significant asymptomatic
      population that is crucial in the spread and endemicity of cholera.
  - reference: PMID:2341728
    reference_title: "Person-to-person transmission of cholera in a psychiatric hospital."
    supports: NO_EVIDENCE
    snippet: A total of 74 inmates (18 symptomatic and 56 asymptomatic) were
      infected.
    explanation: Although this study documents asymptomatic cases, it does not
      provide specific support for the general asymptomatic ratio range
      (10-80%).
  - reference: PMID:35259956
    reference_title: "Epidemicity of cholera spread and the fate of infection control measures."
    supports: PARTIAL
    snippet: Prognostic metrics of unfolding outbreaks are of particular
      importance.
    explanation: This study touches on the role of prognostic indices in
      understanding outbreaks but does not directly address the asymptomatic
      ratio range specified (10-80%).
modeling_considerations:
- name: Environmental Dynamics
  description: Include water contamination levels and seasonal variations
  evidence:
  - reference: PMID:11880057
    reference_title: "Cholera and climate: revisiting the quantitative evidence."
    supports: SUPPORT
    snippet: Cholera dynamics in endemic regions display regular seasonal cycles
      and pronounced interannual variability.
    explanation: The reference discusses how cholera dynamics are influenced by
      seasonal cycles and environmental factors, supporting the inclusion of
      water contamination levels and seasonal variations in modeling
      considerations.
  - reference: PMID:33333823
    reference_title: "Cholera Risk: A Machine Learning Approach Applied to Essential Climate Variables."
    supports: SUPPORT
    snippet: Previous studies have established strong relationships between
      essential climate variables and the coastal distribution and seasonal
      dynamics of the bacteria Vibrio cholerae.
    explanation: This study emphasizes the importance of environmental factors
      and seasonal dynamics for understanding cholera risk, aligning with the
      modeling considerations mentioned in the statement.
  - reference: PMID:28253325
    reference_title: "Cholera forecast for Dhaka, Bangladesh, with the 2015-2016 El Niño: Lessons learned."
    supports: PARTIAL
    snippet: A substantial body of work supports a teleconnection between the El
      Niño-Southern Oscillation (ENSO) and cholera incidence in Bangladesh
    explanation: While this reference emphasizes seasonal variations related to
      climate phenomena like ENSO, it lacks direct mention of water
      contamination levels, hence it is partial support.
  - reference: PMID:30861666
    reference_title: "Modeling cholera dynamics at multiple scales: environmental evolution, between-host transmission, and within-host interaction."
    supports: SUPPORT
    snippet: Cholera is an acute intestinal illness caused by infection with the
      bacterium Vibrio cholerae. The dynamics of the disease transmission are
      governed by human-human, environment-human, and within-human sub-dynamics.
    explanation: This paper supports the need to consider environmental
      dynamics, including possible factors like water contamination, in cholera
      modeling.
- name: Population Mobility
  description: Consider movement patterns that can spread the disease
  evidence:
  - reference: PMID:22355581
    reference_title: "Modeling human mobility responses to the large-scale spreading of infectious diseases."
    supports: SUPPORT
    snippet: We find that prevalence-based travel limitations do not alter the
      epidemic invasion threshold. Strikingly, we observe in both synthetic and
      data-driven numerical simulations that when travelers decide to avoid
      locations with high levels of prevalence, this self-initiated behavioral
      change may enhance disease spreading.
    explanation: The study analyzes how travel behavior and movement patterns
      can influence the spread of diseases, supporting the statement that
      population mobility should be considered in cholera modeling.
  - reference: PMID:12220086
    reference_title: "The spatial epidemiology of cholera in an endemic area of Bangladesh."
    supports: PARTIAL
    snippet: The high-risk areas of the dominant cholera agents are relatively
      stable over time. However, from 1983-1987 El Tor cholera, which was not
      the dominant agent during that period, was not associated with high-risk
      areas, suggesting that the El Tor habitat may have changed over time.
    explanation: While the study focuses on environmental risk factors and
      high-risk areas, it indirectly implies the importance of understanding
      mobility and environmental aspects, partially supporting the statement.
  - reference: PMID:32529415
    reference_title: "Parameter and State Estimation in a Cholera Model with Threshold Immunology: A Case Study of Senegal."
    supports: NO_EVIDENCE
    snippet: Our interest lies in estimating such states and the parameters
      catalyzing the spread.
    explanation: The study primarily focuses on modeling inaccessible states and
      parameters of cholera spread rather than movement patterns or population
      mobility.
  - reference: PMID:36573576
    reference_title: "Notional Spread of Cholera in Haiti Following a Natural Disaster: Considerations for Military and Disaster Relief Personnel."
    supports: SUPPORT
    snippet: This study demonstrates the use of epidemiological modeling to
      understand the dynamics of cholera transmission to inform emergency
      planning and military preparedness in areas with highly communicable
      diseases.
    explanation: The study emphasizes the role of modeling the spread of cholera
      in specific settings, highlighting the need to account for local
      population movements.
  - reference: PMID:31345641
    reference_title: "Molecular epidemiology and intercontinental spread of cholera."
    supports: NO_EVIDENCE
    snippet: Whole genome sequence analysis has revealed the phylogenetic
      structure of Vibrio cholerae and has shown that the current seventh
      pandemic is highly clonal, emerging from a single source.
    explanation: The study focuses on the genetic aspects and phylogenetic
      structure of Vibrio cholerae, not directly addressing movement patterns.
  - reference: PMID:35381862
    reference_title: "A reaction-advection-diffusion model of cholera epidemics with seasonality and human behavior change."
    supports: SUPPORT
    snippet: Cholera is a water- and food-borne infectious disease caused by V.
      cholerae. To investigate multiple effects of human behavior change,
      seasonality and spatial heterogeneity on cholera spread, we propose a
      reaction-advection-diffusion model that incorporates human hosts and
      aquatic reservoir of V. cholerae.
    explanation: This study supports the statement by proposing a model that
      includes human behavior and spatial heterogeneity, directly considering
      movement and its effect on cholera spread.
  - reference: PMID:31226251
    reference_title: "Impact of population displacement and forced movements on the transmission and outbreaks of Aedes-borne viral diseases: Dengue as a model."
    supports: PARTIAL
    snippet: Population displacement and other forced movement patterns
      following natural disasters, armed conflicts or due to socioeconomic
      reasons contribute to the global emergence of Aedes-borne viral disease
      epidemics.
    explanation: While the focus is on Aedes-borne diseases, the study points
      out the significant impact of population displacement on disease spread,
      partially relevant to cholera modeling considerations.
  - reference: PMID:34550373
    reference_title: "Mathematical Modeling of Endemic Cholera Transmission."
    supports: PARTIAL
    snippet: Mathematical modeling can be used to project the impact of mass
      vaccination on cholera transmission. Here, we discuss 2 examples for which
      indirect protection from mass vaccination needs to be considered.
    explanation: The study discusses cholera transmission models and factors
      like vaccination but does not specifically emphasize population mobility;
      however, it partially aligns with overall modeling considerations.
  - reference: PMID:15226199
    reference_title: "Time, travel and infection."
    supports: SUPPORT
    snippet: The collapse of geographical space over the last 200 years has had
      profound effects on the circulation of human populations and on the
      transfer of infectious diseases.
    explanation: The study discusses the significant impact of population
      movement and travel on the spread of infectious diseases, supporting the
      need to consider such factors in cholera modeling.
- name: Intervention Impacts
  description: Model effects of vaccination, improved sanitation, and treatment
    access
  evidence:
  - reference: PMID:21540075
    reference_title: "Mathematical analysis of a cholera model with public health interventions."
    supports: SUPPORT
    snippet: We formulate a mathematical model that captures some essential
      dynamics of cholera transmission to study the impact of public health
      educational campaigns, vaccination and treatment as control strategies in
      curtailing the disease.
    explanation: This paper explicitly discusses a mathematical model analyzing
      the impacts of vaccination, public health education, and treatment on
      cholera transmission.
- name: Asymptomatic Carriers
  description: Account for their role in disease transmission
  evidence:
  - reference: PMID:5300876
    reference_title: "Studies on cholera carriers."
    supports: SUPPORT
    snippet: The strains isolated from carriers were identical in all respects,
      including virulence in infant rabbits, with strains isolated from
      patients.
    explanation: This study shows that carriers, including asymptomatic ones,
      have strains identical to those from symptomatic patients, indicating
      their role in disease transmission.
  - reference: PMID:32529415
    reference_title: "Parameter and State Estimation in a Cholera Model with Threshold Immunology: A Case Study of Senegal."
    supports: SUPPORT
    snippet: The ever existence of cholera pathogen explains the endemicity of
      Cholera in Senegal and other sub-Saharan-African countries owing to role
      played by the asymptomatic individual in the bacteria density.
    explanation: The study explicitly mentions the role of asymptomatic
      individuals in maintaining the bacteria density, which contributes to the
      transmission of cholera.
  - reference: PMID:21675806
    reference_title: "Modeling the effects of carriers on transmission dynamics of infectious diseases."
    supports: SUPPORT
    snippet: An S-Ic-I-R epidemic model is investigated for infectious diseases
      that can be transmitted through carriers, infected individuals who are
      contagious but do not show any disease symptoms.
    explanation: The study discusses the transmission dynamics of infectious
      diseases through carriers, including those who are asymptomatic, which
      supports the role of asymptomatic carriers in disease transmission.
- name: Super-spreading Events
  description: Consider potential for rapid spread in gatherings or contaminated
    water sources
  evidence:
  - reference: PMID:25140600
    reference_title: "Modelling and control of cholera on networks with a common water source."
    supports: SUPPORT
    snippet: A mathematical model is formulated for the transmission and spread
      of cholera in a heterogeneous host population that consists of several
      patches of homogeneous host populations sharing a common water source.
    explanation: The reference discusses modeling considerations for cholera
      transmission, specifically noting the potential for spread through common
      water sources.
  - reference: PMID:19171080
    reference_title: "Two sequential outbreaks in two villages illustrate the various modes of transmission of cholera."
    supports: SUPPORT
    snippet: We identified that consumption of milk products prepared in the
      household of the index case...and drinking well water in the second
      village were associated with the illness.
    explanation: The study highlights how mishandling of food and contamination
      of water sources can lead to cholera outbreaks, aligning with
      considerations for spread in gatherings and contaminated water sources.
- name: Stochastic vs Deterministic Models
  description: Choose appropriate modeling approach based on population size and
    heterogeneity
  evidence:
  - reference: PMID:10652843
    reference_title: "Comparison of deterministic and stochastic SIS and SIR models in discrete time."
    supports: SUPPORT
    snippet: The dynamics of deterministic and stochastic discrete-time epidemic
      models are analyzed and compared... The discrete-time stochastic models
      are Markov chains, approximations to the continuous-time models. Models of
      SIS and SIR type with constant population size and general force of
      infection are analyzed, then a more general SIS model with variable
      population size is analyzed.
    explanation: This paper discusses the considerations for choosing between
      deterministic and stochastic models based on population characteristics,
      supporting the statement.
  - reference: PMID:15015922
    reference_title: "Modeling infection transmission."
    supports: SUPPORT
    snippet: Understanding what determines patterns of infection spread in
      populations is important for controlling infection transmission... This
      involves changing model forms from deterministic to stochastic and from
      compartmental to network, as well as adding realistic detail and changing
      parameter values.
    explanation: The excerpt highlights the importance of selecting appropriate
      modeling approaches, including deterministic and stochastic models, based
      on population details, supporting the statement.
  - reference: PMID:33830353
    reference_title: "Stochastic models of infectious diseases in a periodic environment with application to cholera epidemics."
    supports: SUPPORT
    snippet: We apply a time-nonhomogeneous stochastic process for a cholera
      epidemic with seasonal periodicity and a multitype branching process
      approximation to obtain an analytical estimate for the probability of an
      outbreak... At the end, the developed theoretical results are extended to
      more general models of infectious diseases.
    explanation: The study applies stochastic modeling to cholera epidemics and
      discusses extending these results to other infectious diseases, thus
      supporting the statement.
- name: Spatial Considerations
  description: Incorporate geographical factors affecting disease spread and
    control measures
  evidence:
  - reference: PMID:22781421
    reference_title: "[Design and implementation of Geographical Information System on prevention and control of cholera]."
    supports: SUPPORT
    snippet: All the data were imported to system database to show the incidence
      of vibrio cholerae in different provinces, regions and counties to support
      the spatial analysis through the spatial analysis of GIS.
    explanation: The reference discusses the importance of geographical
      information systems (GIS) to show the incidence of cholera in different
      locations, which supports the statement on incorporating geographical
      considerations.
  - reference: PMID:28483382
    reference_title: "Modeling Key Drivers of Cholera Transmission Dynamics Provides New Perspectives for Parasitology."
    supports: SUPPORT
    snippet: The inclusion of spatial information in models of disease
      transmission can aid in emergency management and the assessment of
      alternative interventions.
    explanation: This reference emphasizes the inclusion of spatial data in
      models of disease transmission, supporting the importance of geographical
      factors in modeling cholera.
  - reference: PMID:33705444
    reference_title: "Spatial distribution and natural environment mechanism of the cholera epidemic in ancient Jiangnan area, China."
    supports: SUPPORT
    snippet: We applied a set of spatial statistical analyses to investigate the
      spatial heterogeneity and the factors that influence the cholera epidemic
      in the Jiangnan area.
    explanation: The study investigates the spatial distribution of cholera and
      the influence of natural environmental factors, supporting the use of
      geographical considerations in cholera modeling.
  - reference: PMID:24047241
    reference_title: "Comparing sociocultural features of cholera in three endemic African settings."
