Infectious Diseases

Vibrio cholerae

OVERVIEW: What every practitioner needs to know

Are you sure your patient has cholera? What should you expect to find?

  • Cholera is a diarrheal disease, easily mistakable for several others; however, there are some clinical features that are characteristic and can help make the diagnosis.

    • The presence of watery diarrhea with the appearance of rice wash is characteristic. This is even more impressive when associated with acute severe dehydration.

    • Other symptoms may include:

      • Abdominal pain

      • Vomiting

      • Tenesmus and later cramps

      • Oliguria

      • Mental status alteration, from alert to restless, somnolent and even comatose

      • Fever is less common

      • Signs associated with dehydration:

        • Loss of skin elasticity

        • Dry mucosa

        • Hoarseness

How did the patient develop cholera? What was the primary source from which the infection spread?

  • Cholera causes large epidemics, and pandemics around the globe. A local outbreak can quickly convert to an epidemic.

  • The life cycle of Vibrio cholerae allows the bacterium to live for years in an aquatic environment, its natural reservoir, where it survives adherent to crustaceans, algae and zooplankton.

  • Under the appropriate environmental conditions, V.Cholerae will multiply and reinitiate the free life cycle. However, if the environment is adverse, this pathogen is capable of maintaining a latent state, inactive, unidentifiable by culture and resistant to chlorine.

  • The infectious cycle of this bacillus occurs when the bacteria moves from its aquatic environment into a human through contaminated water and contaminated food.

  • Infected humans excrete bacteria contaminating a new environment and new water sources. Usually those who are infected excrete high numbers of bacteria, creating massive environmental contamination and rapid transmission to other humans.

  • In July 2012, a cholera outbreak began in Cuba, despite the fact that cholera was thought to have been eradicated in this country. As recently as October 2012, new cases were reported. In the same year, the epidemic in Haiti and the Dominican Republic continued.

  • According to the World Health Organization’s epidemiological report, the number of cholera cases during 2011 was 589,854, with a fatality rate of 1.3%. This number is the total number of cases reported in 58 countries; however, 61% of this number corresponds to the outbreak affecting Haiti and the Dominican Republic since October 2010.

  • Another large percentage of the total of cases during 2011 came from the African continent, where the lethality rates are higher than in Haiti and Dominican Republic (Africa 2.22%, Dominican Republic 1.61% and Haiti 0.84%). We know that the real number of cases reported is much higher, due to underreporting and limitations of the surveillance systems.

  • The last great pandemic worldwide occurred in Latin America; the first cases were reported in Peru in 1991. Peru was also the most affected country, with more than 300,000 cases reported during the first year. Until now the origins of this epidemic have been controversial, and the most supported theory is the one of multiple entry places along the coast of Peru due to contamination of water and food in large coastal cities.

  • New outbreaks keep emerging, even in areas where no case of cholera has ever been reported, which highlights the need of new measures to prevent and control great pandemics. Despite the existence of surveillance systems, water and food sanity, still no effective control to prevent appearance of new outbreaks has been achieved, mainly because such factors cannot be adequately regulated in developing countries.

What laboratory studies should you order and what should you expect to find?

Results that confirm the diagnosis

  • Isolation of the bacteria with a stool culture:

    • The culture medium most commonly used is thiosulfate citrate bile salts sucrose agar and taurocholate and tellurite gelatin agar

    • The serogroup can be identified using antiserum

  • Rapid direct exam with dark field microscopy allows a quick identification:

    • The bacillus can be observed easily with dark field microscopy

    • A characteristic high number of bacteria and chaotic movement is seen

  • A rapid dipstick test (Crystal VC) is now available and has sensitivity comparable to other methods but has relatively poor specificity. It may be suitable for use in the field as it has good negative predictive value.

What imaging studies will be helpful in making or excluding the diagnosis of cholera?

Imaging is not of benefit.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has cholera, what therapies should you initiate immediately?

