Continuing Education Activity

Cholera is a well-known disease caused by intestinal infection with the toxin-producing bacteria Vibrio cholerae. This potentially fatal diarrheal disease results in large volumes of watery stool, causing rapid dehydration that can progress to hypovolemic shock and metabolic acidosis. The case-fatality ratio is up to half in vulnerable groups during outbreaks, but can be under 1 percent if properly treated. Today, cholera persists in regions of the world with unsatisfactory hygienic conditions and regions afflicted by natural disasters and/or humanitarian crises. The development of oral rehydration therapy, antibiotic treatment, and new oral vaccines have led to increased survival and excellent prognosis with appropriate treatment. This activity outlines the evaluation, management, and prevention of cholera and underscores the role of the interprofessional team in improving care for patients with this disease.

Objectives:

• Identify the epidemiology of Vibrio cholerae infection.
• Review the risk factors that predispose patients to Vibrio cholerae infection.
• Summarize the role of oral rehydration for the treatment of patients affected by Vibrio cholerae infection.
• Explain the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by Vibrio cholerae infection.

Introduction

Cholera is a well-known disease caused by intestinal infection with the toxin-producing bacteria Vibrio cholerae. This potentially fatal diarrheal disease results in large volumes of watery stool, causing rapid dehydration that can progress to hypovolemic shock and metabolic acidosis. The case-fatality ratio is up to half in vulnerable groups during outbreaks but can be under 1% if properly treated.[1] Since its endemic origins in Asia, different serotypes of V. cholerae have reached the pandemic level 7 times. Unlike many other infectious diseases, cholera continues to be a worldwide public health concern. Today, cholera persists in regions of the world with unsatisfactory hygienic conditions and regions afflicted by natural disasters and/or humanitarian crises. Research has led to the development of oral rehydration therapy, antibiotic treatment, and new oral vaccines that have saved millions of lives.[2]

Etiology

Toxin-producing strains of V. cholerae cause the disease process. V. cholerae is a highly motile, comma-shaped gram-negative bacteria with a single polar flagellum. It has hundreds of serogroups that include pathogenic and non-pathogenic strains. Until recently, the disease was caused by only 2 of these serotypes, Inaba and Ogawa, and 2 biotypes, classical and El Tor, of toxigenic serogroup O1. In 1992, serogroup O139, or Bengal, emerged as another epidemic variant of V. cholerae.[3][4] Recently, there has been an increased recognition for the role that non-O1 and non-O139 serogroups may be playing in diarrheal illness and gastroenteritis.[5]

Cholera is transmitted through contaminated water and/or food especially in vulnerable communities affected by natural disasters, war, and famines. Humans are the only natural host for V. cholerae, and transmission is by the fecal-oral route. However, V. cholerae is also found as a free-living organism in brackish water and can survive in fresh or saltwater, which explains the occasional infections via shellfish.[4]

Epidemiology

Cholera is endemic to world regions with poor water, sanitation, and hygiene infrastructures, such as Sub-Saharan Africa and regions of the Middle East. In developed countries, it is seen sporadically. Currently, it is endemic in 69 countries including Asia, Africa, and the Americas with 1.3 billion people at risk, Sub-Sahara Africa being the worst.[6] As mentioned above, V. cholerae originated in the Indian subcontinent and caused six pandemics from 1827 through 1923. The seventh pandemic has been ongoing since 1961, reaching South America and most of the Western Hemisphere in 1991.[7] Although widely under-reported, the World Health Organization estimates a total of 2.8 million cases with 91,000 deaths annually. Recently, cholera has continued to affect vulnerable communities like post-earthquake Haiti (2010), Iraq, and Yemen, where natural disasters, refugee movement, war, and conflict increase the risk of infection and outbreaks.[3][8] Although safe drinking water and advanced sanitation systems have made cholera a treatable and limited illness in Europe and North America, new V. cholerae strains, ease of travel and constant migration of possibly infected individuals have raised serious public health concerns.[9]

Pathophysiology

Small intestine colonization is highlighted by V. cholerae's highly effective motility and ease of attachment to the intestinal wall. V. cholerae requires a comparatively high infectious dose (10^8).[10] Cholera toxin is then secreted and eventually endocytosed by the intestinal epithelial cells, altering the electrolyte channels, and resulting in endoluminal fluid loss rich in chloride, bicarbonate, sodium, and potassium.[11] On excretion into the environment, it has been found that the bacteria undergo a period of 24 hours of hyper-infectious activity and are more likely to be transmitted in a human-to-human fashion, explaining the explosive nature of cholera epidemics.[12] Another important pathophysiological feature of V. cholerae is how host susceptibility affects a patient's risk. For example, individuals with blood group O have been found to be more likely to develop severe cholera than other blood types, while individuals previously infected with cholera or vaccinated against it have often been found to gain temporary acquired immunity.[13][14][15] Recently, there has been an increase in the number of non-O1 and non-O139 V. cholerae infections presenting as self-limited gastroenteritis after bathing in contaminated recreational waters or ingestion of raw and undercooked seafood.[5][16]