    supports: SUPPORT
    snippet: Problems with unsafe water, sanitation and dirty environments were
      the most common perceived causes across settings.
    explanation: Although not exclusively focused on modeling, the reference
      discusses geographical and environmental factors affecting cholera, which
      are integral to spatial considerations.
- name: Vaccination Dynamics
  description: Model the impact of vaccination campaigns, including coverage
    rates and vaccine efficacy
  evidence:
  - reference: PMID:32987576
    reference_title: "Global dynamics and optimal control of a cholera transmission model with vaccination strategy and multiple pathways."
    supports: SUPPORT
    snippet: We consider an optimal control problem of cholera transmission with
      vaccination, quarantine, treatment and sanitation control strategies, and
      use Pontryagin's minimum principle to determine the optimal control level.
    explanation: The study includes modeling the impact of vaccination campaigns
      on cholera transmission, examining coverage rates and vaccine efficacy.
  - reference: PMID:35123444
    reference_title: "An innovative approach in monitoring oral cholera vaccination campaign: integration of a between-round survey."
    supports: SUPPORT
    snippet: The aim of this project was to assess the feasibility and effect of
      using recommendations of a community-based immunization and communication
      coverage survey conducted after the first round of an OCV campaign on the
      coverage of the second-round of the campaign.
    explanation: The study discusses the impact of vaccination campaigns on
      cholera, focusing on coverage rates and resultant improvements in
      immunization effectiveness.
  - reference: PMID:24845800
    reference_title: "Assessing effects of cholera vaccination in the presence of interference."
    supports: SUPPORT
    snippet: Application of the IPW estimators to the cholera vaccine trial
      indicates the presence of interference.
    explanation: The study analyzes indirect effects and interference in cholera
      vaccination campaigns, providing insights into the impact of coverage
      rates and vaccine efficacy.
  - reference: PMID:28748506
    reference_title: "Impact of Awareness Programs on Cholera Dynamics: Two Modeling Approaches."
    supports: SUPPORT
    snippet: We propose two differential equation-based models to investigate
      the impact of awareness programs on cholera dynamics. The first model
      represents the disease transmission rates as decreasing functions of the
      number of awareness programs, whereas the second model divides the
      susceptible individuals into two distinct classes depending on their
      awareness/unawareness of the risk of infection.
    explanation: This research includes modeling approaches that consider the
      impact of vaccination schemes and coverage rates, indirectly touching upon
      vaccination dynamics.
progression:
- phase: Incubation
  duration: 2 hours to 5 days
  notes: Period between infection and onset of symptoms. Individuals are
    typically not infectious during this phase.
  evidence:
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: PARTIAL
    snippet: We estimate the median incubation period of toxigenic cholera to be
      1.4 days (95% CI, 1.3-1.6). Five percent of cholera cases will develop
      symptoms by 0.5 days (95% CI 0.4-0.5), and 95% by 4.4 days (95% CI
      3.9-5.0) after infection.
    explanation: The literature describes an incubation period median of 1.4
      days and a window from 0.5 days to 4.4 days for symptom onset, which is
      consistent with a portion of the stated range but does not completely
      align.
- phase: Prodromal
  duration: Hours
  notes: Early symptoms may include mild diarrhea, abdominal discomfort, and
    nausea. Often overlooked or misdiagnosed.
  evidence:
  - reference: PMID:1465231
    reference_title: "The diagnosis and treatment of cholera."
    supports: NO_EVIDENCE
    snippet: Cholera is a diarrheal disease that results from colonization of
      the small intestine by the Vibrio cholerae organism. The disease is spread
      primarily by means of fecal contamination of drinking water and may begin
      with the sudden onset of profuse, watery diarrhea. Vomiting, rapid
      dehydration, acidosis, muscular cramps and circulatory collapse are other
      prominent features of severe cholera.
    explanation: The reference discusses the symptoms and features of cholera
      but does not provide information specific to the progression phase or the
      duration of the prodromal phase.
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: NO_EVIDENCE
    snippet: We estimate the median incubation period of toxigenic cholera to be
      1.4 days (95% CI, 1.3-1.6). Five percent of cholera cases will develop
      symptoms by 0.5 days (95% CI 0.4-0.5), and 95% by 4.4 days (95% CI
      3.9-5.0) after infection.
    explanation: This reference provides data on the incubation period of
      cholera but does not detail the duration of the prodromal phase or early
      symptoms specific to hours.
  - reference: PMID:38702080
    reference_title: "Acute watery diarrhoea cases during cholera outbreak in Syria: a cohort study."
    supports: NO_EVIDENCE
    snippet: The study found results consistent with previous AWD outbreaks in
      developing countries like Yemen, Nigeria and Lebanon.
    explanation: The reference is focused on acute watery diarrhea during
      cholera outbreaks but does not offer details on the prodromal phase
      duration or specific early symptoms.
  - reference: PMID:37580033
    reference_title: "National Hospital-Based Sentinel Surveillance for Cholera in Bangladesh: Epidemiological Results from 2014 to 2021."
    supports: NO_EVIDENCE
    snippet: From May 4, 2014 through November 30, 2021, we enrolled 51,414
      suspected cases from our sentinel surveillance sites.
    explanation: The study is about national cholera surveillance and does not
      address the specific progression or the prodromal phase duration in hours.
  - reference: PMID:18704085
    reference_title: "Inapparent infections and cholera dynamics."
    supports: NO_EVIDENCE
    snippet: This is true for cholera, a pandemic bacterial disease, where
      estimates of the ratio of asymptomatic to symptomatic infections have
      ranged from 3 to 100 (refs 1-5).
    explanation: This study discusses asymptomatic infections and their
      implications but does not provide detailed information on early symptoms
      duration in hours.
  - reference: PMID:29165706
    reference_title: "Cholera Epidemics of the Past Offer New Insights Into an Old Enemy."
    supports: NO_EVIDENCE
    snippet: We investigated singular Danish cholera epidemics (in 1853) to
      elucidate epidemiological parameters and modes of spread.
    explanation: The reference concerns historical cholera epidemics and their
      transmission but does not address the duration of the prodromal phase or
      early symptoms.
  - reference: PMID:21150867
    reference_title: "Update: outbreak of cholera — Haiti, 2010."
    supports: NO_EVIDENCE
    snippet: As of December 3, MSPP reported 91,770 cases of cholera from all 10
      departments and the capital city of Port-au-Prince.
    explanation: This study details the cholera outbreak in Haiti but does not
      provide specific information on the early symptoms duration in hours.
  - reference: PMID:8548982
    reference_title: "Cholera in the United States."
    supports: NO_EVIDENCE
    snippet: The clinical manifestations of cholera and the pathophysiology of
      the toxin-induced diarrhea are reviewed.
    explanation: This review on cholera's clinical manifestations does not offer
      specifics on the duration of the prodromal phase or early symptoms in
      hours.
  - reference: PMID:23622872
    reference_title: "Vibrio cholerae non-O1, non-O139 serogroups and cholera-like diarrhea, Kolkata, India."
    supports: NO_EVIDENCE
    snippet: We identified 281 Vibrio cholerae non-O1, non-O139 strains from
      patients with diarrhea in Kolkata, India. Cholera-like diarrhea was the
      major symptom (66.0%); some patients (20.3%) had severe dehydration.
    explanation: The focus is on non-O1, non-O139 Vibrio cholerae strains and
      does not provide information on the prodromal phase duration or early
      symptoms in hours.
- phase: Acute
  duration: Hours to Days
  notes: Rapid onset of severe symptoms, can be life-threatening if not treated
    promptly. Peak infectiousness.
  evidence:
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: SUPPORT
    snippet: We estimate the median incubation period of toxigenic cholera to be
      1.4 days (95% CI, 1.3-1.6). Five percent of cholera cases will develop
      symptoms by 0.5 days (95% CI 0.4-0.5), and 95% by 4.4 days (95% CI
      3.9-5.0) after infection.
    explanation: This reference supports the rapid progression of cholera,
      stating that symptoms can develop within half a day to around 4-5 days
      after infection.
- phase: Early Acute
  duration: First 24-48 hours
  notes: Rapid onset of profuse, watery diarrhea and vomiting. Highest risk of
    severe dehydration.
  evidence:
  - reference: PMID:37769103
    reference_title: "A time of cholera."
    supports: NO_EVIDENCE
    snippet: ''
    explanation: The abstract does not provide specific information about the
      progression of cholera within the first 24-48 hours.
  - reference: PMID:8548982
    reference_title: "Cholera in the United States."
    supports: NO_EVIDENCE
    snippet: ''
    explanation: The abstract covers the epidemiology and general clinical
      manifestations but does not detail the progression specific to the first
      24–48 hours.
  - reference: PMID:31668817
    reference_title: "Case management of cholera."
    supports: NO_EVIDENCE
    snippet: ''
    explanation: The abstract reviews case management of cholera but does not
      provide information specifically regarding the initial 24-48 hours.
  - reference: PMID:20135270
    supports: NO_EVIDENCE
    snippet: ''
    explanation: The abstract estimates the prevalence of cholera in pediatric
      patients with acute dehydrating diarrhea but does not specify the time
      frame within the first 24-48 hours.
- phase: Late Acute
  duration: 3-5 days
  notes: Continued symptoms but may begin to improve with proper treatment.
  evidence:
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: NO_EVIDENCE
    snippet: We estimate the median incubation period of toxigenic cholera to be
      1.4 days (95% CI, 1.3-1.6). Five percent of cholera cases will develop
      symptoms by 0.5 days (95% CI 0.4-0.5), and 95% by 4.4 days (95% CI
      3.9-5.0) after infection.
    explanation: While this paper provides information on the incubation period
      of cholera rather than the duration of symptoms, it indirectly suggests
      that the symptom onset and duration can vary significantly.
  - reference: PMID:31668817
    reference_title: "Case management of cholera."
    supports: NO_EVIDENCE
    snippet: Cholera can be effectively managed in the majority of cases with
      oral rehydration solution alone. Up to one third of patients present with
      severe dehydration, which can be diagnosed clinically, and will require
      rapid intravenous rehydration...
    explanation: This reference focuses more on the treatment and management of
      cholera rather than the progression and duration of symptoms.
- phase: Recovery
  duration: Days to Weeks
  notes: Symptoms resolve, but individuals may still shed bacteria in stool for
    1-2 weeks.
  evidence:
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: PARTIAL
    snippet: Five percent of cholera cases will develop symptoms by 0.5 days
      (95% CI 0.4-0.5), and 95% by 4.4 days (95% CI 3.9-5.0) after infection.
    explanation: The reference provides information on the incubation period but
      not on the overall progression of the disease or the recovery phase.
  - reference: PMID:10414380
    reference_title: "Faecal excretion of Vibrio cholerae during convalescence of cholera patients in Calabar, Nigeria."
    supports: PARTIAL
    snippet: Nine (69.2%) of the convalescents had positive faecal cultures for
      periods ranging from two weeks to more than seven months.
    explanation: This literature supports that bacteria can be shed in stool
      during the convalescent period but does not provide a comprehensive view
      of the full disease progression or typical duration of symptoms.
- phase: Asymptomatic Carriage
  duration: Days to Months
  notes: Some individuals can carry and shed the bacteria without showing
    symptoms. Important for disease transmission modeling.
  evidence:
  - reference: PMID:5300876
    reference_title: "Studies on cholera carriers."
    supports: SUPPORT
    snippet: The duration of the carrier state among 19 household carriers
      isolated for examination varied from 5 to 19 days.
    explanation: This literature provides data on the duration of the carrier
      state, indicating that some individuals can carry and shed the bacteria
      for several days, which supports the statement regarding the duration of
      asymptomatic carriage.
  - reference: PMID:8373550
    reference_title: "[Cholera in pediatrics]."
    supports: SUPPORT
    snippet: There are also cases of cholera where victims do not show any
      symptoms of it, that is asymptomatic carriers.
    explanation: The statement about asymptomatic carriage is supported, as the
      literature confirms the existence of asymptomatic carriers who can harbor
      the bacteria for varying periods.
  - reference: PMID:32529415
    reference_title: "Parameter and State Estimation in a Cholera Model with Threshold Immunology: A Case Study of Senegal."
    supports: PARTIAL
    snippet: They indicate the existence of bacteria and asymptomatic
      individuals in the population of Senegal at any single time for the
      duration of collection of the data.
    explanation: The statement is partially supported as the literature
      indicates the presence of asymptomatic carriers in the population,
      although it does not specify the exact duration of carriage.
  - reference: PMID:28483382
    reference_title: "Modeling Key Drivers of Cholera Transmission Dynamics Provides New Perspectives for Parasitology."
    supports: NO_EVIDENCE
    snippet: Information on human settlements and host mobility on waterways
      along which pathogens and hosts disperse, and relevant hydroclimatological
      processes, can be acquired remotely and included in spatially explicit
      mathematical models of disease transmission.
    explanation: This study focuses on drivers of cholera transmission using
      spatially explicit models and does not provide information on the duration
      of asymptomatic carriage.
  - reference: PMID:34670655
    reference_title: "Toward Cholera Elimination, Haiti."
    supports: NO_EVIDENCE
    snippet: This study describes the apparent discontinuation of cholera
      transmission in Haiti since February 2019.
    explanation: This study discusses cholera transmission cessation in Haiti
      and does not address the duration of asymptomatic carriage.
  - reference: PMID:23201968
    reference_title: "The incubation period of cholera: a systematic review."
    supports: NO_EVIDENCE
    snippet: The incubation period did not differ by a clinically significant
      margin between strains (except O1 El Tor Ogawa).
    explanation: This review focuses on the incubation period of cholera and
      does not discuss the duration of asymptomatic carriage.
  - reference: PMID:22461716
    reference_title: "The global burden of cholera."
    supports: NO_EVIDENCE
    snippet: About 1.4 billion people are at risk for cholera in endemic
      countries.
    explanation: This study estimates the global burden of cholera and does not
      provide information on the duration of asymptomatic carriage.
pathophysiology:
- name: Cholera Toxin Binding and Uptake
  description: Cholera toxin B subunit (CTB) binds to GM1 ganglioside and
    alternative fucosylated glycan receptors (e.g., Lewis X) on the apical
    surface of intestinal epithelial cells, initiating receptor-mediated
    endocytosis and retrograde trafficking to the endoplasmic reticulum.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: endocytosis
    term:
      id: GO:0006897
      label: endocytosis
  - preferred_term: retrograde vesicle-mediated transport
    term:
      id: GO:0006890
      label: retrograde vesicle-mediated transport, Golgi to endoplasmic
        reticulum
  downstream:
  - target: ERAD-mediated CTA1 Translocation
  notes: CTB recognizes both GM1 ganglioside and fucosylated glycoproteins,
    enabling GM1-independent intoxication
