Cholera: ED presentation, evaluation, and management

Authors: Gaston Omba, MD (EM Resident Physician, Makerere University); Jessica Pelletier, DO (EM Education Fellow, Washington University in St. Louis) // Reviewed by: Joshua Lowe, MD (EM Staff Physician, USAF); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case

A 25-year-old woman presented to the emergency department (ED) in Uganda with acute encephalopathy. The patient was unable to provide a history, but a friend reported that the patient was in her usual state of good health until 24 hours previously, when she developed the acute onset of profuse watery diarrhea, vomiting, and muscle cramps. The villagers had collected all of her diarrheal fluid in a canister kept near the patient, since they believed that part of the reason she was so ill was that her body had been depleted of vital substances contained in the excretions. They report that several other villagers had already died from this type of illness. No other patient history was available.

Vital signs were notable for heart rate of 160 bpm, respiratory rate of 32 breaths/minute, non-invasive blood pressure of 85/56 mmHg, temperature of 36.2 C, and SpO2 95% on room air. On physical examination, the patient was weak and lethargic. Her skin was cool to the touch with poor turgor and a silver-bluish discoloration reminiscent of lead. There was severe maceration to the palmer aspects of her hands (“washerwoman’s hands”). Her facial features were flattened, and her eyes were sunken deep into their sockets.  The patient’s breathing was labored, but breath sounds were normal. The abdomen was soft with mild periumbilical tenderness, normoactive bowel sounds, and no rebound or guarding. The extremities were cold with no peripheral edema. Inspection of the canister showed approximately ten liters of nearly odorless watery fluid containing flecks of mucus (“rice-water” stools) consistent with cholera infection. Laboratory testing was not immediately available.

The clinical picture of this patient was consistent with hypovolemic shock secondary to acute cholera infection. How is this condition diagnosed and treated in the ED?

 

Background

Cholera, caused by Vibrio cholerae, is a gram-negative bacillus that is classified into more than 200 different serogroups. Of those, serogroups O1 and O139 are notably pathogenic due to to their ability to produce cholera toxin (CTox).1 Other serogroups, commonly known as “non-O1/non-O139 V. cholerae,” are usually non-pathogenic or asymptomatic colonizers in humans or cause mild, sporadic disease (e.g., gastroenteritis, wound, or ear infections) in otherwise healthy hosts. However, these normally non-pathogenic serogroups may pose a higher risk in people who are immunocompromised or who have underlying liver disease.2

As of 2022 cholera was estimated to be responsible for over 4 million cases and 143,000 deaths each year, with a case fatality rate of 50% without timely and appropriate treatment.3 Between 1990 and 2019, there were approximately 3 million deaths due to cholera globally, indicating a significant public health issue. Infection rates and mortality, particularly in Africa, have seen an upward trend.4 Cholera poses an increased risk for children under five years of age, with morbidity and mortality exacerbated by malnutrition.5 Breastfeeding is protective against cholera infection due to maternal-to-child transmission of anti-cholera toxin IgA.6

During the 19th and 20th centuries, cholera pandemics emerged and affected the world on seven occasions, affecting  most parts of Asia, Africa, Europe, and the Americas at some point. These pandemics occurred in 1817, 1829, 1852, 1863, 1881, 1889, and 1961. Though the last pandemic ended in 1975, the strain involved is the one still persisting today.7 Infection occurs following ingestion of food or water contaminated or water containing a significant amount of V. cholerae bacteria. Transmission can occur in two ways: the fecal-oral route (i.e, person-to-feces-to-person) or direct contact with the bacteria in the environment (i.e., environmentally-acquired infection). Cholera employs two major virulence factors: the toxin-coregulated pilus (TCP) and CTox. TCP plays a crucial role in the initial colonization of the host gut mucosal layer (typically in the proximal small intestine). Once colonized, CTox is released and passes through the gastric endothelial wall which induces voluminous diarrhea containing water and electrolytes. CTox is composed of A and B subunits. The cholera toxin A subunit is released into the cell, where it activates adenylate cyclase, stimulating fluid loss. The cholera toxin B subunit (CToxB) binds to GM1 ganglioside receptors on the epithelial cell surface. The CToxB is immunogenic, and a recombinant form has been added to some vaccines.8

 

