MED-NERD
Cholera
Outline:
- Introduction
- Epidemiology
- Transmission
- Symptoms
- Diagnosis
- Differential diagnosis
- Treatment
- Prevention
- Prognosis and complications
- References
Introduction:
Cholera infection is acute watery diarrheal syndrome caused by Gram-negative, rod-shaped organism known as Vibrio Cholerae (V. cholerae). The bacterium presents mainly in brackish-water ponds and is transmitted from environmental sources to the human through contaminated food or water.
In 1854, Pacini identified the organism by microscopically. In 1883, Robert Koch isolated the bacterium in pure culture from Egyptian patients. There are more than 200 serogroups of V. cholerae. Recently, cholera epidemics were caused by the serogroups O1 and O139 and O1 is the main infectious organism. These strains caused several endemics in Yemen, Southeast Asia, parts of Africa, and Haiti. In 1992 in Bangladesh, V. cholerae O139 was first identified and recently it caused in sporadic cases. The two serogroups cause the same illness. Classical and El Tor are two subdivisions of V. cholerae O1. The classical biotype was considered the causative organism of the previous 6 pandemics from the years 1817 to 1921, whereas the El Tor biotype 13 is considered the cause of the recent pandemic that started in 1961. Most environmental samples shows El Tor and it is considered that classical biotypes are no longer present.
The El Tor is subdivided into two serotypes that are the most prevalent causatives of pandemics: Ogawa and Inaba. Moreover they are used in Shanchol and Euvichol vaccines.
V.cholerae can cause infection of the stomach with infectious dose more than 10⁸ pathogens. as it is highly sensetive to the low pH. After surviving stomach acidity, colonization of intestinal tract is done aided by the toxin co-regulated pilus (TCP) which promotes microcolony formation. Disruption of ionic transport of gut epithelium is done through cholera toxin (CT) secreted by the bacterium, leading to severe watery efflux into the intestine, fatal diarrhea, and vomiting. The non-O1 or non-O139 do not cause cholera but some cases showed diarrheal symptoms due to the absence of TCP or CT.
Over 3 million cases of cholera with greater than 100,000 deaths were reported annually.
Epidemiology:
The original reservoir of cholera is in the Ganges delta in India in the 19th century. From 1827 to 1923, V.cholerae caused 6 pandemics. The first pandemic started in 1817, and subsequently in 1829, 1852, 1863, 1881, 1889, and 1961. In 1961, The seventh and current pandemic emerged in the Sulawesi Archipelago and reached in 1991 South America and wide areas of the Western Hemisphere.
Cholera emerges mainly in areas of poor hygiene, sanitation, and poor water sources including Africa and some regions of the Middle East. Cholera can occur in enedemic areas (where cholera cases were detected and confirmed in the previous 3 years with local transmission), and also occurs in other countries were cholera does not regularly occur. Sporadic cases are found in developed countries. Recently, 1.3 billion people are at risk of having cholera which is endemic in 69 countries in Africa, Asia, and the Americas, the worst is in Sub-Sahara Africa.
According to the World Health Oeganization (WHO), V.cholerae caused 2.8 million cases with almost 91,000 deaths annually. Currently, areas of natural disasters, war, conflict, Iraq, and Yemen, and Haiti (2010) are at increased risk of cholera infection and outbreaks. New V.cholerae strains, with frequent travel, and spread of infected cases are some factors that caused cholera to reach areas of safe water and advanced sanitation systems including North America and Europe and this is considered a public health concern.
-About 1.3–4 million cholera cases and 21,000–143,000 deaths were reported from 2008 to 2012.
-About 1.2 million cases and 5654 cholera deaths were reported in 2017 globally according to the WHO, 84% cases and 41% deaths of cholera were reported in Yemen in the same year.
-Some cases were unreported due to weak surveillance systems in some countries making the statistics uncertain.
-"A global strategy on cholera control, Ending Cholera: a global roadmap to 2030" was launched in 2017 with a target to reduce cholera by 90%.
-In 2020, 323 369 cholera cases, with 857 deaths were reported from 24 countries.
Transmission:
Cholera is transmitted through faecal-oral route, directly from person-to-person or indirectly from environmental sources by contaminated food, fluids, flies, and fomites. Areas of high risk include camps and peri-urban slums. In addition to contact with infected cases, some risk factors related to the infection include poor sanitation, poor hygiene, poor access to safe water sources, improper food handling behaviours, especially in crowded areas. Improving sanitation systems may help in controlling the disease.