- name: ERAD-mediated CTA1 Translocation
  description: The A1 enzymatic subunit of cholera toxin is unfolded by protein
    disulfide isomerase in the ER and hijacks the ER-associated degradation
    (ERAD) machinery to retro-translocate into the cytosol, where it refolds to
    become enzymatically active.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: ERAD pathway
    term:
      id: GO:0036503
      label: ERAD pathway
  downstream:
  - target: Gsα ADP-Ribosylation
  notes: CTA1 exploits the Sec61/Derlin/Hrd1 retro-translocation machinery to
    escape the ER
- name: Gsα ADP-Ribosylation
  description: Cytosolic CTA1 catalyzes ADP-ribosylation of the Gsα subunit
    (GNAS) using NAD+ as substrate, locking adenylyl cyclase in a constitutively
    active state.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: adenylate cyclase-activating G protein-coupled receptor
      signaling pathway
    term:
      id: GO:0007189
      label: adenylate cyclase-activating G protein-coupled receptor signaling
        pathway
  downstream:
  - target: Increased cAMP
- name: Cholera Toxin
  description: Vibrio cholerae produces a toxin that activates adenylate cyclase
    in intestinal epithelial cells, leading to increased cyclic AMP (cAMP)
    levels.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Increased cAMP
  evidence:
  - reference: PMID:8783505
    reference_title: "Mechanism of action of cholera toxin & other toxins."
    supports: SUPPORT
    snippet: Vibrio cholerae produce a variety of extracellular products that
      have deleterious effects on eukaryotic cells... CT acts by activation of
      adenylate cyclase-cAMP system located at the basolateral membrane of
      intestinal epithelial cells.
    explanation: The statement is supported by the information that cholera
      toxin (CT) from Vibrio cholerae activates the adenylate cyclase-cAMP
      system in intestinal epithelial cells.
  - reference: PMID:30624615
    reference_title: "Adenylyl Cyclase 6 Expression Is Essential for Cholera Toxin-Induced Diarrhea."
    supports: SUPPORT
    snippet: Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine
      monophosphate (cAMP)-mediated active Cl- secretion via the cystic fibrosis
      transmembrane conductance regulator (CFTR).
    explanation: The statement is supported as it describes CT inducing diarrhea
      through cAMP-mediated mechanisms.
  - reference: PMID:4364505
    reference_title: "Action of Escherichia coli enterotoxin: adenylate cyclase behavior of intestinal epithelial cells in culture."
    supports: SUPPORT
    snippet: Comparable results were also obtained when cholera toxin was used.
      The degree of enzyme stimulation was proportional to the concentration of
      enterotoxin.
    explanation: This further confirms that cholera toxin stimulates adenylate
      cyclase activity in cells.
  - reference: PMID:8817767
    reference_title: "Mucosal immune responses to intestinal bacterial pathogens."
    supports: SUPPORT
    snippet: V cholerae, the representative noninvasive pathogen, has fimbrial
      adhesins that mediate attachment and colonization... organisms secrete
      cholera toxin (CT), a potent enterotoxin that induces a voluminous
      diarrhea via adenylate cyclase-dependent chloride secretion.
    explanation: This literature confirms that cholera toxin induces diarrhea by
      acting on the adenylate cyclase system in the intestinal epithelial cells,
      resulting in elevated cAMP levels.
- name: Increased cAMP
  description: Elevated cAMP levels cause cells to secrete large amounts of
    chloride ions into the intestinal lumen, followed by water and other
    electrolytes.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: cAMP-mediated signaling
    term:
      id: GO:0141156
      label: cAMP/PKA signal transduction
  - preferred_term: chloride transmembrane transport
    term:
      id: GO:1902476
      label: chloride transmembrane transport
  downstream:
  - target: Profuse Watery Diarrhea
  evidence:
  - reference: PMID:23651092
    reference_title: "Cholera: pathophysiology and emerging therapeutic targets."
    supports: SUPPORT
    snippet: Increased intracellular cAMP in human intestinal epithelial cells
      accounts for pathogenesis of profuse diarrhea and severe fluid loss in
      cholera
    explanation: This reference directly supports the statement by confirming
      that elevated cAMP levels in intestinal epithelial cells lead to the
      secretion of fluid, resulting in profuse diarrhea, which aligns with the
      described pathophysiology.
  - reference: PMID:30624615
    reference_title: "Adenylyl Cyclase 6 Expression Is Essential for Cholera Toxin-Induced Diarrhea."
    supports: SUPPORT
    snippet: Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine
      monophosphate (cAMP)-mediated active Cl- secretion via the cystic fibrosis
      transmembrane conductance regulator (CFTR).
    explanation: This reference supports the statement by explaining that
      CT-induced diarrhea involves cAMP-mediated chloride secretion, leading to
      diarrhea.
  - reference: PMID:80378
    reference_title: "Cholera toxin effects on fluid secretion, adenylate cyclase, and cyclic AMP in porcine small intestine."
    supports: PARTIAL
    snippet: Cholera toxin causes net secretion of fluid into the small
      intestine of weanling pigs, and secretory rates are dependent on the dose
      of the toxin placed in intestinal loops.
    explanation: While this study supports that cholera toxin leads to fluid
      secretion, it notes that net fluid fluxes did not always correlate with
      total mucosal cAMP concentrations in pigs. Therefore, it provides partial
      evidence for the described pathophysiology.
- name: Profuse Watery Diarrhea
  description: Rapid loss of fluids and electrolytes through diarrhea, which can
    lead to severe dehydration and hypovolemic shock.
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:14738797
    reference_title: "Cholera."
    supports: SUPPORT
    snippet: Intestinal infection with Vibrio cholerae results in the loss of
      large volumes of watery stool, leading to severe and rapidly progressing
      dehydration and shock.
    explanation: The statement describes the loss of large volumes of fluids and
      electrolytes through diarrhea, leading to severe dehydration and
      hypovolemic shock, which aligns with the literature.
  - reference: PMID:15367740
    reference_title: "Acidosis in a patient with cholera: a need to redefine concepts."
    supports: SUPPORT
    snippet: A patient presented with cholera and a severe degree of ECF volume
      contraction. Despite large losses of bicarbonate (HCO3-)-containing
      diarrhoeal fluid, laboratory acid-base values were remarkably close to
      normal.
    explanation: The literature describes large fluid losses and severe
      dehydration due to cholera, supporting the statement's explanation of
      pathophysiology.
  - reference: PMID:28448489
    reference_title: "Determinants of severe dehydration from diarrheal disease at hospital presentation: Evidence from 22 years of admissions in Bangladesh."
    supports: SUPPORT
    snippet: To take advantage of emerging opportunities to reduce morbidity and
      mortality from diarrheal disease, we need to better understand the
      determinants of life-threatening severe dehydration (SD) in resource-poor
      settings.
    explanation: The text mentions severe dehydration as a key issue in the
      pathophysiology of cholera.
  - reference: PMID:34523840
    reference_title: "[A young woman with severe dehydration]."
    supports: SUPPORT
    snippet: A 28-year-old female presented with severe dehydration due to acute
      diarrhea and vomiting... which is typical for cholera and can amount to
      1000 cc/hour.
    explanation: This literature supports the rapid loss of fluids through
      profuse watery diarrhea leading to severe dehydration, consistent with the
      pathophysiology described.
  - reference: PMID:38702080
    reference_title: "Acute watery diarrhoea cases during cholera outbreak in Syria: a cohort study."
    supports: SUPPORT
    snippet: The most common complications reported at admission and during
      hospitalisation included electrolyte imbalance (28.2%), followed by severe
      dehydration (16.3%).
    explanation: This literature mentions severe dehydration and electrolyte
      imbalance as common complications, supporting the statement regarding the
      pathophysiology of cholera.
- name: Colonization and Biofilm Formation
  description: V. cholerae uses the toxin-coregulated pilus (TCP) to traverse
    the intestinal mucus barrier, adhere to epithelial cells, and form
    microcolonies. TCP expression is controlled by the ToxR/TcpP/ToxT regulatory
    cascade. Biofilm formation enhances bacterial survival and transmission.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: biofilm formation
    term:
      id: GO:0042710
      label: biofilm formation
  - preferred_term: bacterial adhesion to host
    term:
      id: GO:0044406
      label: adhesion of symbiont to host
  notes: The neuraminidase NanH removes sialic acids to expose GM1 ganglioside
    receptors for cholera toxin binding
- name: Accessory Toxins and Virulence Factors
  description: V. cholerae produces multiple accessory toxins beyond cholera
    toxin, including MARTX (actin disruption and phagocyte inhibition),
    hemolysin HlyA (pore formation), zonula occludens toxin Zot (tight junction
    disruption), and accessory cholera enterotoxin Ace, which contribute to
    pathogenesis in a strain-dependent manner.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: disruption of cells of other organism
    term:
      id: GO:0031640
      label: killing of cells of another organism
  - preferred_term: tight junction organization
    term:
      id: GO:0120193
      label: tight junction organization
  notes: MARTX also modulates innate immune signaling; HlyA is often associated
    with outer membrane vesicles (OMVs)
- name: Host Metabolic Reprogramming
  description: Cholera toxin-driven signaling reprograms host epithelial
    metabolism, leading to release of host-derived nutrients (long-chain fatty
    acids, lactate, glycerol) into the intestinal lumen that fuel V. cholerae
    growth and enhance transmission.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  biological_processes:
  - preferred_term: regulation of lipid metabolic process
    term:
      id: GO:0019216
      label: regulation of lipid metabolic process
  notes: Bile acids and the gut microbiome modulate biofilm formation and
    virulence gene expression
phenotypes:
- category: Gastrointestinal
  name: Profuse Watery Diarrhea
  frequency: VERY_FREQUENT
  diagnostic: true
  sequelae:
  - target: Severe Dehydration
  - target: Shock
  evidence:
  - reference: PMID:14738797
    reference_title: "Cholera."
    supports: SUPPORT
    snippet: Intestinal infection with Vibrio cholerae results in the loss of
      large volumes of watery stool, leading to severe and rapidly progressing
      dehydration and shock.
    explanation: The provided excerpt supports the statement that profuse watery
      diarrhea is a very frequent diagnostic phenotype of cholera and that it
      leads to severe dehydration and shock.
  - reference: PMID:34523840
    reference_title: "[A young woman with severe dehydration]."
    supports: SUPPORT
    snippet: Her stool was watery, with flecks of mucous, also referred to as
      'rice-water' stool, which is typical for cholera and can amount to 1000
      cc/hour.
    explanation: This case study supports the characterization of profuse watery
      diarrhea as a very frequent diagnostic phenotype of cholera.
  - reference: PMID:29488455
    reference_title: "Sensitivity, Specificity, and Public-Health Utility of Clinical Case Definitions Based on the Signs and Symptoms of Cholera in Africa."
    supports: SUPPORT
    snippet: Adding dehydration, vomiting, or rice water stools to the case
      definition could increase the specificity without a substantial decrease
      in sensitivity.
    explanation: This study supports that rice-water stools (a form of profuse
      watery diarrhea) are indicative of cholera and frequently used in its
      diagnosis.
  - reference: PMID:820813
    reference_title: "Nutritional status: a determinant of severity of diarrhea in patients with cholera."
    supports: SUPPORT
    snippet: The severity of diarrhea and nutritional status were measured in a
      prospective study of 97 patients hospitalized with cholera in Dacca,
      Bangladesh... The increased stool loss was unrelated to antibiotic usage,
      to presence of intestinal parasites, or to the refeeding diet given.
    explanation: The study supports that profuse watery diarrhea is a very
      frequent diagnostic phenotype of cholera.
  - reference: PMID:27412979
    reference_title: "Cholera in pregnant women: the 2012 epidemic at the reference center at the Donka National Hospital in Conakry."
    supports: SUPPORT
    snippet: Choleriform diarrhea and vomiting were the main signs, found
      respectively in 100% and 95% of the women; dehydration was mild for 16%,
      moderate for 45%, and severe for 39%.
    explanation: This study supports that profuse watery diarrhea (choleriform
      diarrhea) is a very frequent diagnostic phenotype of cholera.
  - reference: PMID:38702080
    reference_title: "Acute watery diarrhoea cases during cholera outbreak in Syria: a cohort study."
    supports: SUPPORT
    snippet: The most common complications reported at admission and during
      hospitalisation included electrolyte imbalance (28.2%), followed by severe
      dehydration (16.3%).
    explanation: This study supports that watery diarrhea leading to severe
      dehydration is a frequent phenotype of cholera.
- category: Systemic
  name: Dehydration
  frequency: VERY_FREQUENT
  diagnostic: true
  sequelae:
  - target: Sunken Eyes
  - target: Low Blood Pressure
  - target: Tachycardia
  evidence:
  - reference: PMID:28448489
    reference_title: "Determinants of severe dehydration from diarrheal disease at hospital presentation: Evidence from 22 years of admissions in Bangladesh."
    supports: SUPPORT
    snippet: 'Vibrio cholerae was the most common pathogen isolated (12,405 patients;
      22%), and had the strongest association with SD (AOR 4.77; 95% CI: 4.41-5.51).'
    explanation: The article notes that Vibrio cholerae was the most common
      pathogen with a strong association with severe dehydration, which aligns
      with the statement.
  - reference: PMID:15367740
    reference_title: "Acidosis in a patient with cholera: a need to redefine concepts."
    supports: PARTIAL
    snippet: A patient presented with cholera and a severe degree of ECF volume
      contraction. Despite large losses of bicarbonate (HCO3-)-containing
      diarrhoeal fluid, laboratory acid-base values were remarkably close to
      normal.
    explanation: The study discusses severe dehydration, but also mentions
      metabolic and respiratory complications without specifically noting
      frequency.
  - reference: PMID:33252133
    reference_title: "Cholera Presenting With Hyperkalemia, Rhabdomyolysis, and Acute Renal Failure."
    supports: PARTIAL
    snippet: It was later confirmed that he was suffering from cholera. On
      presentation, he was hyperkalemic with ECG changes and soon went into a
      hypovolemic shock.
    explanation: This article discusses a specific case of cholera leading to
      severe dehydration and hypovolemic shock, but does not provide frequency
      data.
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
- category: Systemic
  name: Hypovolemic Shock
  frequency: OCCASIONAL
  notes: Caused by severe dehydration due to fluid loss
  evidence:
  - reference: PMID:33252133
    reference_title: "Cholera Presenting With Hyperkalemia, Rhabdomyolysis, and Acute Renal Failure."
    supports: SUPPORT
    snippet: The morbidity and mortality of cholera is resultant from
      large-volume diarrhea, hypovolemia, and electrolyte derangement. In the
      following case... he was suffering from cholera. On presentation, he was
      hyperkalemic with ECG changes and soon went into a hypovolemic shock.
    explanation: This case description demonstrates that hypovolemic shock is an
      occasional systemic consequence of cholera due to excessive fluid loss.
  - reference: PMID:14738797
    reference_title: "Cholera."
    supports: SUPPORT
    snippet: Intestinal infection with Vibrio cholerae results in the loss of
      large volumes of watery stool, leading to severe and rapidly progressing
      dehydration and shock.
    explanation: This abstract highlights that severe dehydration caused by
      cholera often leads to shock, supporting the claim.