Rehydration

Hypovolemia can result in lactic acidosis, shock and renal failure. Rehydration is the cornerstone of therapy:

  • Oral hydration is often effective when initiated early in the disease. Hypo-osmolar solutions have proven to be most effective at replacing volume and reducing the volume of diarrhea.

  • The WHO oral solution contains 2.6g sodium chloride, 2.9g trisodium citrate, 1.5g of potassium chloride and 13.5g glucose.

  • Oral hydration containing rice or cereal as the calorie source rather than glucose is more effective at reducing the volume and duration of diarrhea.

  • Rehydration volumes of 2200 to 4400mL are recommended for those over 30kg in weight.

  • Intravenous rehydration is recommended for those who have lost over 10% of their body weight, or are unable to take oral fluids because of vomiting or a depressed mental status.

    • An isotonic intravenous solution is recommended. Alternatives include:

      • Normal saline

      • Ringers lactate

      • Ringers lactate + 5% dextrose

      • Cholera or Dhaka solution (high glucose content)

Anti-infective agents

  • Antibiotics are an adjunct therapy and are generally initiated after the patient has been hydrated.

  • Antibiotic treatment shortens the duration of diarrhea and reduces the infectiousness of the stool. V.cholerae excretion is usually eliminated after 24 hours of antibiotic treatment

  • Oral antibiotics are generally recommended:

    • Doxycyline 300 mg as a single dose is as effective as multiple doses of oral tetracycline 500 mg given every 6 hours.

    • Fluoroquinolones are highly effective in areas where tetracycline resistance is prevalent.

      • Ciprofloxacin 1000 mg as a single dose was shown to be more effective than single dose doxycyline

      • Norfloxacin 400 mg daily x 3 days was shown to be more effective than single dose doxycyline

    • Macrolides have also proved to be effective in treating cholera

      • Erythromycin -12.5 mg/kg every six hours for three days

      • Azithromycin - 1gm single oral dose

How can cholera be prevented?

Vaccines

  • Among the prevention measures for this disease are sanitary education and water decontamination; however these measures have been sometimes impossible to achieve in many countries. That is why a need for cholera vaccines continues.

  • As with every vaccine, an ideal balance between a rapid but lasting immunological response, with minimal side effects and easy access are integral. Despite the efforts, achieving this balance has not been easy, several vaccines have been developed during the last 20 years, not all being successful. Efforts to develop and patent successful vaccines are now progressing rapidly.

  • We know that the ideal vaccine for cholera should be administrated orally. The WC BS vaccine (Whole Cell B Subunit) was promising with short-term positive results; however, in a long-term analysis it proved to be protective in only 50% of patients:

    • Even less protection in children and adults with blood group O

    • Less protection against biotype El Tor

  • Later, live attenuated vaccines, such as Vaxchora showed improved results during the 90’s:

  • Three oral vaccines against cholera are now available:

    1. V. cholerae killed cell vaccine with recombinant B toxin (Dukoral, Crucell). Dukoral has a license in more than 60 countries and has been prequalified by WHO by the UN acquisition to be used in crisis areas for refugees in Indonesia, Sudan, Uganda and Mozambique.

    2. The other vaccine type is available under two different brand labels. The vaccine consists of killed V. cholerae without the recombinant toxin: a) Shanchol, Shantha Biotechnics

      b) mORC-VAX, Va- Biotech

    3. Vaxchora is available as a single dose oral formulation of lyophilized live V cholerae CVD 103-HgR to be administered at least 10 days prior to potential exposure to cholera.

The first two vaccines are given in a 2-dose regimen (with the exception of Dukoral that requires 3 doses for children under 6 years old. There is increasing evidence that one dose may be sufficient in some areas.