Histopathology

V. cholerae is a comma-shaped, gram-negative rod with a single polar flagellum that is highly motile. It exists in aquatic environments, infects the small intestine, and produces cholera toxins. These bacteria have specialized adherence factors that allow them to attach to the hostile microvilli surface. Once attached, Vibrio export 1 of 2 antigenically related but distinct forms of cholera enterotoxin (CT-1 or CT-2) into the intestinal epithelial cell. The cholera toxin causes adenylate cyclase to be locked on the “on mode,” leading to an excess in cAMP and subsequent hypersecretion of chloride and bicarbonate followed by water.[4] Although this organism has almost 200 serogroups, only O1 and O139 have been found to be responsible for the epidemic disease.[17]

History and Physical

Cholera is characterized mainly by profuse painless diarrhea, abdominal discomfort, borborygmi, and vomiting in the absence of fever. Severe cases may present with hypovolemic shock due to the massive volume and electrolyte loss. Although initial diarrhea may include fecal material, the classic diarrhea presentation consists of watery foul-smelling mucous described as "rice-water" stools. The rate of fluid loss (up to 1 liter per hour) and high stool sodium concentrations characterize cholera from other diarrheal diseases.[18] In severe cases, known as cholera gravis, hypotensive shock can ensue within hours of the first symptoms. If treatment is not started immediately, death rates are reported as high as 70%.[19] Patient presentation with hypovolemic shock may include: decreased urine output, cold, clammy skin, decreased skin turgor, sunken eyes, Kussmaul breathing (acidosis), tachycardia, and hypotension. Electrolyte imbalances can cause muscle cramping and weakness with severe acidosis.[20] Cholera sicca is a variant of the disease when fluid accumulates in the intestinal lumen, followed by circulatory collapse and death before any diarrheal symptoms arise.[21]

Evaluation

V. cholerae is mainly diagnosed clinically in the setting of a diarrheal illness outbreak. Various factors differentiate it from other diarrheal diseases. Given the pathophysiology of cholera and its effects on the secretion of chloride via apical channels and inhibition of sodium chloride absorption, laboratory results usually evidence hypokalemia, hypocalcemia, metabolic acidosis, and isonatremic dehydration.[20][22] In children, severe hypoglycemia may ensue, coupled with altered mental status, seizures, and coma.[23] Otherwise, there are no strict laboratory or radiographic findings required for the diagnosis and/or care of cholera patients.

Confirmatory diagnosis of V. cholerae today consists of isolation of the bacteria in stool cultures, polymerase chain reaction (PCR), and rapid tests. Nonetheless, given the morbidity and mortality associated with the disease, treatment is never to be delayed for diagnostic testing given adequate diagnosis can be achieved clinically.[19] Stool culture remains the gold standard for the detection of V. cholerae and susceptibilities using selective media. Nonetheless, this technique is inadequate for rapid diagnosis.[24] On the other hand, rapid diagnostic tests (RDTs) have commanded greater attention for their ease of use in the field setting and being inexpensive, leading to the potential for epidemic-preventive surveillance.[25][26] Most RDTs are set to follow the principles of dipstick tests by applying a characteristic component of the cholera bacteria on a surface and binding it with specific reagents to produce a visible change.[1] Given the importance placed by the World Health Organization (WHO) on faster, easier, and less expensive diagnostic tests, new RDTs are developed periodically. Recently, enriched RDTs have even been shown to have diagnostic performance equivalent to cultures.[27][28][29] On the downside, recent outbreaks like the post-earthquake Haiti event have presented the disadvantages of having too many diagnostic RDTs with significant variations, rendering them suboptimal as point-of-care tests but useful for outbreak response and surveillance.[30]

Treatment / Management

Oral rehydration therapy (ORT) is the mainstay treatment for acute cholera infection and has had a dramatic global impact, not only for V. cholerae but for all dehydrating diarrheal infections.[31] Fluid replacement requirements are determined by the level of hypovolemia on presentation by physical exam (ear, nose, throat [ENT], skin pinch, pulse, and mental status) and classified as: none, some, or severe volume depletion.[32] Given the average loss of 20 mL/kg per hour in patients affected by cholera, rehydration must be started immediately. After assessment of the initial volume deficit, the route of rehydration is determined and started as soon as possible. Patients with severe dehydration are usually in hypovolemic shock and require emergent intravenous rehydration of as much as 350 mL/kg in the first 24 hours, with complete fluid deficit replaced during the first 3 to 4 hours.[33] Oral rehydration then begins as soon as the patient is able to drink.