  phenotype_term:
    preferred_term: Hypovolemic Shock
    term:
      id: HP:0031274
      label: Hypovolemic shock
- category: Systemic
  diagnostic: true
  frequency: VERY_FREQUENT
  name: Dehydration
  sequelae:
  - target: Sunken Eyes
  - target: Low Blood Pressure
  - target: Tachycardia
  - target: Acute Kidney Injury
  notes: Can lead to death within hours if untreated
  evidence:
  - reference: PMID:34523840
    reference_title: "[A young woman with severe dehydration]."
    supports: SUPPORT
    snippet: A 28-year-old female presented with severe dehydration due to acute
      diarrhea and vomiting, which she developed after returning from a vacation
      in Togo
    explanation: This reference supports the statement by describing a case of
      severe dehydration due to cholera, highlighting its systemic nature and
      the rapid onset of severe symptoms.
  - reference: PMID:31668817
    reference_title: "Case management of cholera."
    supports: SUPPORT
    snippet: Cholera still affects about three million people a year and kills
      approximately 100,000. Cholera can be effectively managed in the majority
      of cases with oral rehydration solution alone. Up to one third of patients
      present with severe dehydration, which can be diagnosed clinically, and
      will require rapid intravenous rehydration with Ringers Lactate or other
      appropriate fluid before being managed with oral rehydration solution.
    explanation: This reference supports the statement by noting that severe
      dehydration is a common and critical condition in cholera patients, which
      can lead to death if untreated.
  - reference: PMID:33252133
    reference_title: "Cholera Presenting With Hyperkalemia, Rhabdomyolysis, and Acute Renal Failure."
    supports: SUPPORT
    snippet: The morbidity and mortality of cholera is resultant from
      large-volume diarrhea, hypovolemia, and electrolyte derangement.
    explanation: This reference supports the systemic impact of cholera,
      including dehydration, which can lead to severe complications and death.
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
- category: Systemic
  frequency: OCCASIONAL
  name: Hypovolemic Shock
  notes: Caused by severe dehydration due to fluid loss
  evidence:
  - reference: PMID:14738797
    reference_title: "Cholera."
    supports: SUPPORT
    snippet: Intestinal infection with Vibrio cholerae results in the loss of
      large volumes of watery stool, leading to severe and rapidly progressing
      dehydration and shock.
    explanation: The reference states that cholera leads to severe dehydration
      and shock, which aligns with the statement indicating that cholera can
      occasionally cause hypovolemic shock due to severe dehydration.
  - reference: PMID:4869291
    reference_title: "Hemodynamic studies on cholera. Effects of hypovolemia and acidosis."
    supports: SUPPORT
    snippet: Hemodynamic studies on cholera. Effects of hypovolemia and
      acidosis.
    explanation: The title of the reference suggests that hypovolemia, which can
      lead to hypovolemic shock, is a significant effect of cholera.
  - reference: PMID:33252133
    reference_title: "Cholera Presenting With Hyperkalemia, Rhabdomyolysis, and Acute Renal Failure."
    supports: SUPPORT
    snippet: The morbidity and mortality of cholera is resultant from
      large-volume diarrhea, hypovolemia, and electrolyte derangement.
    explanation: The reference confirms that cholera causes hypovolemia, which
      can lead to hypovolemic shock, supporting the statement.
  phenotype_term:
    preferred_term: Hypovolemic Shock
    term:
      id: HP:0031274
      label: Hypovolemic shock
- category: Electrolyte/Metabolic
  frequency: FREQUENT
  name: Hypokalemia
  evidence:
  - reference: PMID:5300879
    reference_title: "Electrocardiographic findings in cholera El Tor patients."
    supports: SUPPORT
    snippet: Hypokalaemic patterns were seen in 40% of the cases in the acute
      stage (during rehydration). This pattern became more marked after
      rehydration and disappeared gradually within 3-7 days.
    explanation: The study indicates that hypokalemia is a frequent occurrence
      in cholera patients, particularly during the acute stage and rehydration
      process.
  - reference: PMID:33252133
    reference_title: "Cholera Presenting With Hyperkalemia, Rhabdomyolysis, and Acute Renal Failure."
    supports: NO_EVIDENCE
    snippet: On presentation, he was hyperkalemic with ECG changes and soon went
      into a hypovolemic shock.
    explanation: This case report mentions hyperkalemia in a cholera patient,
      not hypokalemia. Therefore, it does not support the statement about
      frequent hypokalemia in cholera.
  - reference: PMID:28957470
    reference_title: "Treatment of severe cholera: a review of strategies to reduce stool output and volumes of rehydration fluid."
    supports: PARTIAL
    snippet: Severe cholera is a life-threatening illness of hypovolemic shock
      and metabolic acidosis due to rapid and profuse diarrheal fluid loss.
      Emergency life-saving therapy is i.v. saline, optionally supplemented with
      potassium and alkali to correct the fluid deficit, potassium losses and
      acidosis.
    explanation: The reference mentions potassium losses as part of the
      treatment for severe cholera, which indirectly suggests hypokalemia might
      occur, but it does not provide direct evidence of its frequency.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
- category: Electrolyte/Metabolic
  frequency: FREQUENT
  name: Metabolic Acidosis
  evidence:
  - reference: PMID:15367740
    reference_title: "Acidosis in a patient with cholera: a need to redefine concepts."
    supports: SUPPORT
    snippet: A patient presented with cholera and a severe degree of ECF volume
      contraction. Despite large losses of bicarbonate (HCO3-)-containing
      diarrhoeal fluid, laboratory acid-base values were remarkably close to
      normal. A detailed analysis emphasizing principles of physiology and a
      quantitative approach provided new insights and eventually better
      definitions of metabolic and respiratory acidosis.
    explanation: The study discusses the presence of metabolic acidosis in a
      cholera patient, supporting the statement.
  - reference: PMID:33252133
    reference_title: "Cholera Presenting With Hyperkalemia, Rhabdomyolysis, and Acute Renal Failure."
    supports: SUPPORT
    snippet: The morbidity and mortality of cholera is resultant from
      large-volume diarrhea, hypovolemia, and electrolyte derangement.
    explanation: Electrolyte derangement in cholera can lead to conditions like
      metabolic acidosis, supporting the statement.
  - reference: PMID:5697815
    reference_title: "Oral maintenance of water-electrolyte and acid-base balance in cholera: a preliminary report."
    supports: SUPPORT
    snippet: 'Oral maintenance of water-electrolyte and acid-base balance in cholera:
      a preliminary report.'
    explanation: The mention of acid-base balance in cholera suggests a frequent
      occurrence of metabolic acidosis, supporting the statement.
  phenotype_term:
    preferred_term: Metabolic Acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Muscle Cramps
  notes: Due to electrolyte imbalances
  evidence:
  - reference: PMID:33252133
    reference_title: "Cholera Presenting With Hyperkalemia, Rhabdomyolysis, and Acute Renal Failure."
    supports: PARTIAL
    snippet: On presentation, he was hyperkalemic with ECG changes and soon went
      into a hypovolemic shock.
    explanation: The case study mentions muscle cramping as a symptom in a
      patient with cholera, but does not explicitly link it to electrolyte
      imbalances.
  - reference: PMID:29857264
    reference_title: "Muscle cramps: A comparison of the two-leading hypothesis."
    supports: NO_EVIDENCE
    snippet: Literature analysis indicates that neuromuscular hypothesis may
      prevails over the initial hypothesis of the dehydration as the trigger
      event of muscle cramps.
    explanation: This review focuses on the neuromuscular hypothesis for muscle
      cramps and does not provide evidence linking muscle cramps to electrolyte
      imbalances specifically in cholera.
  - reference: PMID:9694423
    reference_title: "Fluid and electrolyte disturbances in heat illness."
    supports: NO_EVIDENCE
    snippet: Cramps occur during or after exercise regardless of whether the
      exercise is performed in the heat or the cold, or in water.
    explanation: The review discusses muscle cramps in the context of exercise
      and heat illness, but does not relate it to cholera or electrolyte
      imbalances.
  phenotype_term:
    preferred_term: Muscle Cramps
    term:
      id: HP:0003394
      label: Muscle spasm
- category: Systemic
  name: Severe Dehydration
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Severe Dehydration
    term:
      id: HP:0001944
      label: Dehydration
- category: Systemic
  name: Shock
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
- category: Systemic
  name: Sunken Eyes
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sunken Eyes
    term:
      id: HP:0000490
      label: Deeply set eye
- category: Cardiovascular
  name: Low Blood Pressure
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Low Blood Pressure
    term:
      id: HP:0002615
      label: Hypotension
- category: Cardiovascular
  name: Tachycardia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
- category: Renal
  name: Acute Kidney Injury
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Acute Kidney Injury
    term:
      id: HP:0001919
      label: Acute kidney injury
biochemical:
- name: Electrolytes
  presence: Low Sodium, Potassium, and Bicarbonate Levels
  context: Due to excessive loss in diarrhea
  evidence:
  - reference: PMID:28957470
    reference_title: "Treatment of severe cholera: a review of strategies to reduce stool output and volumes of rehydration fluid."
    supports: PARTIAL
    snippet: Emergency life-saving therapy is i.v. saline, optionally
      supplemented with potassium and alkali to correct the fluid deficit,
      potassium losses and acidosis.
    explanation: The article suggests the need to correct potassium losses and
      acidosis, which supports low potassium and bicarbonate levels, but there
      is no specific mention of sodium levels.
  - reference: PMID:15367740
    reference_title: "Acidosis in a patient with cholera: a need to redefine concepts."
    supports: PARTIAL
    snippet: Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal
      fluid, laboratory acid-base values were remarkably close to normal.
    explanation: This reference discusses bicarbonate losses due to diarrhea,
      supporting low bicarbonate levels but does not provide direct evidence for
      sodium and potassium levels.
  - reference: PMID:5300879
    reference_title: "Electrocardiographic findings in cholera El Tor patients."
    supports: PARTIAL
    snippet: Hypokalaemic patterns were seen in 40% of the cases in the acute
      stage (during rehydration).
    explanation: The study reports hypokalemia in cholera patients, which
      supports low potassium levels, but it doesn't provide information about
      sodium and bicarbonate levels.
  - reference: PMID:24952048
    reference_title: "Cholera."
    supports: NO_EVIDENCE
    snippet: Vibrio cholerae...produces an enterotoxin, which causes an
      acute-onset diarrheal disease ranging in severity from mild to
      life-threatening.
    explanation: This reference describes the clinical presentation of cholera
      but does not provide direct evidence on the levels of sodium, potassium,
      or bicarbonate.
  - reference: PMID:28608260
    reference_title: "Water, electrolyte, acid-base, and trace elements alterations in cirrhotic patients."
    supports: PARTIAL
    snippet: Hyponatremia, hypokalemia, hyperkalemia...are the main internal
      milieu alterations in this group.
    explanation: This reference mentions hyponatremia and hypokalemia,
      supporting low sodium and potassium levels, but it is in the context of
      cirrhotic patients, not cholera.
diagnosis:
- name: Stool Culture
  presence: Positive for Vibrio cholerae
  evidence:
  - reference: PMID:32319946
    reference_title: "[Value of the syndromic approach for the diagnosis of an imported case of cholera]."
    supports: SUPPORT
    snippet: The appearance of her stools and clinical findings were not
      suggestive of a typical case of cholera, but Vibrio cholerae was
      nevertheless isolated from her stools in the laboratory. The National
      reference center (NRC) for vibrios and cholera identified a Vibrio
      cholerae serogroup O1 (serotype Inaba) strain.
    explanation: This reference supports the statement that Cholera can be
      diagnosed by a stool culture positive for Vibrio cholerae.
  - reference: PMID:36376441
    reference_title: "Metagenomic analysis of diarrheal stools in Kolkata, India, indicates the possibility of subclinical infection of Vibrio cholerae O1."
    supports: SUPPORT
    snippet: We examined the stools of 23 patients in Kolkata, who were
      diagnosed as cholera patients because Vibrio cholerae O1 was detected from
      their stools by culturing methods...
    explanation: This reference also supports the statement by indicating that
      stool cultures detecting V. cholerae O1 were used for diagnosis.
  - reference: PMID:6680124
    reference_title: "A rapid test for the identification of Vibrio cholerae in stools."
    supports: SUPPORT
    snippet: A rapid test for the identification of Vibrio cholerae in stools.
    explanation: This reference supports the idea of using stool culture for
      diagnosing Cholera by identifying V. cholerae.
  - reference: PMID:13356145
    reference_title: "Cholera studies. 7. Practical laboratory diagnosis."
    supports: SUPPORT
    snippet: The first portion of this study describes in detail the different
      aspects of stool examinations, including the collection, preservation, and
      pooling of specimens, macroscopic and bacterioscopic examination,
      enrichment methods, and cultivation on a variety of solid media.
    explanation: This reference discusses stool examinations and cultivation on
      solid media as methods of identifying V. cholerae, thereby supporting the
      statement.
  - reference: PMID:35130995
    reference_title: "Vibrio cholerae was found in cultured bullfrog."
    supports: SUPPORT
    snippet: A bacterial pathogen was isolated from the diseased bullfrog
      intestines. The bacterium was identified as Vibrio cholerae using
      morphological, biochemical and 16S rRNA phylogenetic analysis.
    explanation: This reference talks about isolating and identifying V.
      cholerae from intestines using culture methods, supporting the statement.
- name: Rapid Diagnostic Test
  presence: Positive
  notes: Detects cholera toxin or other bacterial antigens in stool
  evidence:
  - reference: PMID:23886437
    reference_title: "Performance and utility of a rapid diagnostic test for cholera: notes from Haiti."
    supports: SUPPORT
    snippet: The sensitivity and specificity of RDT were 95% and 80%,
      respectively, with a positive predictive value of 89% and negative
      predictive value of 91%.
    explanation: This study from Haiti indicates that RDTs are effective and
      reliable for detecting cholera, supporting their use in diagnosis.
  - reference: PMID:11883125
    reference_title: "Rapid diagnosis of cholera by coagglutination test."
    supports: SUPPORT
    snippet: A total of 553 stool specimens were processed from cases of acute
      gastro-enteritis. The sensitivity and specificity of coagglutination test
      was 92.77% and 95.65% respectively.
    explanation: This study supports the effectiveness of rapid diagnostic tests
      (coagglutination test) for cholera detection in stool samples.
- name: Darkfield Microscopy
  notes: Can show motile Vibrio cholerae in a fresh stool sample.
  evidence:
  - reference: PMID:14215188
    reference_title: "RAPID IDENTIFICATION OF VIBRIO CHOLERAE BY DARKFIELD MICROSCOPY."
    supports: SUPPORT
    snippet: This article describes a rapid, simple and reproducible method for
      detecting Vibrio cholerae in diarrhoeal patients. The method involves
      darkfield examination of a liquid stool specimen or a rectal swab immersed
      in broth and immobilization of V. cholerae by the addition of specific
      vibrio antisera.
    explanation: The method mentioned in the article uses darkfield microscopy
      to detect Vibrio cholerae in stool samples, aligning with the statement
      that darkfield microscopy can show motile Vibrio cholerae in a fresh stool
      sample.
  - reference: PMID:18024592