Evaluation

History and Physical Exam

A cholera patient’s history may involve the consumption of contaminated food or water and/or travel to an endemic area. Symptoms associated with cholera usually develop within 24-48 hours of infection. The acute diarrheal illness caused by cholera is often mild or without symptoms but can sometimes be severe and life-threatening. Patients usually present with sudden-onset, painless, odorless, rice-watery, large-volume stool; abdominal cramps, leg cramps, vomiting, fever, thirst, and restlessness or irritability. About 10% of  people with cholera will experience severe symptoms. As the disease progress the patients will experience profound dehydration and start to develops signs and symptoms such as:

  • Rapid heart rate
  • Loss of skin elasticity
  • Dry mucous membranes
  • Low blood pressure

If left untreated, severe dehydration may lead to kidney failure, shock, coma, and death within hours.9

The diagnosis of cholera is frequently based on clinical signs and symptoms in resource-limited areas where laboratory facilities are not available.10 In non-endemic regions, suspicion arises in patients with severe dehydration or death from acute watery diarrhea. In a cholera-endemic setting, cholera is suspected if a patient has acute watery diarrhea more than three times with or without vomiting within 24 hours.11

The presentation of cholera on physical examination depends on the patient’s level of dehydration. Patients may present with tachycardia, postural hypotension, somnolence, dry mucous membranes, sunken eyes, and/or oliguria. The typical symptoms of dehydration include dizziness (due to low blood pressure), wrinkled hands, muscle cramps (due to hypokalemia), and decreased urine output.12

 

Labs

Generally, in high-resource settings, stool or rectal swab culture is the gold-standard reference method for the diagnosis of cholera.13 The specimens are placed into an enrichment broth made of alkaline peptone water, which enhances the sensitivity of the culture, and are later subcultured on selective thiosulfate citrate bile salt (TCBS) agar or taurocholate tellurite gelatin agar (TTGA), which is the ideal culture medium.14 Cary-Blair medium is commonly used as the medium for transport from field settings to the laboratory.13 Dark-field microscopy can be used to rapidly detect V. cholerae in stool samples before culture.15 PCR can be used to detect molecular markers of certain phenotypes with target genes such as ctxA, tcpA and ompW.16 In resource-constrained settings, rapid diagnostic tests (RDTs) on stool samples offer a viable option. Different categories of RDTs are available on the market, with a wide range of sensitivities and specificities. Monoclonal antibodies in Crystal VC (72% sensitive and 86.8% specific) and Cholkit (68% sensitive and 97.5% specific), can easily detect the  LPS antigens of  both V. cholerae O1 and O139 serogroups. Given their high specificity and low sensitivity these RDTs are best utilized as early warning tools for public health experts in monitoring for when a cholera outbreak is imminent.17

 

Management

1. Rehydration Therapy

More than 99% of cholera patients will survive if appropriate rehydration is administered without delay. Rehydration therapy for patients with cholera should include volume resuscitation and electrolyte repletion. Oral rehydration solution (ORS) is the first-line therapy for dehydrated patients who can sit up and drink, particularly those with mild illness (Table 1). Many commercial products are available over the counter. ORS should be made with safe water, i.e. water that has been boiled or treated with household bleach or a chlorine product, at least 15 minutes before adding prepackaged oral rehydration salts. To make the solution, the oral rehydration salts should be mixed with 1 liter of safe water.18

Figure 2. Instructions for making ORS. Source: Centers for Disease Control and Prevention (U.S.). Posters for the Prevention & Control of Cholera: How to Make Oral Rehydration Solution (ORS). Published online October 20, 2021. Accessed March 5, 2024. https://www.cdc.gov/healthywater/pdf/global/posters/11_229310-J_ORS_print-africa.pdf

If ORS powder is not available but patients are able to tolerate oral fluid intake an ORS substitute can be made by adding 6 teaspoons of table sugar and 1/2 teaspoon of table salt (iodinated preferable) to each liter of water. If that is not available clean water, broth, and/or other fluids may substitute. Drinks with a high sugar content (both natural sugars and so called sugar free options that are high in sugar-alcohols), such as juice, soft drinks, or sports drinks should be avoided, as these may worsen diarrhea. For patients who are nauseated or vomiting, combining antiemetics with small, frequent sips of fluid or administering fluid by nasogastric (NG) tube are potential options. Cholera patients require strict measurement of intake and output (I&O). Patients who cannot tolerate oral intake of fluids should receive intravenous (IV) fluid resuscitation but are encouraged to start drinking ORS as soon as they are able.18

