Vibrio cholerae infections cluster in households. This study' s objective was to quantify the relative contribution of direct, within-household exposure (for example, via contamination of household food, water, or surfaces) to endemic cholera transmission. Quantifying the relative contribution of direct exposure is important for planning effective prevention and control measures. Symptom histories and multiple blood and fecal specimens were prospectively collected from household members of hospital-ascertained cholera cases in Bangladesh from 2001–2006. We estimated the probabilities of cholera transmission through 1) direct exposure within the household and 2) contact with community-based sources of infection. The natural history of cholera infection and covariate effects on transmission were considered. Significant direct transmission (p-value<0. 0001) occurred among 1414 members of 364 households. Fecal shedding of O1 El Tor Ogawa was associated with a 4. 9% (95% confidence interval: 0. 9%–22. 8%) risk of infection among household contacts through direct exposure during an 11-day infectious period (mean length). The estimated 11-day risk of O1 El Tor Ogawa infection through exposure to community-based sources was 2. 5% (0. 8%–8. 0%). The corresponding estimated risks for O1 El Tor Inaba and O139 infection were 3. 7% (0. 7%–16. 6%) and 8. 2% (2. 1%–27. 1%) through direct exposure, and 3. 4% (1. 7%–6. 7%) and 2. 0% (0. 5%–7. 3%) through community-based exposure. Children under 5 years-old were at elevated risk of infection. Limitations of the study may have led to an underestimation of the true risk of cholera infection. For instance, available covariate data may have incompletely characterized levels of pre-existing immunity to cholera infection. Transmission via direct exposure occurring outside of the household was not considered. Direct exposure contributes substantially to endemic transmission of symptomatic cholera in an urban setting. We provide the first estimate of the transmissibility of endemic cholera within prospectively-followed members of households. The role of direct transmission must be considered when planning cholera control activities.
Cholera disproportionately affects less-developed areas of Asia, Africa, and Latin America, leading to an estimated 3–5 million cases and 100–130 thousand deaths per year [1]. Vibrio cholerae O1/O139 transmission is associated with two general modes of exposure to infection. Community-to-person transmission results from ingestion of contaminated water from environmental sources [2]. Direct transmission results from exposure to food, water, and surfaces shared by a cluster of individuals, such as a household, and contaminated by an infectious member of the cluster [1]. The relative contributions of community-to-person and direct exposure to endemic cholera transmission are subject to ongoing debate [2]–[7]. Community-to-person exposure is a well-established mode of transmission for cholera infection [8]–[11], whereas the relative contribution of direct exposure is poorly quantified. Evidence of herd immunity from cholera vaccine studies [12]–[14], reports from cholera outbreak investigations [15]–[17], the clustering of V. cholerae clones by household [18], and mathematical modeling of epidemics [3]–[5] suggest that direct transmission is an important component of overall transmission. John Snow himself believed that cholera transmission had a direct as well as a waterborne component. After describing many case studies of potential cholera transmission in England during the mid 1800' s, Snow stated: “Besides the facts above mentioned, which prove that cholera is communicated from person to person, …” [19]. The effectiveness of interventions for the control of endemic cholera depends, in part, upon the prevailing mode of transmission. Dominant transmission through direct exposure is expected to generate clusters of cases within close contact groups, such as households. Transmission primarily via community-to-person exposure is expected to generate a more diffuse spatial pattern of cases within a population. Knowledge of the dominant mode of transmission is important for informing the selection of optimal intervention strategies, such as vaccination strategies for preventing ongoing cholera transmission in Haiti [20]. Here, we estimate the probabilities of endemic V. cholerae O1/O139 transmission through 1) exposure to community sources of infection and 2) direct exposure within the household. The modifying role of covariates and aspects of the natural history of V. cholerae infection are also described. To our knowledge, this study provides the first estimates of the transmission potential of endemic cholera via direct exposure among the members of prospectively-followed households.