Endemics are mainly related to seasonal climate changes and tidal seawater intrusions. On the other hand, epidemics occur if weather conditions encourage bacterial growth especially near waterways.
V.choreae is excreted in the stool of infected patients for one day in asymptomatic cases, and up to 1-2 weeks in symptomatic cases. Bacterial shedding may be more prolonged. Free-swimming cells of V. cholerae and biofilm-like aggregates are found in the stool of infected patients. Alternation between motile form and biofilm form helps colonization of the small intestine. Biofilms of V.cholerae have low infective dose, more resistance to stressful conditions in the human host, more dissemination of the disease.
The transient hyperinfective properity of V. cholerae in fresh stool that may present for few hours after dissemination may be the cause of rapid spread of cholera feco-orally in areas of high populations.
The incubation period (the time from infection to the onset of disease) is 1-4 days, 95% develop symptoms after 4.4 days, 5% may develop symptoms 12 hours after infection.
Direct person-to-person contact causes rapid transmission in families and crowded areas.
A study in Bangladesh showed that in rectal swab-positive contacts, greater than 70% developed diarrhea 21 days of observation, and a quarter of 294 household contacts of cholera patients developed the infection and had bacterial shedding.
Symptoms:
After 12 hours to 5 days of infection, cholera symptoms develop as acute watery diarrhoea. V.cholerae produces enterotoxin leading to the copious, painless, watery diarrhoea. Both children and adults can be affected by V.cholerae with high mortality rate if left untreated. In-spite of the presence of the organism in stool 1-10 days following infection, cholera is mainly asymptomatic. The shedding of V.cholerae in stool increase the risk of transmission to other people. The symptoms are mainly mild or moderate and the severe condition develops only in few people. About 80-90% of patients develop mild or moderate symptoms. Approximately 1 in 20 people will develop severe cholera with acute watery diarrhoea. The severe stage include the following symptoms:
-Vomiting, thirst
-Restlessness or irritability
-Profuse watery diarrhea, known as “rice-water stools”
-leg cramps
Signs of dehydration include:
-Low blood pressure
-Rapid heart rate
-Loss of skin elasticity ( slow return of skin to its original position after pinching)
-Dry mucous membranes( dry mouth, throat, eyelids, and nose)
-Severe dehydration leads to kidney failure, shock, coma, death within hours
Rapid initiation of treatment usually leads to recovery without long-term effects. Patients can get infection again if they were exposed to the organism. People with suppressed immunity such as HIV patients are at higher risk of mortality. Careful collection of stool samples from patients and regular washing hands can reduce the risk of transmission from cholera patients to other people.
Diagnosis:
In cholera outbreaks the diagnosis is mainly clinical and the treatment should be started immediately. There are no specific laboratory findings in cholera patients.
-Culture of stool specimen and identification and isolation of V.cholerae O1 or O139 is considered the gold standard for diagnosis of cholera.
-For transport of the specimen, Cary Blair media is best used.
-For isolation and identification of V.cholerae, the selective thiosulfate–citrate–bile salts agar (TCBS) is ideal.
-Rapid test kits are used in epidemics, but should not be used as a routine in diagnosis of cholera, and do not produce an isolate for antimicrobial susceptibility testing and sub-typing.
-Laboratory results showing: metabolic acidosis, hypokalemia, hypocalcemia, and isonatremic dehydration due to inhibition of sodium chloride absorption by the organism.
-Severe hypoglycemia, altered mental status, seizures, and coma especially in children.
According to the WHO, if laboratory testing is not available, suspected cases can be identified clinically.
-Any patient 2 years or older with acute watery diarrhea and severe dehydration or a patient dying from acute watery diarrhea from an area where cholera outbreak has not been declared.
-Any patient with acute watery diarrhea and severe dehydration or a patient dying from acute watery diarrhea from an area where cholera outbreak was declared.
-Rapid diagnostic tests (RDTs), that are easy to use and inexpensive, can be used such as the Crystal® VC dipstick rapid test if laboratory tests are not available, but its sensitivity and specificity is not ideal. The test is done by binding of a specific component on the surface of V.cholerae to a specific reagent producing visible change used for diagnosis. If stool specimens are positive for V.cholerae by the Crystal® VC dipstick, confirmation by traditional culture-based methods for identification of the organism is recommended. Enriched RDTs have been developed recently showing diagnostic significance similar to cultures, but RDTs are still sub-optimal and used for surveillances and outbreaks.