Patients with signs and symptoms of severe dehydration or shock, including stupor, coma, uncontrollable vomiting, extreme fatigue that prevents drinking, and unstable vital signs should receive IV fluid resuscitation. Clinicians should switch from IV hydration to ORS once hydration is improved and the patient can drink. This will conserve IV fluids and reduce the risk of complications, such as superficial thrombophlebitis or bacteremia.18

Table 1. Recommended cholera rehydration strategies by level of illness severity. Adapted from: Centers for Disease Control and Prevention (U.S.). Rehydration Therapy. Published online November 14, 2022. Accessed February 27, 2024.https://www.cdc.gov/cholera/treatment/rehydration-therapy.html

2. Antibiotics/Antimicrobials

The objective of antibiotics to treat cholera infections is to reduce both (1) the time and severity of the illness and (2) the transmission to other individuals. Acute infection with severe dehydration is treated with oral rehydration therapy (ORT) and antibiotics to produce synergistic efficacy. Oral antibiotic administration should take place for patients with severe cholera infection as soon as they are able to tolerate oral intake, which usually occurs after rehydration and administration of antiemetics. Doxycycline is considered first-line for the treatment of cholera, though azithromycin or ciprofloxacin may be considered depending on patient allergies and local antibiograms. Most guidelines now recommend the use of doxycycline even in women and children.19 The World Health Organization (WHO) guidelines consider tetracycline to be equally first-line with doxycycline for patients with severe dehydration due to cholera infection;20 however, despite equal efficacy to doxycycline, tetracycline has many more side effects, including gastrointestinal upset, hepatitis (higher risk in pregnant women), bone dysplasia in the developing fetus when administered to pregnant women, and tooth staining (with a much greater risk than doxycycline).21,22 For patients < 3 years old, the WHO guidelines still recommend erythromycin or azithromycin rather than doxycycline. Thus, there is controversy among guidelines, and antibiotic selection should rely heavily on local recommendations and antibiotic resistance patterns.20

 

Table 2. Antimicrobial therapies for cholera infection. Adapted from:

  • Centers for Disease Control and Prevention (U.S.) Recommendations for the Use of Antibiotics for the Treatment of Cholera. Published online June 1, 2022. Accessed February 26, 2024.https://www.cdc.gov/cholera/treatment/antibiotic-treatment.html#summary
  • Williams PCM, Berkley JA. Guidelines for the management of paediatric cholera infection: a systematic review of the evidence. Paediatr Int Child Health. 2018 Nov;38(sup1):S16-S31. doi: 10.1080/20469047.2017.1409452. PMID: 29790841; PMCID: PMC5972638.

3. Zinc therapy

The Centers for Disease Control and Prevention (CDC) recommends starting zinc supplementation in children with cholera infection.23 This is based on a randomized controlled trial from Bangladesh in which 179 children ages 3-14 with confirmed cholera which showed a shorter duration of diarrhea and decreased stool output compared with the placebo group, when given  30 mg elemental zinc daily until recovery.24 CDC currently recommends 20 mg zinc per day in children 6 months or older and specifies that antibiotics should be administered 2 hours before or 4-6 hours after zinc to prevent interference with antibiotic absorption. The CDC does not provide guidance on zinc supplementation in adults with cholera infection given that there is no data in this population; however, it is a low-risk intervention that has the potential for substantial benefit. Some pre-packaged ORS already contains zinc, so clinicians should refer to the packaging to determine whether additional zinc supplementation is warranted.23

 

4. Experimental therapies

An emerging concept in microbiology is the ability of the host microbiome to prevent or limit infections. Animal studies using probiotics to induce colonization resistance to cholera have proven promising, demonstrating decreased cholera infection mortality in treated mice.25–27 Owing to the excessive fluid accumulation, V. cholerae elicits severe disruption to the gut microbiome during infection. Furthermore, the type VI secretion system of V. cholerae can deliver effector toxins to the gut microbiome or modulate host cells themselves, both of which alter the gut microbiota to facilitate colonization.28 For these reasons, restoration of the gut microbiome or prevention of colonization through probiotic treatment is a promising new approach to treat cholera infections, though human trials are still pending.

