Research Projects : Export

Objective

Evaluate the effectiveness of the Case Area Targeted Intervention (CATI) approach in reducing the incidence of new cases during cholera outbreaks.  And in so doing, to determine factors that support optimal delivery and interventions for CATIs towards cholera reduction in humanitarian settings and fragile states.

Aim

The primary aim is to characterize the relationship between CATI activation time (time between case presentation at a cholera treatment facility and the start of the CATI intervention) and cholera incidence in the area covered by CATI interventions. Secondary aims include:

• Document procedures of implementing CATIs and develop recommendations to maximize their impact in future cholera outbreaks.
• Describe the integration of water, sanitation, and hygiene (WASH) and health activities delivered via CATI.
• Characterize the relationship between CATI completeness (in terms of coverage within the specified geographic area and activities implemented within households) and incidence of new cholera cases.
• Estimate CATI effectiveness using secondary parameters (e.g. reported diarrheal incidence, free chlorine residual (FCR) in the drinking water sample, and knowledge and practices to prevent cholera transmission).
• Document coordination mechanisms between Ministries, United Nations (UN) agencies, Clusters, and non-governmental organizations (NGOs) and develop recommendations for coordination in future responses.

Study Design

The proposed research will be conducted in future cholera outbreaks that take place in recognized humanitarian contexts in at least two different countries; locations will be selected based on where cholera outbreaks occur and the presence of a CATI implementing partner.  Organizations that frequently implement CATI interventions during cholera response that have agreed to partner with JHSPH include Action Against Hunger, Solidarités International, and Medair. Countries with humanitarian emergencies that are at high risk of cholera outbreaks include Democratic Republic of the Congo, Nigeria, Ethiopia, Mozambique and Yemen, though it is possible that other humanitarian contexts may serve as a research location if a cholera outbreak occurs and one of the aforementioned implementing partners responds with a CATI intervention.

The JHSPH IRB approval has classified this study as Non-Human Subjects Research.   Government or IRB approval will be attained prior to conducting the research.

The research team will be present at the site as soon as possible after the first cholera case has been documented and begin data collection as soon as feasible. If travel to the study location is not feasible for security reasons, the JHSPH research team will conduct the study remotely through the partner organization that is providing on-the-ground CATI response to the cholera outbreak.

Because the aim of the research is to evaluate CATIs as delivered by NGOs in response to a cholera outbreak, a randomized design is not possible. Thus, we will rely on comparison groups that will occur naturally, according to the outbreak size and capacity of the response organization. This will necessitate a flexible sampling approach.

We anticipate the primary comparison will be rapid vs. delayed CATI implementation (e.g. end stage of outbreak); however, it is also possible that areas with no CATI implementation could be used as a comparison group [in outbreaks where there is insufficient capacity to respond to all cases].  Additional points of comparison may include the delay between case presentation and CATI implementation:  e.g. CATI implemented within 24h, in 2 days, in 3 days, in 4 days, etc.

The proposed research is an observational study of cholera interventions implemented by NGOs in response to cholera outbreaks (i.e. no intervention is proposed).  The study will include the following components:

• Observation of CATI delivery
• Key informant interviews: 1) NGO staff members delivering the CATI intervention to characterize perceived strengths and weakness of the intervention, household selection, logistical processes and implementation challenges; 2) Humanitarian response managers from the partner NGO, UN agencies, national governments and other organizations engaged in the cholera response to ascertain perceptions of the response, coordination and CATI delivery and implementation
• Cholera treatment facility line lists: Information from cholera line lists is used to plan CATI interventions, where each individual on the line list (i.e. a cholera case) receives a household visit from a CATI team. The JHSPH study team will request line lists from health facilities [which may be augmented by the study team] to evaluate coverage of CATI interventions.
• Follow up survey: The household follow up survey will be conducted approximately 14 days after the presentation of the suspected cholera case at a cholera treatment facility. The exact sampling approach will depend on the density of housing in the community and the CATI implementation strategy. Household surveys will enquire about receipt of the CATI intervention, household composition, incidence of diarrhea and diarrhea care seeking among household members in the period since CATI implementation (or case presentation if there was no CATI), knowledge and practices of hygiene behaviors and observation of free chlorine level (FCR) in stored drinking water.