If confirmed cases:
-Stool culture of V.cholerae and polymerase chain reaction (PCR) can be done.
Differential diagnosis:
The symptoms and findings of cholera are not specific. It is important to notice the history and geographical area from which the cases came from. Infection is the most common cause of diarrhoea worldwide and infections other than cholera may be associated with travel history to an endemic area. Differential diagnosis of cholera include viral infections such as adenoviruses, norovirus, astrovirus, and rotavirus. Other bacterial causes of diarrhoea include Clostridium difficile, Salmonella, Shigella, different strains of Escherichia coli, and Campylobacter. On the other hand, protozoa infections include Cyclospora, Cryptosporidium, Giardia, and Entamoeba. A patient with with rapidly dehydrating, painless, watery diarrhoea and a history of travel to or coming from endemic area should be considered cholera until prove otherwise.
Treatment:
Oral rehydration therapy (ORT):
Immediate starting treatment of cholera patients is crucial. Most patients can be treated with oral rehydration solution (ORS) or oral rehydration therapy (ORT) to restore fluid and electrolyte balance. Before ORT, mortality rate of cholera reached more than 50%. ORT reduced mortality rate of cholera by more than 97% representing its importance in treatment of cholera cases. According to the WHO/UNICEF, standard sachet dissolved in 1 litre (L) of clean water is used as ORS. ORT should be given 100 ml of ORS every 5 minutes in children and adults until stabilization of patients. The conventional ORT recommended by the WHO contains vital ions (sodium, chloride, and potassium) in addition to glucose. Glucose enhances Na + absorption in the small intestine faster than rice starch, but the rice-based ORT has been proved to reduce the stool volume by 36% which is more than glucose ORT. Moreover, starch-based ORT is resistant to metabolic degradation allowing longer duration of action.
In case of moderate dehydration, adults may require up to 6 L of ORS on the first day. The amount of ORT given can be increased or decreased depending on the need. Reassessment is done after 1 hour of therapy and then every 1-2 hours until completing rehydration. If ORS is not available, water, broth, other fluids without high sugar content can be used. In case of severe dehydration stupor, coma, uncontrollable vomiting, or extreme fatigue, intravenous fluids should be rapidly administrated with 24 hour observation. Ringer’s lactate IV fluid is better used, but If not available, normal saline or dextrose solution can be used. Once the patient becomes hydrated, shifting to ORT is done to reduce the risk of phlebitis and other complications.
Patients can continue normal diet after stoppage of vomiting.
Antibiotics/Antimicrobials:
The benefits of using antibiotics in cholera patients include reducing the volume of rehydration fluids required, diminishing the duration of diarrhoea, shortening the amount and duration of V. cholerae excretion stool, and reducing transmission of the infection. Antibiotics were found to reduce the volume of stool by 8–92%, duration of positive bacterial culture by 26–83%, and reduce the duration of diarrhea by 50–56%. Proper and careful use of antibiotics is necessary to avoid antibiotic resistance. Some effective antibiotics that can be used include doxycycline, tetracycline, and azithromycin. Administration of 12.5 mg of tetracycline multiple doses for 3 days may reduce the stool volume from 21 L to 8 L and reduce the duration of symptoms from 4 to 2 days. Administration of 300 mg of doxycycline as a single dose in adults and 6 mg in children may be also effective. Administration of 20 mg of azithromycin as a single dose may stop diarrhea within 48 hours or less, decrease vomiting, reduce stool volume to 5 L. It is recommended to use azithromycin in pregnant women ad children. Unfortunately, V. cholerae O1 and O139 strains have developed resistance to most antibiotics such as ciprofloxacin (a type of fluoroquinolone), and nalidixic acid. Some strains in India, Bangladesh, Thailand, and Northern Vietnam developed resistance to tetracycline. Antibiotic resistance may be due to genetic mutations or acquisition of genetic elements including conjugative elements, plasmids, or introns. Side effects of antibiotics include hypersensitivity reactions, irregular cardiac rhythm, commonly in azithromycin and ciprofloxacin. The most common side effect is hypersensitivity reaction which is life-threatening condition. Tetracycline should be avoided in pregnancy due to its teratogenic effects, and in children due to dental discoloration.
Zinc treatment:
Zinc (20 mg/day) may be used in children less than 5 years and has a synergistic effect reducing the duration of diarrhoea as well as preventing other episodes of acute watery diarrhoea. In case of using antibiotics like ciprofloxacin, the antibiotic should be used 2 hrs before or 4-6 hrs after zinc, as zinc may reduce the absorption of antibiotic. It is recommended to use Zinc in general for treatment of paediatric diarrhoea.