A recent Cochrane review on oral vaccines against cholera concluded that whole cell inactivated vaccines can prevent 50-60% of cholera episodes during the first two years after the primary vaccine schedule. However, the authors recommend that the impact and cost effectiveness of incorporating these vaccines into the regular primary vaccine schedule in endemic countries should be restricted to areas where the prevalence and frequency of epidemics is high, and where there is limited access to basic sanitation and health services that provide quick treatment and rehydration.

The use of vaccine in Haiti has been debated by public health experts, now that the epidemic in this area has continued for more than 2 years. To date, a consensus about vaccine use has not been achieved. Nevertheless there is great interest in the development of a vaccine as a control measure for this disease.

WHO presently recommends use of vaccine during epidemics.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Seas, C, Gotuzzo, E, Mandel, GL, Bennett, JE, Dolin, R. "Vibrio cholerae". Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Churchill Livingstone. 2000. pp. 2266-72.

"Cholera, diarrhea and dysentery update 2012, Cuba". http://www.promedmail.org/.

"Cholera annual report 2011". Wkly Epidemiol Rec. vol. 87. 2012. pp. 289-304.

Seas, C, Miranda, J, Gil, AI, Leon-Barua, R, Patz, J, Huq, A. "New insights on the emergence of cholera in Latin America during 1991: the Peruvian experience". The American journal of tropical medicine and hygiene. vol. 62. 2000. pp. 513-7.

Seas, C, Gotuzzo, E, Rakel, R, Bope, E. "The infectious Diseases - Cholera". Conn’s Current Therapy. ELSEVIER. 2009.

Seas, C, Gotuzzo, E, Yu, V, Weber, R. "Vibrio cholerae (Cholera)". Antimicrobial Therapy and Vaccines. Apple Trees Productions. 2003.

Waldor, MK, Hotez, PJ, Clemens, JD. "A national cholera vaccine stockpile--a new humanitarian and diplomatic resource". The New England journal of medicine. vol. 363. 2010. pp. 2279-82.

Sur, D, Kanungo, S, Sah, B, Manna, B, Ali, M, Paisley, AM. "Efficacy of a low-cost, inactivated whole-cell oral cholera vaccine: results from 3 years of follow-up of a randomized, controlled trial". PLoS Negl Trop Dis. vol. 5. 2011. pp. e1289.

Sinclair, D, Abba, K, Zaman, K, Qadri, F, Graves, PM, Anh, DD. "Oral vaccines for preventing cholera - Use of oral cholera vaccines in an outbreak in Vietnam: a case control study". Cochrane Database Syst Rev. vol. 5. 2011. pp. CD008603.

Ryan, ET. "Haiti in the context of the current global cholera pandemic". Emerg Infect Dis. vol. 17. 2011. pp. 2175-6.

Clemens, JD. "Vaccines in the time of cholera". Proceedings of the National Academy of Sciences of the United States of America. vol. 108. 2011. pp. 8529-30.

Shin, S, Desai, SN, Sah, BK, Clemens, JD, Chao, DL, Halloran, ME. "Oral vaccines against cholera - Vaccination strategies for epidemic cholera in Haiti with implications for the developing world". Clin Infect Dis. vol. 52. 2011. pp. 1343-9.

"Outbreak of cholera in Cuba, potential risk for European travellers". 12 July 2012. http://ecdc.europa.eu/en/publications/Publications/TER-Rapid-risk-assessment-cholera-Cuba-July-2012.pdf.

Ley, B, Khatib, AM, Thriemer, K, von Seidlein, L, Deen, J, Mukhopadyay, A. "Evaluation of a rapid dipstick (Crystal VC) for the diagnosis of cholera in Zanzibar and a comparison with previous studies". PLoS One.. vol. 7. 2012. pp. e36930.

Qadri, Firdausi, Wierzba, Thomas F., Ali, Mohammad, Chowdhury, Fahima, Khan, Ashraful I., Saha, Amit. "Efficacy of a Single-Dose, Inactivated Oral Cholera Vaccine in Bangladesh". N Engl J Med. vol. 374. 2016. pp. 1723-1732.

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