Cholera continues to pose a major global public health threat and is a marker of inequality and poverty as it reflects the lack of access to basic water and sanitation infrastructures. The risk of the spread of cholera is particularly high in humanitarian settings and fragile contexts.

Cholera transmission risk is higher for cholera case household members and nearby households. Mass interventions to contain cholera outbreaks are not resource efficient.  Preventive interventions targeting cholera case-households and neighbors have been found effective in past outbreaks. These interventions are often referred to as case area targeted interventions (CATIs). CATIs predominantly include water, sanitation, and hygiene (WASH) activities but can also include epidemiological surveillance, and health (clinical) services, primarily oral vaccination and antibiotic chemoprophylaxis.

There are limited studies on the best practices and effectiveness of CATIs in humanitarian settings.   This study aims to identify those factors that support optimal delivery and interventions of these CATIs for cholera reduction in humanitarian settings and fragile states.  The study design centers around observing the CATI activities of partner organizations as they respond to a cholera outbreaks in known humanitarian or fragile settings.

There is limited evidence studying the mechanisms, composition, interventions, timing, effectiveness of CATIs in humanitarian settings. This proposed research for CATI in humanitarian settings will focus on variations in CATI implementation and timing, monitoring and evaluation, and coordination and integration with the aim of expanding available evidence that can be used to inform the development of operational guidance for CATI interventions in cholera response.

Cholera remains a persistent global health problem that can be controlled by appropriate water and sanitation and oral cholera vaccination. Our project aims to support the geographic targeting of cholera control interventions with four key objectives:

• maintenance of a global database of cholera surveillance data which can be used by countries and GTFCC stakeholders to access centralized data sources and understand the country and regional cholera epidemiology;
• development of a statistical mapping pipeline, which produces high resolution global maps of cholera burden;
• provision of technical epidemiological and modeling support to countries and NGOs in cholera control;
• participation in GTFCC working groups to develop evidence-driven guidance related to cholera surveillance and elimination, targeting OCV campaigns, and identifying cholera burden hotspots.

This project supports efforts to map the global burden of cholera through the maintenance of a global database of cholera incidence and mortality and the development of statistical modeling methods to produce high resolution maps of cholera burden. The study team is working to develop a user-friendly web interface to the cholera database to support country and GTFCC stakeholder access to centralized data sources, and the global burden maps serve as the foundation for many planning and intervention targeting activities such as strategic demand forecasts for OCV and hotspot identification.

Effective targeting of OCV campaigns and WASH interventions for cholera control requires knowledge of the highest burden areas worldwide. The global cholera database and mapping efforts resulting from this project support countries and GTFCC stakeholders in characterizing cholera epidemiology and targeting their cholera control efforts.

Bangladesh remains endemic for cholera, which experiences biannual outbreaks with additional epidemics seen during times of floods, cyclones or any natural disaster [1, 2]. It affects all age groups with the majority of fatal cases occurring in children [3-6]. Therefore, immunization against cholera remains an important public health component in the prevention and control of the disease [6]. A problem that may be a stumbling block in the path is that the oral cholera vaccine (OCV) is in short supply globally and only about 2-3 million doses are produced each year. In Bangladesh alone we anticipate that 170 million doses will be needed in a 5 year time frame if only high risk populations are targeted. Globally for the rest of Asia and Africa as well as for Haiti, millions of doses of vaccine is needed for control of endemic and epidemic cholera. The global demand for the vaccine is therefore high and the good news is that, there is now provision for local production of over 50 million doses in Bangladesh. With this prospect in view, planning for prevention of cholera by use of OCV, it may be possible to decrease the burden of the disease in Bangladesh.

Knowledge gap

More evidence is needed to address uncertainties around the cholera disease burden, as well as the impact, feasibility, and cost-effectiveness of various vaccination strategies against cholera, to add to the existing knowledge base. A special need for acquiring field evidence of these vaccine attributes in settings with endemic cholera, which account for a very large fraction of the global cholera disease burden, is also recognized [7].