In order to respond to the severe electrolyte and fluid losses of the small intestine, equimolar oral rehydration solutions rich in sodium and glucose were produced in the 1960s.[34] The physiologic basis of this therapy, involving the sodium-glucose linked transporter (SGLT) found in the intestinal epithelial cells discovered by Dr. Robert K. Crane, explained the effectiveness of ORT.[35] Today, there are different oral rehydration solutions (ORS) recommended for the treatment of cholera. Since 2002, WHO has recommended a reduced osmolar ORS that has been proven to reduce stool fluid and electrolyte depletion.[36] Other ORS solutions such as rice-derived, non-absorbed starch, polymer-based, and homemade ORS claim to reduce stool output and fluid/electrolyte losses.[37][38][39][40] Some reports take into consideration the initial administration of glucose solution without salts for a more gradual correction of dehydration.[41] Nonetheless, any solution basically composed of salt, water, and glucose has been proven to increase the reabsorption of sodium through the above-mentioned SGLT symporter in the intestinal wall and could be a life-saving measure.[42]

Regardless of volume deficit, special considerations must be taken with patients who present with profound vomiting. Often, ORS is not sufficient and intravenous rehydration must be started to avoid the progression of dehydration. Subsequently, it is paramount to assess for ongoing fluid losses in order to keep up with fluid replacement and reassess for volume status periodically. For this purpose, litters, where patients defecate directly into a measuring collection bucket, were developed and named cholera cots.[9]

It has been found that the most common errors in the treatment of patients with cholera are underestimating the fluid needs. This is due to errors in estimating initial dehydration and not reassessing the patient to be aware of increased fluid losses.[43]

Antibiotics are considered as an adjunctive treatment for V. cholerae and are typically administered once the initial volume deficit is corrected and vomiting has ceased. Antibiotics result in substantial improvements in clinical and microbiological outcomes by shortening the mean duration of diarrhea by a day and a half, reducing the total stool volume by 50%, reducing the amount of rehydration fluids required by 40%, and reduction of excretion of hyperinfective bacteria by 3 days.[44] Although mainly based on availability and resistance patterns, the main antibiotics used include tetracyclines, macrolides, and fluoroquinolones. Tetracyclines are the most studied and used antibiotics.[45] In comparison studies, tetracyclines and azithromycin may have advantages over other antibiotics when comparing the duration of diarrhea.[44]

For infants, breastfeeding in conjunction with ORS and zinc supplementation has been recommended.[46] In addition, vitamin A supplementation has been shown to reduce morbidity and mortality in children from 6 months to 5 years of age.[47]

Anti-emetics and anti-motility agents have been found to have no benefit and may actually impede ORS therapy, hence producing worse outcomes.[19][48]

Differential Diagnosis

Given the non-specific finding of acute watery diarrhea associated with V. cholerae, special considerations must be taken into account when determining a differential diagnosis. The differential diagnosis should be informed by geography and history. Although the most common cause of diarrhea worldwide is infectious, the setting of the infection or recent travel to endemic countries may make some infections more likely. Viral causes include norovirus, rotavirus, adenoviruses, and astrovirus, among others. Bacterial causes include Campylobacter, Shigella, Clostridium difficile, Salmonella, and different strains of Escherichia coli. Protozoa infections include Cryptosporidium, Giardia, Cyclospora, Entamoeba, among others.[49] Cholera should be high on the list if the patient has traveled to or comes from an endemic country, has known sick contacts, and presents with rapidly dehydrating, painless, watery diarrhea.