The therapeutic use of lytic bacteriophages is an experimental treatment that holds promise for future cholera infection management. Phage therapy has been used for decades in Eastern Europe and Russia and, with the emergence of antibiotic-resistant bacteria, has been developed and used to treat infections caused by Pseudomonas, Salmonella, and Staphylococcus. Phage therapy has many advantages over antibiotics. For example, phages are able to kill antibiotic resistant bacteria, the amount of phages increases proportionally to the number of infecting bacteria, and early results suggest that the phages exert a minimal impact on the host microbiome in animal models.25 Animal studies suggest that single-dose phage therapy could be highly effective for treating cholera infection;26 however, human clinical trials are still pending.27

 

Prevention

Vaccines

The WHO advocates the use of oral cholera vaccines (OCVs), including both live-attenuated and inactivated oral whole cell (WC) vaccines, in endemic areas or during outbreaks as a transient protection since they have been shown to be effective in combination with other correlative treatments, including antibiotics, ORT, and health management.29 OCVs principally stimulate mucosal immunity mediated by antibodies, particularly IgA, against the pathogen. These antibodies are directed against antigens such as O1-specific polysaccharide and CT. Although IgA has limited systemic circulation (~6 months), the memory B cells that are responsible for preventing cholera infection persist and can quickly expand and differentiate into plasmablasts and eventually the plasma cells, which can reseed protective antibodies upon antigen-contact activation.30Moreover, OCVs administered to children in endemic regions could provide herd immunity to unvaccinated adults, but the effect in unvaccinated children requires further study.31

The CDC recommends cholera vaccination in these circumstances:

  • In areas where local transmission of cholera is common
  • During cholera outbreaks
  • During humanitarian crises with a high risk of cholera
  • People traveling to or living in areas of active cholera transmission

Vaxchora is recommended for Americans aged 2–64 who are traveling to an area of active cholera transmission, and must be administered a minimum of 10 days before travel. This vaccine reduces the risk of moderate to severe diarrhea by 90% at 10 days after vaccination and by 80% at 3 months after vaccination. Long-term immunity beyond 6 months is unknown at this time.32

Table 3. Cholera vaccines. Adapted from: Centers for Disease Control and Prevention (U.S.). Vaccines. Published online August 7, 2023. Accessed February 27, 2024. https://www.cdc.gov/cholera/vaccines.html

Hygiene

Key preventative measures for cholera infection include frequent hand washing and ensuring the use of safe food and water. It is essential that handwashing occurs before and after food preparation, after urination or defecation, and after contacting or caring for someone suffering from diarrhea to avoid further spread of disease. If soap and water are unavailable, the CDC recommends an alcohol-based hand rub with at least 60% alcohol.33

In areas without potable tap water or reliable sources of safe water, bottled water should be used for drinking, as well as brushing teeth and washing/preparing food. If bottled water is unavailable, water should be boiled, filtered, or properly chlorinated/bleached. In low-resource settings, it is critical to ensure that lavatories are not located in proximity to areas where food preparation occurs.33

 

Prognosis and Complications

Cholera infection can cause a severe diarrheal disease with acute and substantial loss of water and electrolytes. The incubation period is very short (12 hours to 5 days), which allows the number of cases in the area to rise extremely quickly.3 Failure to promptly administer oral rehydration therapy or inadequate rehydration can result in complications such as hypotension, electrolyte imbalances like hypokalemia, and if untreated, severe metabolic acidosis, renal failure, hypovolemic shock, coma and death. Among children, hypoglycemia is common and can lead to seizures.34 If patients with cholera are treated quickly and properly, the mortality rate can be reduced to less than 1%.3

 

Pearls and Pitfalls

  • Cholera infection is a life-threatening diarrheal illness that is increasing in prevalence globally and is associated with high mortality rates if not promptly treated.
  • This illness disproportionately impacts children suffering from malnutrition in low-resource settings, but travelers to endemic areas – particularly those who are immunocompromised – are also at risk.
  • Immediate rehydration therapy using ORS or IV fluids should be initiated to correct electrolyte imbalances and manage dehydration. ORS is the standard of care.
  • Antibiotic treatment with doxycycline is administered to shorten the duration of symptoms and reduce the shedding of the bacteria.
  • Zinc supplementation is a key component of management that may reduce the duration and severity of symptoms, particularly in children.
  • Public health measures including chlorination of water sources, provision of clean drinking water, promotion of hygiene practices such as handwashing and proper sanitation, and education to raise awareness of cholera within the community.

 

References

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