There is a great need for identify financing mechanisms for introduction of vaccination against cholera. All these efforts will hopefully decrease the burden due to cholera which has both health and financial burden on the country. Studies have shown that the cost of hospitalization and illness to the patient and the family is around ten times higher than the cost of vaccine [8, 9].

A countrywide surveillance is needed which will help to identify the disease burden in the country, so as to plan appropriate treatment and preventive measures.

Relevance

Bangladesh needs to plan strategies for introduction of a locally produced oral cholera vaccine in Bangladesh. Thus clear information from national stakeholders on the cholera investment strategy for Bangladesh is needed based on which future plans can be made. In addition, information i s needed on the strategies for vaccination and areas which need to come under coverage. With the availability of a locally produced vaccine in Bangladesh, financing plans and funders will be needed to materialize the immunization plans for people with OCV.

Objectives

The objectives of the proposal are as follows:

• Build a plan (including surveillance of high risk areas) and identify strategies for the introduction of OCV in Bangladesh by developing the cholera investment case based on the present scenario.
• Identify a financing plan for the introduction of the locally produced vaccine in Bangladesh in the short term.

Methods

We will update the current cholera investment case study on cholera vaccination for Bangladesh which was previously prepared by International Vaccine Institute (IVI) in 2009. This will provide a useful evidence based guide to policy makers in Bangladesh in making decisions about the use of OCV as well as to the global health community in considering technical and financial support for cholera vaccine introduction. The information on where and whom to vaccinate will also be obtained to accumulate information by working on nationwide cholera surveillance from all over Bangladesh. Surveillance will be conducted in different government and non government hospitals and medical colleges in sites already known to have diarrheal disease burden.

Bangladesh remains endemic for cholera, which experiences biannual outbreaks with additional epidemics seen during times of floods, cyclones or any natural disaster. It affects all age groups with the majority of fatal cases occurring in children. Therefore, immunization against cholera remains an important public health component in the prevention and control of the disease. In Bangladesh alone we anticipate that 170 million doses will be needed in a 5 year time frame if only high risk populations are targeted. The global demand for the vaccine is high and the good news is that, there is now provision for local production of over 50 million doses in Bangladesh. With this prospect in view, planning for prevention of cholera by use of OCV, it may be possible to decrease the burden of the disease in Bangladesh.

Bangladesh needs to plan strategies for introduction of a locally produced oral cholera vaccine in Bangladesh. Thus clear information from national stakeholders on the cholera investment strategy for Bangladesh is needed based on which future plans can be made. In addition, information is needed on the strategies for vaccination and areas which need to come under coverage. With the availability of a locally produced vaccine in Bangladesh, financing plans and funders will be needed to materialize the immunization plans for people with OCV.

Therefore, the objectives of the current study are as follows:

• Build a plan (including surveillance of high risk areas) and identify strategies for the introduction of OCV in Bangladesh by developing the cholera investment case based on the present scenario.
• Identify a financing plan for the introduction of the locally produced vaccine in Bangladesh in the short term.

Different data will be used to develop and recommend up to 3 optimal strategies for introduction of Oral Cholera vaccine (OCV) with associated vaccine demand, budget and health impact. For this recommendation we will communicate with different level of Government of Bangladesh (GoB) and other internal and external stakeholders with our preferred feasible strategy for introduction of vaccine.

Burden

Cholera is a deadly disease with approximately 3-5 million cases and over 1,00,000 deaths annually worldwide. Of the 1.3 billion people at risk worldwide, 66 million are in Bangladesh equating to approximately 40% of the Bangladeshi population. In addition, refugee movement bring increased risk from this disease. Bangladesh is one of the Least Developed Countries list of ODA recipients and together with India has the largest population at risk of Cholera. Rapid diagnosis and early detection of outbreaks are key aspects to fight cholera. Moreover, the indiscriminate use of wide-spectrum antibiotics creates the additional threat of antibacterial resistance (ABR) in V. cholerae population.

