OBJECTIVE: To estimate the global burden of cholera using population-based incidence data and reports. METHODS: Countries with a recent history of cholera were classified as endemic or non-endemic, depending on whether they had reported cholera cases in at least three of the five most recent years. The percentages of the population in each country that lacked access to improved sanitation were used to compute the populations at risk for cholera, and incidence rates from published studies were applied to groups of countries to estimate the annual number of cholera cases in endemic countries. The estimates of cholera cases in non-endemic countries were based on the average numbers of cases reported from 2000 to 2008. Literature-based estimates of cholera case-fatality rates (CFRs) were used to compute the variance-weighted average cholera CFRs for estimating the number of cholera deaths. FINDINGS: About 1.4 billion people are at risk for cholera in endemic countries. An estimated 2.8 million cholera cases occur annually in such countries (uncertainty range: 1.4-4.3) and an estimated 87,000 cholera cases occur in non-endemic countries. The incidence is estimated to be greatest in children less than 5 years of age. Every year about 91,000 people (uncertainty range: 28,000 to 142,000) die of cholera in endemic countries and 2500 people die of the disease in non-endemic countries. CONCLUSION: The global burden of cholera, as determined through a systematic review with clearly stated assumptions, is high. The findings of this study provide a contemporary basis for planning public health interventions to control cholera.

ANTECEDENTES: Las vacunas orales contra el cólera son las nuevas alternativas de las vacunas parenterales; se considera que estas últimas solamente confieren inmunidad moderada y a corto plazo. OBJETIVOS: El objetivo de esta revisión fue evaluar el efecto de las vacunas contra el cólera para prevenir casos de cólera y muertes. ESTRATEGIA DE BÚSQUEDA: Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Enfermedades Infecciosas (Cochrane Infectious Diseases Group), Medline, Embase y las listas de referencias de los artículos. Se realizaron búsquedas manuales en la revista Vaccine; se estableció contacto con los investigadores en el área y con los fabricantes. CRITERIOS DE SELECCIÓN: Estudios aleatorios y cuasialeatorios que compararan vacunas contra el cólera (muertas o vivas) versus placebo, vacunas de control o ninguna intervención, o que compararan tipos, dosis o esquemas de administración de las vacunas contra el cólera. Se incluyeron adultos y niños, independientemente del estado inmunitario o de la categoría de riesgo especial. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos revisores realizaron de forma independiente la extracción de datos y la evaluación de la calidad del ensayo. RESULTADOS PRINCIPALES: Se incluyen 25 ensayos. Se incluyeron 18 ensayos de eficacia, de calidad relativamente buena, que probaron las vacunas parenterales y orales de células enteras muertas en 2,6 millones de adultos, niños y lactantes. No se dispuso de ensayos de eficacia aleatorios de vacunas vivas, por lo que esta revisión se limita solamente a las vacunas muertas. Se realizaron 11 ensayos de seguridad, con 9342 personas, para ambos tipos de vacunas de células enteras muertas. En la comparación de las vacunas de células enteras muertas versus placebo, el riesgo relativo de contraer cólera a los 12 meses fue 0,51; intervalo de confianza del 95%: 0,42 a 0,61 (modelo de efectos aleatorios). Esta cifra se traduce en un 51% de eficacia, intervalo de confianza del 95%: 41% a 59%. Tanto la administración parenteral como oral resultaron relativamente eficaces, pero sólo las vacunas de células enteras muertas orales ofrecieron una protección significativa hasta el tercer año. La protección duró un año en los niños menores de cinco años, y hasta tres años en adultos y niños de mayor edad. Las vacunas parenterales de células enteras muertas se asociaron con un aumento de los efectos adversos sistémicos y locales en comparación con el placebo; este no fue el caso con las vacunas orales de células enteras muertas. CONCLUSIONES DE LOS AUTORES: Las vacunas de células enteras muertas contra el cólera parecen ser relativamente eficaces y seguras. La protección contra el cólera parece persistir hasta dos años después de una sola dosis de vacuna, y hasta tres a cuatro años con un refuerzo anual.