    reference_title: "Complexity of rice-water stool from patients with Vibrio cholerae plays a role in the transmission of infectious diarrhea."
    supports: PARTIAL
    snippet: At the International Centre for Diarrhoeal Disease Research,
      Bangladesh, one-half of the rice-water stool samples that were
      culture-positive for Vibrio cholerae did not contain motile V. cholerae by
      standard darkfield microscopy and were defined as darkfield-negative
      (DF(-)).
    explanation: While darkfield microscopy is used to detect motile Vibrio
      cholerae, the study indicates that it may not always be successful in
      detecting motile bacteria in all stool samples, leading to
      'darkfield-negative' results in some instances.
environmental:
- name: Contaminated Water
  notes: Major source of infection
  evidence:
  - reference: PMID:29949592
    reference_title: "Cholera outbreak caused by drinking contaminated water from a lakeshore water-collection site, Kasese District, south-western Uganda, June-July 2015."
    supports: SUPPORT
    snippet: We concluded that this cholera outbreak was caused by drinking lake
      water collected from inside the lakeshore water-collection site X.
    explanation: This study explicitly identifies contaminated water as the
      source of a cholera outbreak.
  - reference: PMID:33844507
    reference_title: "Update on Environmental and Host Factors Impacting the Risk of Vibrio cholerae Infection."
    supports: SUPPORT
    snippet: Cholera is transmitted primarily by the ingestion of drinking water
      contaminated with fecal matter...
    explanation: This review supports the statement that contaminated water is a
      major environmental source of cholera infection.
  - reference: PMID:37930488
    reference_title: "Microbial Waterborne Diseases in India: Status, Interventions, and Future Perspectives."
    supports: SUPPORT
    snippet: '...acute diarrheal disease (ADD), typhoid, cholera, hepatitis, and shigellosis
      are common waterborne diseases in India.'
    explanation: The abstract indicates that cholera is one of the primary
      diseases transmitted through contaminated water in India.
  - reference: PMID:36573678
    reference_title: "The forgotten threat of cholera in Syria."
    supports: SUPPORT
    snippet: Cholera is a diarrheal infection caused by ingested water or food
      contaminated with the bacterium Vibrio cholerae.
    explanation: This study confirms that cholera is caused by ingesting
      contaminated water, which aligns with the statement.
  environment_context:
    preferred_term: Contaminated water environment
    term:
      id: ENVO:00002186
      label: contaminated water
- name: Poor Sanitation
  notes: Facilitates the spread of the bacteria
  evidence:
  - reference: PMID:30512613
    reference_title: "[Cholera]."
    supports: SUPPORT
    snippet: Prevention is based on universal access to water, sanitation and
      hand hygiene.
    explanation: The snippet suggests that poor sanitation is linked to cholera
      and can help prevent its spread with proper sanitation.
  - reference: PMID:20074356
    reference_title: "Local population and regional environmental drivers of cholera in Bangladesh."
    supports: SUPPORT
    snippet: In both pre- and post-monsoon seasons, SES significantly influences
      these patterns, likely because it is a proxy for poor water quality and
      sanitation in poorer households.
    explanation: The snippet implies that poor sanitation is a significant
      factor influencing cholera patterns.
  - reference: PMID:34961483
    reference_title: "Cholera outbreak caused by drinking unprotected well water contaminated with faeces from an open storm water drainage: Kampala City, Uganda, January 2019."
    supports: SUPPORT
    snippet: Drinking contaminated water from an unprotected well was associated
      with this cholera outbreak.
    explanation: The outbreak was associated with poor sanitation practices
      involving unprotected water sources.
  - reference: PMID:29903037
    reference_title: "Cyclical cholera outbreaks in Ghana: filth, not myth."
    supports: SUPPORT
    snippet: ranked among the world''s dirtiest countries, Ghana has poor
      environmental sanitation and hygiene, and a lack of potable water, all of
      which combined have been largely blamed as the underscoring reasons for
      cholera outbreaks.
    explanation: The snippet explicitly states that poor sanitation and hygiene
      are key factors in cholera outbreaks.
  - reference: PMID:34695790
    reference_title: "Evidence-Based Health Behavior Interventions for Cholera: Lessons from an Outbreak Investigation in India."
    supports: SUPPORT
    snippet: A water pipeline was damaged in the vicinity of a stream flowing
      from a site of open defecation.
    explanation: This incident of poor sanitation led to a cholera outbreak.
treatments:
- name: Oral Rehydration Solution (ORS)
  description: Mixture of clean water, salt, and sugar to replace lost fluids
    and electrolytes.
  evidence:
  - reference: PMID:8783513
    reference_title: "Current status of oral rehydration as a strategy for the control of diarrhoeal diseases."
    supports: SUPPORT
    snippet: For more than two decades, WHO and UNICEF have recommended a single
      formulation of oral rehydration salts (ORS) solution based on glucose and
      three salts. This product has proven safe and highly effective in treating
      and preventing dehydration from diarrhoea of all causes and in all age
      groups in worldwide use and has substantially contributed to the saving of
      lives in developing countries.
    explanation: The use of Oral Rehydration Solution (ORS) is supported as a
      treatment for cholera, as it involves a mixture of water, salts, and
      glucose to replace lost fluids and electrolytes.
  - reference: PMID:49561
    reference_title: "Sucrose in oral therapy for cholera and related diarrhoeas."
    supports: SUPPORT
    snippet: The data contrast with the rarity of treatment failures of oral
      glucose-electrolyte solutions. Glucose, therefore, is preferable to
      sucrose for oral therapy of diarrhoeal diseases.
    explanation: This study emphasizes the effectiveness of glucose-based ORS
      over sucrose, supporting the use of ORS with clean water, salt, and
      glucose as a treatment for cholera and related diarrheal diseases.
  - reference: PMID:12562304
    reference_title: "An evaluation of current cholera treatment."
    supports: SUPPORT
    snippet: The mainstay of therapy of cholera patients is rehydration with
      oral rehydration salt solution or intravenous Ringer's lactate depending
      upon the degree of dehydration.
    explanation: This reference affirms that ORS is a primary treatment method
      for cholera, consistent with the use of clean water, salt, and sugar to
      replace lost fluids and electrolytes.
  treatment_term:
    preferred_term: hydrotherapy
    term:
      id: MAXO:0000458
      label: hydrotherapy
- name: Intravenous Rehydration
  description: Used for severe dehydration when rapid fluid replacement is
    necessary.
  evidence:
  - reference: PMID:8736618
    reference_title: "Practical guidelines for the treatment of cholera."
    supports: SUPPORT
    snippet: Patients with severe dehydration should be treated intravenously,
      as should those patients who do not tolerate oral rehydration solution
      (ORS).
    explanation: The literature clearly states that intravenous rehydration is
      used for severe dehydration in cholera patients.
  - reference: PMID:3171790
    reference_title: "Rapid intravenous rehydration by means of a single polyelectrolyte solution with or without dextrose."
    supports: SUPPORT
    snippet: We compared the efficacy and safety of a single polyelectrolyte
      solution, Dhaka solution (DS), containing 133 mmol/L sodium, 13 mmol/L
      potassium, 98 mmol/L chloride, and 48 mmol/L acetate with and without 139
      mmol/L (25 gm/L) dextrose in the rapid (4 hours) rehydration of 67
      patients with diarrhea and moderate or severe dehydration requiring
      parenteral fluid therapy.
    explanation: The study supports the use of intravenous rehydration for
      moderate or severe dehydration, which includes severe dehydration caused
      by cholera.
  - reference: PMID:35465904
    reference_title: "Fluid and Electrolyte Therapy During Vomiting and Diarrhea."
    supports: PARTIAL
    snippet: Fluid therapy is the most important therapeutic measure in patients
      suffering from dehydration or hypovolemia owing to gastrointestinal
      diseases. The therapy should be tailored based on the patient's condition,
      physical examination, and diagnostic findings.
    explanation: The literature discusses the importance of fluid therapy for
      dehydration but does not explicitly focus on intravenous rehydration for
      severe dehydration in cholera patients.
  - reference: PMID:19174284
    reference_title: "Treatment of calf diarrhea: intravenous fluid therapy."
    supports: NO_EVIDENCE
    snippet: Severely dehydrated calves that are unable to suckle need
      intravenous fluids for effective resuscitation.
    explanation: The article discusses intravenous fluid therapy in calves,
      which is not directly relevant to cholera treatment in humans.
  treatment_term:
    preferred_term: hydrotherapy
    term:
      id: MAXO:0000458
      label: hydrotherapy
- name: Antibiotics
  description: Shorten the course of the illness and reduce the severity,
    examples include doxycycline, azithromycin.
  evidence:
  - reference: PMID:24944120
    reference_title: "Antimicrobial drugs for treating cholera."
    supports: SUPPORT
    snippet: Overall, antimicrobial therapy shortened the mean duration of
      diarrhoea by about a day and a half compared to placebo or no treatment
      (MD -36.77 hours, 95% CI -43.51 to -30.03, 19 trials, 1013 participants,
      moderate quality evidence). Antimicrobial therapy also reduced the total
      stool volume by 50% (ROM 0.5, 95% CI 0.45 to 0.56, 18 trials, 1042
      participants, moderate quality evidence) and reduced the amount of
      rehydration fluids required by 40% (ROM 0.60, 95% CI 0.53 to 0.68, 11
      trials, 1201 participants, moderate quality evidence).
    explanation: The reference indicates that antimicrobial treatment, including
      antibiotics like doxycycline and azithromycin, significantly shortens the
      duration of diarrhea and reduces stool volume, thereby supporting the
      statement.
  - reference: PMID:11378428
    reference_title: "Cholera."
    supports: SUPPORT
    snippet: Antibiotics such as tetracycline and doxycycline shorten the
      duration of illness but do not significantly affect overall mortality.
    explanation: This reference supports the statement as it specifies that
      antibiotics such as doxycycline shorten the illness duration, aligning
      with the value description.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
- name: Zinc Supplementation
  description: Recommended for children to reduce the duration and severity of
    diarrhea.
  evidence:
  - reference: PMID:18184631
    reference_title: "Zinc supplementation in children with cholera in Bangladesh: randomised controlled trial."
    supports: SUPPORT
    snippet: Zinc supplementation significantly reduced the duration of
      diarrhoea and stool output in children with cholera. Children with cholera
      should be supplemented with zinc to reduce its duration and severity.
    explanation: This study found that zinc supplementation reduced both the
      duration and severity of diarrhoea in children with cholera.
  - reference: PMID:17582575
    reference_title: "Micronutrients and diarrheal disease."
    supports: SUPPORT
    snippet: Short-course daily zinc supplementation shortens the duration (a
      15%-24% reduction) and severity of the episode and is now recommended for
      the treatment of all episodes of diarrhea occurring among children <5
      years of age.
    explanation: This reference supports the statement by recommending zinc
      supplementation to reduce the duration and severity of diarrhea in
      children under 5 years of age.
  - reference: PMID:30269306
    reference_title: "Chinese clinical practice guidelines for acute infectious diarrhea in children."
    supports: SUPPORT
    snippet: Zinc supplements are recommended in children with acute infectious
      diarrhea.
    explanation: This guideline recommends zinc supplementation specifically for
      children with acute infectious diarrhea.
  - reference: PMID:37842003
    reference_title: "Characterization of changes in the intestinal microbiome following combination therapy with zinc preparation and conventional treatment for children with rotavirus enteritis."
    supports: SUPPORT
    snippet: Zinc supplementation has previously been shown to improve
      resolution of symptoms from infectious diarrhea.
    explanation: This literature shows that zinc supplementation improves
      symptom resolution in children with infectious diarrhea, including those
      caused by rotavirus.
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
- name: Vaccination
  description: Oral cholera vaccines can provide protection in endemic areas or
    during outbreaks.
  evidence:
  - reference: PMID:22634452
    reference_title: "Cholera vaccine: new preventive tool for endemic countries."
    supports: SUPPORT
    snippet: This vaccine should be used in areas where cholera is endemic,
      particularly in those at risk of outbreaks, in conjunction with other
      prevention and control strategies.
    explanation: This supports that oral cholera vaccines can provide protection
      in endemic areas or during outbreaks.
  - reference: PMID:15193408
    reference_title: "Can oral cholera vaccination play a role in controlling a cholera outbreak?"
    supports: SUPPORT
    snippet: Retrospective analysis suggests that mass vaccination with oral
      cholera vaccines can be a useful adjunct tool for controlling outbreaks,
      particularly if implemented early in association with other standard
      control measures.
    explanation: This indicates that oral cholera vaccines can be a valuable
      tool during outbreaks.
  - reference: PMID:36255170
    reference_title: "Mucosal and systemic immune responses to Vibrio cholerae infection and oral cholera vaccines (OCVs) in humans: a systematic review."
    supports: PARTIAL
    snippet: Efficacies of the currently licensed cholera vaccines are not
      optimal in endemic settings and low in children below the age of five, a
      section of the population most susceptible to the disease.
    explanation: While oral cholera vaccines can provide protection, their
      efficacy is not optimal in endemic settings, especially for children under
      five.
  - reference: PMID:26494426
    reference_title: "The scenario approach for countries considering the addition of oral cholera vaccination in cholera preparedness and control plans."
    supports: PARTIAL
    snippet: Oral cholera vaccination could be deployed in a diverse range of
      situations from cholera-endemic areas and locations of humanitarian
      crises, but no clear consensus exists.
    explanation: The deployment of oral cholera vaccines is suggested for
      endemic areas and crises, but a clear consensus on their use is lacking.
  treatment_term:
    preferred_term: vaccination
    term:
      id: MAXO:0001017
      label: vaccination
review_notes: Cholera is an acute diarrheal illness caused by infection with the
  bacterium Vibrio cholerae. It can cause rapid and severe dehydration that can
  be lethal. Additional key features include "rice-water" diarrhea, vomiting,
  and electrolyte imbalances like hypokalemia and metabolic acidosis due to the
  massive fluid losses. Hypovolemic shock is the most severe complication. Rapid
  fluid and electrolyte replacement is critical.
disease_term:
  preferred_term: cholera
  term:
    id: MONDO:0015766
    label: cholera
references:
- reference: DOI:10.1007/978-1-60327-265-0_15
  title: Toxins of Vibrio cholerae and Their Role in Inflammation, Pathogenesis,
    and Immunomodulation
  findings: []
- reference: DOI:10.1016/j.mib.2023.102421
  title: The intersection between host–pathogen interactions and metabolism
    during Vibrio cholerae infection
  findings: []
- reference: DOI:10.1371/journal.ppat.1006862
  title: GM1 ganglioside-independent intoxication by Cholera toxin
  findings: []
- reference: DOI:10.3389/fmed.2023.1155751
  title: Vibrio cholerae, classification, pathogenesis, immune response, and
    trends in vaccine development
  findings: []
- reference: DOI:10.3390/toxins2030310
  title: 'Cholera Toxin: An Intracellular Journey into the Cytosol by Way of the Endoplasmic
    Reticulum'
  findings: []
📚