The Ethical and Research Review Committees of the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh (icddr, b) and the Institutional Review Board of the Massachusetts General Hospital reviewed and approved this study. Written informed consent was collected from all participants, with consent provided by a parent or legal guardian for participants under 18 years-old. This analysis was conducted using de-identified data. A case-ascertained [21] study was conducted from January 2001 to May 2006 among households of Dhaka, Bangladesh, as previously described [18], [22]–[24]. Individuals older than six months of age presenting to the hospital of the icddr, b with severe acute watery diarrhea, stool positive for V. cholerae infection by culture, and without a history of significant co-morbidities were selected for inclusion as index cases. Antimicrobial therapy was provided to all index cases, as per the standard clinical practice for the management of acute watery diarrhea at the icddr, b. The study timeline is expressed relative to the enrollment day of the index case (day 1). Written informed consent was requested from the members of the index case' s household on day 2 of the study. Households are defined as individuals who ate from the same cooking pot during the preceding three days. For children under 18 years of age, informed consent was requested from a parent or legal guardian. Consenting household members were enrolled if they were not participating in other icddr, b studies. Figure 1 describes the data collection schedule for each household. Upon enrollment, stool samples were obtained from the index cases. Study staff visited each household on days 2 through 7,14, and 21. On day 2, information about age and sex was collected for all enrolled household members, along with an eight-day clinical history for preceding symptoms of diarrheal disease, i. e. , for days −7 to 1 (there was no day 0). Similar seven-day clinical histories were collected on days 7,14, and 21. Rectal swabs were collected from all study participants on days 2 through 7,14, and 21. Blood specimens were collected from all study participants on days 2,4, 7, and 21. Using previously-described methods [22], stool samples and rectal swabs were tested for V. cholerae, and blood specimens were assayed for vibriocidal antibody titers and ABO blood type. The serogroup (O1 or O139) and serotype of serogroup O1 El Tor biotype (Ogawa or Inaba) were determined for positive stool specimens.
The study enrolled 1491 individuals living in 399 households (one index case each). We excluded 24 households with only one enrolled member (the index case) from the analysis, because they impart no information about transmission. An additional 11 households (53 members) were excluded from the analysis for lack of serum vibriocidal antibody titer measurements. The resulting study population of 1414 people lived in 364 households. Table S1 in Text S1 provides the frequency of the households included in the analysis by the number of enrolled members, infections among the enrolled, and the serogroup-serotype of infection. The 53 enrolled study members who were excluded from the analysis because of missing vibriocidal antibody titer data did not substantially differ from the study population in the distributions of age (p<0. 580), sex (p<0. 981), the prevalence of O blood group (p<0. 320), the attack rate for watery diarrhea (p<0. 508), or the proportion of members with at least one stool/rectal swab specimen positive for V. cholerae (p<0. 098) (Table 1). Non-primary cholera infections were significantly younger than index cholera infections (p<0. 001), but not uninfected household contacts (p<0. 200) (Table 1). The sex ratio and the prevalence of O blood group were similar for infected and uninfected household contacts (p<0. 896 and p<0. 145, respectively). When compared to household contacts, index cases were more commonly female (p<0. 027) and of the O blood group (p<0. 004). Among the 1050 household contacts, 22. 5% (318) developed V. cholerae infection (Table 1). The proportion of non-index V. cholerae infections with watery diarrhea was 56. 7% (180 of 318). The number of days between the symptom onset dates of the primary (onset of symptoms on or before onset in the household index infection) and non-primary symptomatic cholera cases in a household was not uniformly distributed (Figure 3); the mean (standard deviation) duration was 9 (4) days. For each serogroup-serotype, we rejected the null hypothesis of no direct transmission (p-value<0. 001). The SAR estimates were 4. 9% (95% CI: 0. 9%–22. 8%) for, 3. 7% (95% CI: 0. 7%–16. 6%) for, and 8. 2% (95% CI: 2. 1%–27. 1%) for. The CPI estimates for a comparable 11-day period were 2. 5% (0. 8%–8. 0%) for, 3. 4% (1. 7%–6. 7%) for, and 2. 0% (0. 5%–7. 3%) for. Serogroup-serotype specific estimates for the risk of infection resulting from a month (30 days) of community-to-person exposure were 6. 7% (2. 1%–20. 4%) for, 9. 0% (4. 5%–17. 3%) for, and 5. 3% (1. 4%–18. 7%) for. For all serogroup-serotypes combined, the estimated risk of cholera infection associated with community-to-person exposure varied by calendar month of the year (Figure S2). In the univariate and multivariate transmission models, children under five years of age were significantly more susceptible than adults 18 years and older to cholera infection (Table 2). The susceptibility of children 5–17 years-old to cholera infection did not significantly differ from that of adults 18 years and older. There was no evidence of significant differences in the susceptibility of contacts based upon either sex or ABO blood group. Serum vibriocidal antibody titers demonstrated some protection against infection by O1 El Tor Ogawa and O139. This protection was only statistically significant for O1 El Tor Ogawa in the multivariate model, providing an estimated 9% (95% CI: 1%–17%) reduction in susceptibility to infection per two-fold higher initial titer for serum vibriocidal antibody. The magnitude of protection against O139 infection was larger than the effect for O1 El Tor Ogawa, but lacked statistical significance in every model. The unadjusted transmission model, both including (-and-) and excluding (-only) transmission through direct exposure, demonstrated adequate fit to the study data (Figure S3 in Text S1). For both unadjusted transmission models, chi-squared tests rejected the null hypothesis for a difference between the observed and expected final size distributions (p-value< = 0. 001). There was little evidence to suggest that the quality of the fit of the unadjusted transmission model including direct transmission differed from that of the model excluding this mode of exposure.