BACKGROUND: Killed whole-cell oral cholera vaccines (kOCVs) are becoming a standard cholera control and prevention tool. However, vaccine efficacy and direct effectiveness estimates have varied, with differences in study design, location, follow-up duration, and vaccine composition posing challenges for public health decision making. We did a systematic review and meta-analysis to generate average estimates of kOCV efficacy and direct effectiveness from the available literature. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Review Library on July 9, 2016, and ISI Web of Science on July 11, 2016, for randomised controlled trials and observational studies that reported estimates of direct protection against medically attended confirmed cholera conferred by kOCVs. We included studies published on any date in English, Spanish, French, or Chinese. We extracted from the published reports the primary efficacy and effectiveness estimates from each study and also estimates according to number of vaccine doses, duration, and age group. The main study outcome was average efficacy and direct effectiveness of two kOCV doses, which we estimated with random-effect models. This study is registered with PROSPERO, number CRD42016048232. FINDINGS: Seven trials (with 695 patients with cholera) and six observational studies (217 patients with cholera) met the inclusion criteria, with an average two-dose efficacy of 58% (95% CI 42-69, I(2)=58%) and effectiveness of 76% (62-85, I(2)=0). Average two-dose efficacy in children younger than 5 years (30% [95% CI 15-42], I(2)=0%) was lower than in those 5 years or older (64% [58-70], I(2)=0%; p<0·0001). Two-dose efficacy estimates of kOCV were similar during the first 2 years after vaccination, with estimates of 56% (95% CI 42-66, I(2)=45%) in the first year and 59% (49-67, I(2)=0) in the second year. The efficacy reduced to 39% (13 to 57, I(2)=48%) in the third year, and 26% (-46 to 63, I(2)=74%) in the fourth year. INTERPRETATION: Two kOCV doses provide protection against cholera for at least 3 years. One kOCV dose provides at least short-term protection, which has important implications for outbreak management. kOCVs are effective tools for cholera control. FUNDING: The Bill & Melinda Gates Foundation.

BACKGROUND: Cholera is an acute watery diarrhoea caused by infection with the bacterium Vibrio cholerae, which if severe can cause rapid dehydration and death. Effective management requires early diagnosis and rehydration using oral rehydration salts or intravenous fluids. In this review, we evaluate the additional benefits of treating cholera with antimicrobial drugs. OBJECTIVES: To quantify the benefit of antimicrobial treatment for patients with cholera, and determine whether there are differences between classes of antimicrobials or dosing schedules. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; African Index Medicus; LILACS; Science Citation Index; metaRegister of Controlled Trials; WHO International Clinical Trials Registry Platform; conference proceedings; and reference lists to March 2014. SELECTION CRITERIA: Randomized and quasi-randomized controlled clinical trials in adults and children with cholera that compared: 1) any antimicrobial treatment with placebo or no treatment; 2) different antimicrobials head-to-head; or 3) different dosing schedules or different durations of treatment with the same antimicrobial. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied inclusion and exclusion criteria, and extracted data from included trials. Diarrhoea duration and stool volume were defined as primary outcomes. We calculated mean difference (MD) or ratio of means (ROM) for continuous outcomes, with 95% confidence intervals (CI), and pooled data using a random-effects meta-analysis. The quality of evidence was assessed using the GRADE approach. MAIN RESULTS: Thirty-nine trials were included in this review with 4623 participants. Antimicrobials versus placebo or no treatment 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). The mean duration of fecal excretion of vibrios was reduced by almost three days (MD 2.74 days, 95% CI -3.07 to -2.40, 12 trials, 740 participants, moderate quality evidence). There was substantial heterogeneity in the size of these benefits, probably due to differences in the antibiotic used, the trial methods (particularly effective randomization), and the timing of outcome assessment. The benefits of antibiotics were seen both in trials recruiting only patients with severe dehydration and in those recruiting patients with mixed levels of dehydration. Comparisons of antimicrobials In head-to-head comparisons, there were no differences detected in diarrhoea duration or stool volume for tetracycline compared to doxycycline (three trials, 230 participants, very low quality evidence); or tetracycline compared to ciprofloxacin or norfloxacin (three trials, 259 participants, moderate quality evidence). In indirect comparisons with substantially more trials, tetracycline appeared to have larger benefits than doxycycline, norfloxacin and trimethoprim-sulfamethoxazole for the primary review outcomes. Single dose azithromycin shortened the duration of diarrhoea by over a day compared to ciprofloxacin (MD -32.43, 95% CI -62.90 to -1.95, two trials, 375 participants, moderate quality evidence) and by half a day compared to erythromycin (MD -12.05, 95% CI -22.02 to -2.08, two trials, 179 participants, moderate quality evidence). It was not compared with tetracycline. AUTHORS' CONCLUSIONS: In treating cholera, antimicrobials result in substantial improvements in clinical and microbiological outcomes, with similar effects observed in severely and non-severely ill patients. Azithromycin and tetracycline may have some advantages over other antibiotics.