References & Deep Research

References

5
DOI:10.1007/978-1-60327-265-0_15
Toxins of Vibrio cholerae and Their Role in Inflammation, Pathogenesis, and Immunomodulation
No top-level findings curated for this source.
DOI:10.1016/j.mib.2023.102421
The intersection between host–pathogen interactions and metabolism during Vibrio cholerae infection
No top-level findings curated for this source.
DOI:10.1371/journal.ppat.1006862
GM1 ganglioside-independent intoxication by Cholera toxin
No top-level findings curated for this source.
DOI:10.3389/fmed.2023.1155751
Vibrio cholerae, classification, pathogenesis, immune response, and trends in vaccine development
No top-level findings curated for this source.
DOI:10.3390/toxins2030310
Cholera Toxin: An Intracellular Journey into the Cytosol by Way of the Endoplasmic Reticulum
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Cholera
  • Category: Infectious Disease
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 197

Key Pathophysiology Nodes

  • Cholera Toxin Binding and Uptake
  • ERAD-mediated CTA1 Translocation
  • Gsα ADP-Ribosylation
  • Cholera Toxin
  • Increased cAMP
  • Profuse Watery Diarrhea
  • Colonization and Biofilm Formation
  • Accessory Toxins and Virulence Factors
  • Host Metabolic Reprogramming
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/978-1-60327-265-0_15
  • DOI:10.1007/978-1-60327-265-0_15
  • DOI:10.1016/j.mib.2023.102421
  • DOI:10.1371/journal.ppat.1006862
  • DOI:10.3389/fmed.2023.1155751
  • DOI:10.3390/toxins2030310
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 21 citations 2025-12-15T09:10:45.506928

Disease Pathophysiology Research Report

Target Disease - Disease Name: Cholera - MONDO ID: - Category: Infectious Disease

Pathophysiology description Cholera is a toxin-mediated secretory diarrheal disease caused by intestinal infection with toxigenic Vibrio cholerae. The central pathophysiologic axis is driven by cholera toxin (CT), an AB5 protein complex in which the pentameric B subunit (CTB) binds host glycoconjugate receptors at the apical surface of small-intestinal epithelial cells and the A1 enzymatic subunit (CTA1) catalyzes ADP-ribosylation of the heterotrimeric G protein Gsα (GNAS). This locks adenylyl cyclase in an active state, elevating intracellular cAMP, activating protein kinase A (PKA), and driving CFTR-mediated chloride efflux and massive osmotic water secretion into the lumen, culminating in profuse “rice‑water” diarrhea and hypovolemic shock if untreated (Wernick et al., Toxins, 2010; https://doi.org/10.3390/toxins2030310, published 5 Mar 2010) (wernick2010choleratoxinan pages 1-4). A recent concise synthesis emphasizes the same core sequence—CT → adenylyl cyclase → cAMP → PKA → CFTR—while highlighting that CT-driven signaling also reprograms host epithelial metabolism to release host-derived nutrients that can fuel intraluminal V. cholerae growth and transmission (Dominguez et al., Curr Opin Microbiol, 2024; https://doi.org/10.1016/j.mib.2023.102421, published Feb 2024) (dominguez2024theintersectionbetween pages 1-2, dominguez2024theintersectionbetween pages 8-10, dominguez2024theintersectionbetween pages 10-11).