This study and analysis have several limitations that are expected to result in underestimation of the true serogroup-serotype specific household secondary attack rates for V. cholerae infection. Initial serum vibriocidal antibody titers may incompletely account for levels of pre-existing immunity to V. cholerae infection [30]. In addition, we only considered direct transmission within the households of study participants. Some of the transmission attributed to community-to-person exposure may have actually resulted from direct exposure outside of the participant' s own household. Theoretically, the observed pattern of cholera infections could have been solely attributable to community-to-person transmission. The inability to discern between transmission of V. cholerae through exposure to direct versus short-duration community-based sources of infection has been demonstrated through mathematical modeling investigations using mass action transmission models [3], [4]. If the only source of exposure to cholera infections in one of our study households was a common community-based source of infection that occurred on a single day, a pattern of illness onset dates consistent with acute direct transmission could occur. If this scenario occurred in every household enrolled in this study, our statistical model would errantly attribute some or all transmission to direct exposure. If a community-based source of infection exposed the members of a household for a period longer than one day (a plausible scenario), our statistical model would be able to differentiate between transmission due to that source and that resulting from direct exposure within the household. The fact that the mean time between the onset of symptoms in primary and associated non-primary symptomatic cholera cases was longer than the maximum length of the incubation period supports the assertion that direct and/or multi-day community-based sources of exposure to infection were operating in this population during this study. The current study categorizes the cholera infections by bacterial phenotype, i. e. , biotype, serogroup, and serotype. The primary limitation of using this categorization schema relates to the substantial genetic variation evident among vibrios of the same bacterial phenotype. Since the probability of direct transmission of cholera within households is likely to be strongly associated with genetic similarity of the infecting vibrios, this analysis would certainly have been enhanced by incorporation of measures of the genetic similarity between the cholera bacteria isolated from the participants in the same household. If this type of information had been available for the current study, our analysis could have either 1) estimated genotype specific SAR' s (analogous to the approach used here to estimate SAR' s by bacterial phenotype) or 2) directly incorporated measures of genetic distance into the likelihood for the transmission model. Whole genome sequencing has been used characterize genetic variability among clinical V. cholerae isolates, for example, to characterize the origins of the recent outbreak of cholera in Haiti [34]. Ongoing work by the authors [35] seeks to address this limitation through a combination of ongoing field studies and statistical methodologic research. Cholera remains an important public health issue for low-resource settings with limited public health facilities. Recent experiences in Zimbabwe and Haiti underscore the urgent need for effective intervention strategies [1], [36]. Our results demonstrate that exposure through direct contact significantly contributes to the endemic transmission of cholera infection. Greater emphasis needs to be placed on implementing interventions targeting transmission through direct exposure. Consideration should be given to evaluating the utility of pre-emptive administration of antimicrobial agents to the household contacts of patients with cholera in areas lacking adequate sanitation. Vaccination of entire households prior to the onset of seasonal transmission may allow for additional control of transmission by bolstering existing immunity among members, thereby reducing the level of direct transmission and protecting against community-to-person transmission from other contaminated sources.
Since John Snow' s ground-breaking investigations of the devastating outbreaks in 19th-century London, cholera has been considered the quintessential waterborne human infection, transmitting via fecal contamination of environmental water sources. Recently, renewed interest has been paid to the potential importance of transmission through direct exposure within close-contact groups, such as, via fecal contamination of surfaces, food, or drinking water within households. Significant direct transmission of cholera within close contact groups would represent a new target for innovative prevention and control strategies. We estimated the probability of transmission 1) via direct contact within 364 urban households located in an endemic cholera setting (Dhaka, Bangladesh) and 2) via exposure to sources located outside of these households. In this setting we estimated a 4 to 8 percent probability of becoming infected with cholera via direct exposure within households in this setting versus a 2 to 3 percent likelihood of infection due to exposure to external sources over a comparable time period. Our results demonstrate that direct (within-household) transmission is a significant component of endemic cholera transmission, suggesting that biomedical and behavioral-modification interventions specifically targeting this mode of transmission could substantially reduce the cholera burden in this type of setting.
medicine and health sciences
tropical diseases
microbiology
health care
multivariate analysis
bacterial diseases
mathematics
statistics (mathematics)
global health
neglected tropical diseases
population biology
statistical inference
research and analysis methods
public and occupational health
infectious diseases
cholera
disease ecology
epidemiology
mathematical and statistical techniques
hygiene
ecology
sanitization
biology and life sciences
physical sciences
statistical methods
organisms
maximum likelihood estimation
Household Transmission of Vibrio cholerae in Bangladesh