OBJECTIVES: Recent large cholera outbreaks highlight the need for improved understanding of the pathogenesis and epidemiology of cholera. The incubation period of cholera has important implications for clinical and public health decision-making, yet statements of the incubation period of cholera are often imprecise. Here we characterize the distribution of cholera's incubation period. METHODS: We conducted a systematic review of the literature for statements of the incubation period of cholera and data that might aid in its estimation. We extracted individual-level data, parametrically estimated the distribution of toxigenic cholera's incubation period, and evaluated evidence for differences between strains. RESULTS: The incubation period did not differ by a clinically significant margin between strains (except O1 El Tor Ogawa). 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. CONCLUSIONS: We recommend that cholera investigations use a recall period of at least five days to capture relevant exposures; significantly longer than recent risk factor studies from the Haitian epidemic. This characterization of cholera's incubation period can help improve clinical and public health practice and advance epidemiologic research.

In a controlled field trial on some 584 000 people in an endemic cholera El Tor area in the Philippines, it was demonstrated that cholera vaccines gave moderate protection of short duration. Injection of a single dose of vaccine prepared from either Vibrio cholerae or Vibrio El Tor gave over 50% protection for the first two months. The immunity conferred by the V. cholerae vaccine rapidly declined after three to four months. The V. El Tor vaccine gave protection for six months, but its effectiveness declined. An oil-adjuvant vaccine prepared from V. cholerae conferred an increasing degree of protection of long duration, but, owing to severe vaccination reactions, its use could not be recommended.

Tetracycline continues to be an effective antimicrobial agent in the clinical control of cholera but because of its high cost, relatively short shelf-life and recent reports of increased resistance of vibrios to tetracycline in vitro, alternative antimicrobial agents have been tested. Furazolidone, effective against cholera caused by the El Tor biotype in adults, was found to be as effective as tetracycline in reducing the volume and duration of diarrhoea in children with classical cholera and, given over a period of 7 days, only slightly less effective in reducing duration of vibrio excretion.Therapy with an antimicrobial agent over a period of 7 days was associated with a significantly smaller rise in vibriocidal antibody titre (of no clinical significance) in the youngest age-group studied; this was probably due to a diminished antigenic stimulus from the primary infection. Undernourished children showed a poorer response to anti-microbial therapy.The study indicated that furazolidone is a reasonable alternative to tetracycline in the treatment of cholera.

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A controlled field trial on some 584 000 people in an endemic cholera El Tor area in the Philippines demonstrated that cholera vaccines gave moderate protection of short duration. Injection of a single dose of vaccine prepared from either Vibrio cholerae or El Tor vibrios gave over 50% protection for the first 2 months. The immunity conferred by the V. cholerae vaccine declined rapidly after 3 to 4 months. The effectiveness of the El Tor vaccine continued for 6 months. An oil-adjuvant vaccine prepared from V. cholerae conferred an equally high degree of protection for a longer period of time, but, owing to severe vaccination reactions, its use could not be recommended.