Beyond GM1 ganglioside, CTB recognizes alternative glycan ligands, including fucosylated glycoproteins such as the Lewis X (LeX) antigen. In human enteroids and other models, GM1-independent intoxication occurs and is blockable by fucosylated oligosaccharides or anti-LeX antibodies, demonstrating that glycoprotein glycans can serve as functional receptors in addition to GM1 (Cervin et al., PLoS Pathog, 2018; https://doi.org/10.1371/journal.ppat.1006862, published 12 Feb 2018) (cervin2018gm1gangliosideindependentintoxication pages 1-2). Once bound, CTB–receptor complexes undergo endocytosis and traffic retrograde through early endosomes and the trans-Golgi network to the endoplasmic reticulum (ER). There, CTA1 separates, unfolds via protein disulfide isomerase, and hijacks the ER-associated degradation (ERAD) retro-translocation machinery to reach the cytosol, where it refolds and ADP-ribosylates Gsα to activate adenylyl cyclase (Wernick et al., 2010) (wernick2010choleratoxinan pages 1-4). As directly stated: “the A1-chain is unfolded by protein disulfide isomerase and retro-translocated to the cytosol by hijacking components of the ER associated degradation pathway… [then] ADP-ribosylates the large G-protein Gs and [activates] adenylyl cyclase” (wernick2010choleratoxinan pages 1-4).

V. cholerae successfully colonizes the small intestine by traversing the mucus barrier, adhering to the epithelium, and forming microcolonies through the toxin-coregulated pilus (TCP). Virulence factor expression—CTX and TCP—is controlled by a regulatory cascade centered on ToxR, TcpP, and the AraC-family regulator ToxT; ToxR also remodels outer membrane porins (e.g., upregulating OmpU) to resist bile and antimicrobial peptides, while the neuraminidase NanH exposes GM1 for CT binding (Montero et al., Front Med, 2023; https://doi.org/10.3389/fmed.2023.1155751, published May 2023) (montero2023vibriocholeraeclassification pages 5-6, montero2023vibriocholeraeclassification pages 6-7). Accessory toxins and effectors—MARTX (actin cytoskeleton disruption, phagocyte inhibition, innate signaling modulation), hemolysin HlyA (pore formation/ion leakage, often OMV-associated), zonula occludens toxin (Zot; tight junction perturbation), and accessory cholera enterotoxin Ace (secretory effects)—contribute to pathogenesis in a strain- and context-dependent manner (Montero et al., 2023) (montero2023vibriocholeraeclassification pages 6-7). The acute disease is often non-inflammatory during peak secretory phases, with CT-linked immunomodulatory properties, yet infection triggers adaptive immune responses, and biofilm growth in vivo supports a hyperinfectious state and fecal–oral transmission (Dominguez et al., 2024; Montero et al., 2023) (dominguez2024theintersectionbetween pages 1-2, dominguez2024theintersectionbetween pages 10-11, montero2023vibriocholeraeclassification pages 6-7).

Key quotes (mechanistic anchors) - “The A1-chain is… retro-translocated to the cytosol by hijacking… ERAD… [and] ADP-ribosylates… Gs and [activates] adenylyl cyclase.” (Wernick et al., 2010; https://doi.org/10.3390/toxins2030310) (wernick2010choleratoxinan pages 1-4) - “CT increases cellular cAMP, activating PKA which phosphorylates and activates CFTR to secrete chloride ions” (Dominguez et al., 2024; https://doi.org/10.1016/j.mib.2023.102421) (dominguez2024theintersectionbetween pages 10-11) - “CTB binds fucosylated proteins… binding correlates with expression of the fucosylated Lewis X (LeX) glycan… CT can induce toxicity in the absence of GM1.” (Cervin et al., 2018; https://doi.org/10.1371/journal.ppat.1006862) (cervin2018gm1gangliosideindependentintoxication pages 1-2) - “Toxigenic vibrios express CTX and TCP as main virulence determinants… NanH… exposing GM1… Accessory toxins include MARTX, HlyA, Zot, and Ace.” (Montero et al., 2023; https://doi.org/10.3389/fmed.2023.1155751) (montero2023vibriocholeraeclassification pages 6-7)

1) Core Pathophysiology - Primary mechanisms: CTB binds GM1 and alternative glycans (e.g., LeX) on enterocytes; holotoxin undergoes retrograde trafficking to the ER; CTA1 exploits ERAD to enter the cytosol and ADP-ribosylates Gsα; adenylyl cyclase activation elevates cAMP, activates PKA, and opens CFTR, producing chloride and water secretion (Wernick 2010; Dominguez 2024; Cervin 2018) (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11, dominguez2024theintersectionbetween pages 1-2, cervin2018gm1gangliosideindependentintoxication pages 1-2). - Dysregulated pathways: cAMP/PKA signaling and epithelial ion transport (CFTR-mediated Cl− secretion) dominate the secretory phenotype; paracellular permeability can be enhanced by Zot; pore formation and ion leakage by HlyA; cytoskeletal and innate signaling disruption by MARTX (Montero 2023; Dominguez 2024) (montero2023vibriocholeraeclassification pages 6-7, dominguez2024theintersectionbetween pages 10-11, dominguez2024theintersectionbetween pages 8-10). - Affected cellular processes: receptor-mediated endocytosis and retrograde transport; ER protein quality control (ERAD) repurposed by CTA1; epithelial ion channel regulation; mucus barrier interactions and biofilm-linked colonization (Wernick 2010; Montero 2023; Dominguez 2024) (wernick2010choleratoxinan pages 1-4, montero2023vibriocholeraeclassification pages 6-7, dominguez2024theintersectionbetween pages 1-2).

2) Key Molecular Players - Genes/Proteins: GNAS (Gsα; ADP-ribosylation target), CFTR (apical Cl− channel), ToxR/TcpP/ToxT (virulence regulation), NanH (sialidase), CTA1/CTB (toxin subunits), HlyA, Zot, Ace, MARTX (Wernick 2010; Montero 2023; Dominguez 2024; Cervin 2018) (wernick2010choleratoxinan pages 1-4, montero2023vibriocholeraeclassification pages 6-7, dominguez2024theintersectionbetween pages 10-11, cervin2018gm1gangliosideindependentintoxication pages 1-2). - Chemical entities: GM1 ganglioside and fucosylated glycans (e.g., LeX) as CTB receptors; cAMP (second messenger); NAD+ as ADP-ribose donor; bile acids (host cues modulating virulence) (Cervin 2018; Wernick 2010; Dominguez 2024; Montero 2023) (cervin2018gm1gangliosideindependentintoxication pages 1-2, wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11, montero2023vibriocholeraeclassification pages 5-6). - Cell types: small-intestinal enterocytes as principal targets; mucus-producing cells provide glycoconjugate ligands/decoys (Cervin 2018; Wernick 2010; Dominguez 2024) (cervin2018gm1gangliosideindependentintoxication pages 1-2, wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 1-2). - Anatomical sites: ileal small intestine; apical membrane microdomains; mucus layer; lumenal milieu enriched in host nutrients during disease (Dominguez 2024; Montero 2023; Wernick 2010) (dominguez2024theintersectionbetween pages 8-10, montero2023vibriocholeraeclassification pages 6-7, wernick2010choleratoxinan pages 1-4).

3) Biological Processes (GO annotation candidates) - “Adenylyl cyclase-activating G protein-coupled receptor signaling pathway” and “cAMP-mediated signaling” are centrally activated by CTA1→Gsα modification, with downstream “protein phosphorylation” (PKA) regulating “chloride transmembrane transport” via CFTR (Wernick 2010; Dominguez 2024) (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11, dominguez2024theintersectionbetween pages 1-2). - “Endocytosis,” “retrograde vesicle-mediated transport,” and “ER-associated protein catabolic process (ERAD)” support CTA1 entry to cytosol (Wernick 2010) (wernick2010choleratoxinan pages 1-4). - “Tight junction organization” and “paracellular transport” perturbed by Zot; “membrane pore formation” by HlyA; “actin cytoskeleton organization” modulated by MARTX; “mucin catabolic process” and “adhesion to host” in colonization (Montero 2023) (montero2023vibriocholeraeclassification pages 6-7).

4) Cellular Components - Apical plasma membrane/lipid rafts (GM1 clustering) and early/recycling endosomes, trans-Golgi network, and ER are essential compartments for CT trafficking (Wernick 2010) (wernick2010choleratoxinan pages 1-4). - ERAD machinery (e.g., Sec61/Derlin/Hrd1 axis) is co-opted for CTA1 retro-translocation (Wernick 2010) (wernick2010choleratoxinan pages 1-4). - Tight junctions at epithelial apical junctional complex are a target for Zot; CFTR resides in apical membrane (Montero 2023; Wernick 2010) (montero2023vibriocholeraeclassification pages 6-7, wernick2010choleratoxinan pages 1-4).

5) Disease Progression - Incubation spans ~12 hours to 5 days, reflecting acid sensitivity and infectious dose; colonization entails mucus penetration, adhesion (GbpA/TCP), and microcolony formation under ToxR/ToxT/TcpP regulation. CT and accessory toxins are secreted via the type II secretion system and OMVs, binding to epithelial receptors to initiate intoxication and secretory diarrhea (Montero 2023) (montero2023vibriocholeraeclassification pages 5-6, montero2023vibriocholeraeclassification pages 6-7). - Cellular sequence: CTB binds GM1 and/or fucosylated glycoproteins → endocytosis and retrograde trafficking → CTA1 ERAD escape → Gsα ADP-ribosylation → AC activation → cAMP surge → PKA activation → CFTR phosphorylation/activation → Cl− and water secretion. MARTX, HlyA, Zot, and Ace add cytoskeletal disruption, membrane permeabilization, junctional changes, and additional secretory drive (Wernick 2010; Montero 2023; Dominguez 2024) (wernick2010choleratoxinan pages 1-4, montero2023vibriocholeraeclassification pages 6-7, dominguez2024theintersectionbetween pages 10-11).

6) Phenotypic Manifestations - Key clinical phenotypes: sudden, voluminous “rice‑water” stools; rapid dehydration and electrolyte losses; hypovolemic shock; acidosis when severe. Mechanistically, these reflect CFTR-dependent chloride secretion and osmotic water flux, with accessory effects on paracellular permeability and membrane integrity (Dominguez 2024; Wernick 2010; Montero 2023) (dominguez2024theintersectionbetween pages 10-11, wernick2010choleratoxinan pages 1-4, montero2023vibriocholeraeclassification pages 6-7).

Recent developments and latest research (2023–2024) - Human-relevant host–pathogen metabolism: CT not only drives CFTR-dependent secretion but also reshapes epithelial metabolism to release nutrients (LCFAs, lactate, glycerol), potentially enhancing V. cholerae luminal growth and transmission; bile acids and the microbiome modulate biofilm formation and virulence gene expression (Dominguez 2024; https://doi.org/10.1016/j.mib.2023.102421) (dominguez2024theintersectionbetween pages 10-11, dominguez2024theintersectionbetween pages 8-10). - Receptor diversity on human enteroids: CT binding/intoxication in primary jejunal enteroids involves GM1-scarce surfaces and fucosylated glycoproteins; inhibition of fucosylation/glycosylation alters susceptibility, emphasizing decoy versus functional ligands and inter-individual variability (Cervin 2018; https://doi.org/10.1371/journal.ppat.1006862; see also Montero 2023 for NanH–GM1 exposure) (cervin2018gm1gangliosideindependentintoxication pages 1-2, montero2023vibriocholeraeclassification pages 5-6, montero2023vibriocholeraeclassification pages 6-7). - Updated synthesis of colonization and accessory toxins: 2023 review consolidates roles for TCP, T6SS, OmpU, mucinases (HapA/TagA), adhesins (GbpA/FrhA), and accessory toxins (MARTX, HlyA, Zot, Ace) as contributors to disease severity and transmission (Montero 2023; https://doi.org/10.3389/fmed.2023.1155751) (montero2023vibriocholeraeclassification pages 6-7, montero2023vibriocholeraeclassification pages 5-6).

Current applications and real-world implementations - Mechanism-informed clinical priorities: The cAMP–PKA–CFTR axis underpins standard supportive therapy targeting rapid correction of water and electrolyte deficits; mechanistic understanding of CT trafficking and CFTR activation informs the rationale for antisecretory strategies in development (Wernick 2010; Dominguez 2024) (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11). - Vaccine/colonization insights: TCP’s centrality to colonization and its role as the CTXΦ receptor continue to guide vaccine antigen choices; environmental sensing by ToxR/TcpP/ToxT and OMV packaging of CT inform next-generation approaches (Montero 2023) (montero2023vibriocholeraeclassification pages 6-7, montero2023vibriocholeraeclassification pages 5-6).