Breast feeding:
Breast feeding should be encouraged.
Prevention:
Prevention of cholera includes cholera vaccines, surveillance, community Engagement, treatment of cholera cases, safe water sources, sanitation and hygiene.
Surveillance:
After clinical evaluation of suspected cholera cases, confirmation is done through stool sample cultures and identification of V.cholerae, rapid diagnostic tests (RDTs), and PCR. Detection, diagnosis, and monitoring of cholera cases enhance surveillance systems and help to control the disease. According to the International Health Regulations, patients with acute watery diarrhea and meeting the criteria of cholera infection are notified to health authorities.
Safe water sources, sanitation and hygiene:
Access to safe water sources and proper sanitation and hygiene are crucial in preventing cholera infection as they represent major sources of infection and transmission of the disease and these are included in the adapted long-term sustainable WASH solutions. Implementation of environmental solutions contributes to preventing other water-borne infections. Managing poverty, malnutrition, and improving education also help in prevention of cholera infection.
Community Engagement:
People and communities are part of cholera prevention programs. Raising awareness about protective good hygiene including hand-washing with soap, toilet hygiene, proper preparation of food and drinks. Special funeral practices for cholera deaths to prevent transmission of the disease to attendees. Raising awareness about symptoms, risk factors, precautions to prevent cholera may also help to reduce cholera infection.
Cholera vaccine:
There are three oral cholera vaccines (OCV) that require two doses and are qualified by the WHO: Shanchol™, Dukoral®, and Euvichol-Plus® and they are inactivated oral whole cell (WC) vaccines. OCVs act by stimulating immunity mediated antibodies especially IgA against V.cholerae such as O1-specific polysaccharide.
All individuals above 2 years of age can be given Dukoral® with 7 days to 6 weeks delay between doses. Children from 2 to 5 years require three doses of the vaccine. It is given to high risk groups including travellers and can give protection for two years against cholera. The effectiveness of Dukoral® is ranging from 55% to 88%. Shanchol™ and Euvichol-Plus® can be given to individuals above one year of age with at least two weeks delay between the doses. Protection against cholera for at least 3 years can be achieved by two doses of Shanchol™ and Euvichol-Plus®, and for short term protection one dose is given. The effectiveness of Shanchol™ is about 65%.
According to the WHO in 2017, OCV should be given in the following conditions:
-Cholera-Endemic area
-Groups of high risk
-During humanitarian crises with high risk
-In cholera outbreaks
-Associated with other preventive measures.
An oral live-attenuated vaccine Vaxchora (CVD 103-HgR) is approved by the US Food and Drug Administration (FDA), given in a single dose and can protect against Inaba or Ogawa serotype. The effectiveness of Vaxchora is almost 90% and produces rapid cell-mediated immunity.
Breastfeeding:
Breastfeeding may enhance the response of infants to cholera vaccines by increasing IgA antibodies secretion in breastmilk, but oral vaccines produce lower effect. A study has shown that giving OCVs to mothers reduce the risk of cholera in their breastfed infants by 47%.
Prognosis and complications:
Mortality rate of cholera in some countries is less than 5% whereas in other countries may reach 50% in outbreaks. Severe dehydration, hypovolemic shock, and metabolic acidosis are the main complications of cholera if left untreated. Mortality rate of cholera if left untreated may reach 25-50% and treatment reduce the mortality to less than 1%.Long-term complications and consequences were not found to be associated with cholera infection.
References:
(1)Hsueh BY, Waters CM. Combating Cholera. F1000Res. 2019 Apr 30;8:F1000 Faculty Rev-589. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492228/
(2)Deen J, Mengel MA, Clemens JD. Epidemiology of cholera. Vaccine. 2020 Feb 29;38 Suppl 1:A31-A40. https://www.sciencedirect.com/science/article/pii/S0264410X19309995?via%3Dihub
(3)Cholera, the World Health Organization (WHO).
(4)Cholera - Vibrio cholerae infection, Centers for disease control and prevention (CDC).
https://www.cdc.gov/cholera/index.html
(5) Cholera, Mary Anne Dunkin, Webmd.
https://www.webmd.com/a-to-z-guides/cholera-faq
(6)Cholera, Pan American Health Organization(PAHO).
https://www.paho.org/en/topics/cholera
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