Pertinent Studies and Ongoing Trials

The best choice for long-term cholera infection and outbreak control is improving water and sanitation. This is highlighted by the fact that cholera continues to be a potentially fatal epidemic illness in developing countries, while only occurring sporadically or as limited outbreaks in the developed world.[50] In 2011, the first oral cholera vaccine (OCV) was recognized by the WHO, stockpiling began in 2013, and the supply was increased in 2016 by pre-qualifying 2 more OCVs. Although found to be a cost-effective short-to-medium term option when compared to the high up-front costs of creating water, sanitation, and hygiene infrastructure from scratch, OCVs have encountered numerous challenges that continue to be studied.[51] A 2017 study of the last 12 OCV campaigns identified three main challenges: regulatory hurdles (country-specific and time-consuming), cold-chain logistics (challenging to maintain in low-resource settings), and vaccine coverage/uptake (problems with dual dose follow-up and single-dose effectiveness).[52] Another hot topic for research is the development of an effective reactive approach with the use of OCVs from the global stockpile given the multiple country-specific hurdles with disease prevention[53][54][55]

Prognosis

As mentioned above, the case-fatality rate (CFR) in most affected countries is less than 5%, while in other countries the CFR can reach up to 50% during outbreaks.[1][50] There are no long-term consequences of cholera infection.

Complications

The most common and life-threatening complication of V. cholerae is severe volume depletion leading to hypovolemic shock and metabolic acidosis. Cholera is characterized by extensive fluid loss via diarrhea, reaching as high as 1 liter per hour in adults and 20 mL/kg per hour in children.[3] No long-term complications have been found.

Deterrence and Patient Education

Cholera is an infectious disease caused by the ingestion of food or water contaminated by the bacteria Vibrio cholerae. Patients living in endemic areas and travelers to these regions should be educated on the importance of hand hygiene. Additionally, boiling water before it is consumed or used to rinse food is imperative. As stated above there are vaccines that can be used in endemic areas as well. Patients that live or have traveled to endemic countries should be encouraged to seek medical attention immediately if they develop signs of cholera infection.

Pearls and Other Issues

• Cholera is an acute secretory diarrheal illness caused by the toxins of the comma-shaped gram-negative Vibrio cholerae bacterium that is known worldwide for its pandemic potential.
• Cholera affects resource-poor and developing countries where water, sanitation, and hygiene infrastructure are lacking. Historically, it has been responsible for 7 pandemics. Currently, it is endemic in 69 countries with particular severity in Sub-Saharan Africa and the Middle East.
• Infection begins with ingestion of food or water contaminated with V. cholerae that goes on to colonize the small intestine and produce toxins. These toxins produce changes in the electrolyte channels causing massive fluid and electrolyte losses in the form of watery diarrhea.
• The clinical presentation consists of painless severe watery diarrhea that often resembles rice water and can rapidly lead to hypovolemic shock from massive volume depletion in the first 6 hours if not treated.
• Diagnosis is clinical, but confirmation using stool cultures on special selective media is recognized as the gold standard. Given stool cultures are impractical for use in the field, the use of rapid diagnostic tests (RDTs) such as dipsticks has been favored for outbreak surveillance and control.
• Oral rehydration solution (ORS) is the mainstay treatment for cholera and consists of aggressive volume repletion depending on the initial level of volume depletion and ongoing fluid losses.
• Patients with cholera must be front-loaded with fluids by replacing the initial volume deficit in the first 4 to 6 hours and as much as 350 ml/kg in the first 24 hours. Close monitoring of ongoing fluid losses is essential to preventing mortality.
• Isotonic oral fluids are favored except in severe cases and in patients who are actively vomiting when intravenous (IV) hydration may be needed.
• Other treatment modalities such as antibiotics and nutritional supplements have been proven to help with symptom duration and severity. Tetracyclines and macrolides are considered respective first- and second-line therapy.
• Although adequate water, sanitation, and hygiene infrastructure is the main preventive measure, oral cholera vaccines (OCVs) have been found to be effective, comparably inexpensive, and safe for outbreak control in high-risk endemic areas.

Enhancing Healthcare Team Outcomes

Healthcare outcomes involving cholera in resource-poor and developing countries have been a public health concern and a hot topic for research during the last decades. Cholera infection rates and outbreaks have been closely linked to the socio-economic characteristics of the region. [Level 4][56] Cholera reveals how a countries' socio-economic status can propagate a preventable disease. This fact has led to an increase in research and teamwork between public health, government, and medical authorities to develop oral cholera vaccines and improve implementation practices and strategies. [Level 1 and 5][53][55] Cholera is a public health issue that involves an interprofessional team of healthcare workers that include an epidemiologist, infectious disease specialist, primary care provider, infection control nurse, social workers, dietitians, and emergency department personnel. The key to reducing the morbidity from cholera is patient education and improving the environmental living conditions. Furthermore, understanding and addressing the social dynamics that lead to cholera risk may be more effective for better targeting of efforts and the possibility of eliminating Cholera. [Level 1 and 5][57][58]