Expert opinions and analysis - A mechanistic consensus view: “CT… activates adenylyl cyclase, elevating cAMP, and driving chloride secretion” (Wernick 2010) and “CT increases cellular cAMP, activating PKA… CFTR” (Dominguez 2024) articulate a consistent expert framework for cholera’s core secretory mechanism (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11). - Emerging expert emphasis: recent analyses posit that CT-mediated metabolic reprogramming and microbiome/bile acid interactions are integral to pathogenesis and transmission fitness, extending beyond pure ion flux pathology (Dominguez 2024) (dominguez2024theintersectionbetween pages 8-10, dominguez2024theintersectionbetween pages 10-11).

Relevant statistics and data - Incubation and colonization context: acid sensitivity necessitating high infectious dose in healthy volunteers; incubation about 12 h to 5 days; thick intestinal mucus barrier (≈100–400 µm) to be traversed (Montero 2023; https://doi.org/10.3389/fmed.2023.1155751) (montero2023vibriocholeraeclassification pages 5-6). While quantitative electrolyte-loss statistics can vary by outbreak and treatment context, the molecular pathway consistently links cAMP–PKA–CFTR activation to the massive fluid loss that defines severe cholera (Dominguez 2024; Wernick 2010) (dominguez2024theintersectionbetween pages 10-11, wernick2010choleratoxinan pages 1-4).

Gene/protein annotations with ontology terms (HGNC, GO) - GNAS (HGNC:4392): substrate for CTA1 ADP-ribosylation → adenylyl cyclase activation; cAMP-mediated signaling (wernick2010choleratoxinan pages 1-4). - CFTR (HGNC:1884): apical Cl− channel phosphorylated by PKA; chloride transmembrane transport and fluid secretion (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11). - ToxR/TcpP/ToxT: virulence regulators controlling ctxAB and tcpA (colonization); environmental sensing and bile resistance (montero2023vibriocholeraeclassification pages 6-7). - NanH (neuraminidase): exposes GM1 on host cells to enhance CT binding (montero2023vibriocholeraeclassification pages 5-6).

Phenotype associations (HP terms; descriptive mapping) - Acute watery diarrhea with “rice‑water” stools; severe dehydration; hypovolemic shock; metabolic acidosis in severe cases—mechanistically linked to CFTR‑mediated chloride secretion and water efflux and junctional/membrane perturbations (dominguez2024theintersectionbetween pages 10-11, montero2023vibriocholeraeclassification pages 6-7, wernick2010choleratoxinan pages 1-4).

Cell type involvement (CL terms) - Enterocytes (CL:0000584): principal intoxicated cells executing chloride and water secretion (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11). - Mucus-associated epithelial cells provide glycoprotein ligands/decoys for CTB (cervin2018gm1gangliosideindependentintoxication pages 1-2).

Anatomical locations (UBERON terms) - Small intestine, especially ileum (UBERON:0002116): site of colonization, intoxication, and secretion (dominguez2024theintersectionbetween pages 8-10, montero2023vibriocholeraeclassification pages 6-7).

Chemical entities (CHEBI terms) - cAMP (second messenger), NAD+ (CTA1 substrate), GM1 ganglioside (glycolipid receptor), bile acids (host cues), fucosylated LeX glycan (alternative receptor) (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11, cervin2018gm1gangliosideindependentintoxication pages 1-2, montero2023vibriocholeraeclassification pages 5-6).

Evidence items with PMIDs/DOIs and dates (URLs included) - Wernick NLB et al. Cholera toxin: an intracellular journey into the cytosol by way of the endoplasmic reticulum. Toxins. 2010 Mar 5. doi:10.3390/toxins2030310. URL: https://doi.org/10.3390/toxins2030310 (wernick2010choleratoxinan pages 1-4). - Montero DA et al. Vibrio cholerae, classification, pathogenesis, immune response, and trends in vaccine development. Front Med. 2023 May. doi:10.3389/fmed.2023.1155751. URL: https://doi.org/10.3389/fmed.2023.1155751 (montero2023vibriocholeraeclassification pages 5-6, montero2023vibriocholeraeclassification pages 6-7). - Dominguez SR et al. The intersection between host–pathogen interactions and metabolism during Vibrio cholerae infection. Curr Opin Microbiol. 2024 Feb. doi:10.1016/j.mib.2023.102421. URL: https://doi.org/10.1016/j.mib.2023.102421 (dominguez2024theintersectionbetween pages 10-11, dominguez2024theintersectionbetween pages 1-2, dominguez2024theintersectionbetween pages 8-10). - Cervin J et al. GM1 ganglioside-independent intoxication by Cholera toxin. PLoS Pathog. 2018 Feb 12. doi:10.1371/journal.ppat.1006862. URL: https://doi.org/10.1371/journal.ppat.1006862 (cervin2018gm1gangliosideindependentintoxication pages 1-2). - Walia K, Ganguly NK. Toxins of Vibrio cholerae and their role in inflammation, pathogenesis, and immunomodulation. 2011 Sep. doi:10.1007/978-1-60327-265-0_15. URL: https://doi.org/10.1007/978-1-60327-265-0_15 (walia2011toxinsofvibrio pages 272-274).

Entity–ontology mapping artifact | Entity | Category | Ontology | Ontology ID | Role in Cholera Pathophysiology | Key supporting sources | |---|---|---|---|---|---| | GNAS | Gene/Protein | HGNC | HGNC:4392 | Gs alpha subunit ADP-ribosylated by CTA1 -> constitutive adenylate cyclase activation | (wernick2010choleratoxinan pages 1-4) | | CFTR | Gene/Protein | HGNC | HGNC:1884 | cAMP/PKA-activated apical Cl- channel driving chloride and water secretion | (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11) | | GM1 ganglioside | Chemical (glycolipid) | CHEBI | | Cell-surface receptor for CTB that mediates endocytosis and retrograde trafficking | (wernick2010choleratoxinan pages 1-4, montero2023vibriocholeraeclassification pages 5-6) | | CTA1 (A1 chain) | Protein (toxin) | | | Enzymatic ADP-ribosyltransferase that modifies Gsα (GNAS) to raise cAMP | (wernick2010choleratoxinan pages 1-4) | | CTB (B subunit) | Protein (toxin) | | | Pentameric lectin that binds GM1 and alternative glycans (e.g., LeX) to enable uptake | (cervin2018gm1gangliosideindependentintoxication pages 1-2, wernick2010choleratoxinan pages 1-4) | | Adenylate cyclase activation pathway | Process | GO | GO:0007189 | Activation of AC downstream of Gsα modification leading to cAMP production | (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11) | | cAMP signaling | Process/Chemical | CHEBI / GO | | Second-messenger cascade (cAMP → PKA) that drives CFTR phosphorylation and ion secretion | (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11) | | PKA (protein kinase A) | Protein | | | cAMP-activated kinase that phosphorylates CFTR and modulates epithelial ion transport | (dominguez2024theintersectionbetween pages 10-11) | | CFTR-mediated chloride secretion | Process | GO | GO:0006821 | PKA-phosphorylated CFTR increases apical Cl- efflux, producing osmotic water loss (rice-water stool) | (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11) | | ERAD retro-translocation | Process | GO | | ER-associated degradation pathway hijacked by CTA1 for cytosolic entry of A1 chain | (wernick2010choleratoxinan pages 1-4) | | ToxR / ToxT / TcpP / TCP | Regulatory system / Structure | | | Transcriptional regulatory cascade controlling toxT, ctxAB and TCP for toxin production and colonization | (montero2023vibriocholeraeclassification pages 5-6, dominguez2024theintersectionbetween pages 10-11) | | NanH neuraminidase | Protein (enzyme) | | | Removes sialic acids to expose GM1 and enhance CT binding to enterocytes | (montero2023vibriocholeraeclassification pages 5-6) | | MARTX | Toxin (multifunctional) | | | Large effector toxin disrupting actin, inhibiting phagocytosis and modulating innate signaling | (montero2023vibriocholeraeclassification pages 5-6) | | HlyA (hemolysin) | Protein (toxin) | | | Pore-forming toxin causing cell damage and ion leakage; associated with OMVs | (montero2023vibriocholeraeclassification pages 5-6) | | Zot (zonula occludens toxin) | Protein (toxin) | | | Disrupts tight junctions and increases paracellular permeability contributing to secretory diarrhea | (montero2023vibriocholeraeclassification pages 5-6, walia2011toxinsofvibrio pages 272-274) | | Ace (accessory cholera enterotoxin) | Protein (toxin) | | | Alters ion transport and contributes to fluid secretion (generally milder effect) | (montero2023vibriocholeraeclassification pages 5-6, walia2011toxinsofvibrio pages 272-274) | | Enterocyte | Cell | CL | CL:0000584 | Intestinal absorptive epithelial cell targeted by CT; mediates secretion and barrier function | (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11) | | Goblet cell | Cell | CL | | Mucin-secreting epithelial cell; source of mucus and glycoprotein decoy ligands for CTB | (cervin2018gm1gangliosideindependentintoxication pages 1-2) | | Small intestine (ileum) | Anatomy | UBERON | UBERON:0002116 | Primary site of V. cholerae colonization and CT-mediated secretory responses | (dominguez2024theintersectionbetween pages 10-11, montero2023vibriocholeraeclassification pages 5-6) | | Mucus layer | Anatomy / ECM | | | Barrier containing glycoconjugates that V. cholerae must penetrate; provides decoy and functional CT ligands | (montero2023vibriocholeraeclassification pages 5-6, cervin2018gm1gangliosideindependentintoxication pages 1-2) | | cAMP (chemical) | Chemical (second messenger) | CHEBI | | Intracellular messenger produced by AC; activates PKA and downstream secretion | (wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11) | | NAD+ | Chemical (cofactor) | CHEBI | | ADP-ribose donor substrate for CTA1-catalyzed ADP-ribosylation of Gsα | (wernick2010choleratoxinan pages 1-4) | | Bile acids | Chemical (host metabolite) | CHEBI | | Host-derived signals that modulate V. cholerae virulence regulation (ToxR/ToxT) and colonization dynamics | (dominguez2024theintersectionbetween pages 10-11) | | Fucosylated Lewis X glycan (LeX) | Chemical (glycan) | | | Alternative CTB ligand on glycoproteins enabling GM1-independent intoxication of human enterocytes | (cervin2018gm1gangliosideindependentintoxication pages 1-2) | | Outer membrane vesicles (OMVs) | Structure / Particle | | | Vehicles packaging CT and accessory toxins for protected delivery to host cells | (montero2023vibriocholeraeclassification pages 5-6) |

Table: Compact, evidence-linked table mapping key molecular, cellular, anatomical, and chemical entities in cholera pathophysiology with ontology IDs where available and supporting source citations (context IDs).

References (supporting specific claims; see in-text IDs) - CT structure, trafficking, ERAD escape, and Gsα ADP-ribosylation: (wernick2010choleratoxinan pages 1-4). - GM1-independent binding and glycan receptors (LeX): (cervin2018gm1gangliosideindependentintoxication pages 1-2). - Colonization determinants (TCP, adhesins, mucinases), virulence regulation (ToxR/ToxT/TcpP), and accessory toxins (MARTX, HlyA, Zot, Ace): (montero2023vibriocholeraeclassification pages 6-7, montero2023vibriocholeraeclassification pages 5-6). - Core secretory mechanism and host metabolic remodeling; bile acid/microbiome modulation: (dominguez2024theintersectionbetween pages 10-11, dominguez2024theintersectionbetween pages 1-2, dominguez2024theintersectionbetween pages 8-10). - Ion transport, paracellular effects, and clinical secretory phenotype doctrines: (walia2011toxinsofvibrio pages 272-274, wernick2010choleratoxinan pages 1-4, dominguez2024theintersectionbetween pages 10-11).

Notes on evidence scope Where detailed population statistics (e.g., case counts) and certain host genetic susceptibility factors were sought, the most recent, directly mechanistic sources available in the present corpus emphasized molecular pathways and colonization biology rather than comprehensive epidemiologic quantifications. Consequently, quantitative epidemiology is referenced only where supported by the included 2023–2024 reviews, while mechanistic inferences and quotes are directly cited from the sources listed (wernick2010choleratoxinan pages 1-4, montero2023vibriocholeraeclassification pages 5-6, walia2011toxinsofvibrio pages 272-274, cervin2018gm1gangliosideindependentintoxication pages 1-2, montero2023vibriocholeraeclassification pages 6-7, dominguez2024theintersectionbetween pages 10-11, dominguez2024theintersectionbetween pages 1-2, dominguez2024theintersectionbetween pages 8-10).

References

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