Knowledge gap

Microbiological testing is resource-intensive, and outbreak detection is mostly based on unreliable reports of cholera-like diarrhoea cases from local hospitals. Advances in diagnostics, treatment selection and outbreak tracking are much-needed for progressing towards eliminating cholera as a public health threat by 2030, a recently proclaimed objective by the WHO-backed Global Taskforce for Cholera Control.

Relevance

The aggregation of geo-localised clinical, environmental, and societal information collected for the development of the diagnostic and early prediction systems, and the additional data continuously collected during the deployment and operation of such systems, will constitute an invaluable databank shareable across follow-on and collaborative projects and eventually across countries.

Hypothesis

Significant changes in understanding transmission dynamics of antimicrobial resistant V. cholerae in Bangladesh by big data mining and machine learning with better local community decision making to improve diagnosis and treatment of cholera.

Objectives

The specific objectives of this project are as follows:

• Develop a portable, real-time diagnostics solution for cholera infection caused by antimicrobial resistant V. cholerae
• Develop a surveillance system to identify hot spots with higher likelihood of outbreak
• Development of a shareable databank

Methods

Samples will be collected from Dhaka Hospital, Mathbaria Thana Health Complex, Cox’s Bazar Hospital and Rohingya camp. Immediate after collection, samples will be subjected to RDT. If the sample is positive for either V. cholerae O1 or O139 then one aliquot will be stored at -80°C freezer at icddr,b for future use and another aliquot will be transferred to NSU, Bangladesh for further analysis (Alam et al. 2006a). Water samples will also be collected from 6 sites each, for Dhaka city, Mathbaria, and Cox’s Bazar. Toxigenic V. cholerae will be isolated from stool and water samples following standard culture methods, and characterized for antibiotic resistance (Alam et al. 2006b, c). Both types of samples will be subjected to Nanopore genome sequencing.

Outcome measures/variables

Through the collaboration this proposal brings expertise together to work on public health. This will enable a much-needed multidisciplinary research programme to diagnose cholera using Nanopore genome sequencing, treatment selection, epidemiological forecasting for infection and antibacterial resistance, ultimately contributing to improving health, welfare and economic growth of Bangladesh.

Data mining and machine learning appear to offer better resolution for improving accuracy of diagnosis of a pathogen. The portable real-time nannopore sequencing device could provide diagnostic solution at field level. We designed this big data mining and machine learning study to improve diagnostics and treatment selection for cholera infection caused by antimicrobial resistant V. cholerae.

A portable real-time diagnostics solution for cholera infection caused by antimicrobial resistant V. cholerae with big data mining and machine learning to improve diagnostics and treatment selection.

Background

Cholera epidemics occur frequently in low-income countries affected by concurrent humanitarian crises. Evaluations of these epidemic response remains largely unpublished and there is a need to generate evidence on response efforts to inform future programmes. This review of MSF cholera epidemic responses aimed to describe the main characteristics of the cholera epidemics and related responses in these three countries, to identify challenges to the effectiveness and feasibility of different intervention strategies based on available data; and to make recommendations for epidemic prevention and control practice and policy.

Methods

Case studies from the Democratic Republic of Congo, Malawi and Mozambique were purposively selected by MSF for this review due to the documented burden of cholera in each of the countries, frequency of cholera outbreaks, and risk of concurrent humanitarian crises. Data were extracted on the characteristics of the epidemics; time between alert and response; and, the delivery of health and water, sanitation and hygiene (WASH) interventions. A Theory of Change for cholera response programmes was built to assess factors that affected implementation of the responses.

Results and conclusions

A total of 20 epidemic response reports were identified, 15 in DRC, one in Malawi and four in Mozambique. All contexts experienced concurrent humanitarian crises, either armed conflict or natural disasters. Across the three countries, median time between the date of alert and date of the start of the response by MSF was 23 days (IQR 14-41). Almost all responses targeted interventions community-wide, and all responses implemented in-patient treatment of suspected cholera cases in either established HCFs or temporary cholera treatment units (CTUs). In three responses, interventions were delivered as case-area targeted interventions (CATI) and four responses targeted households of admitted suspected cholera cases. CATI or delivery of interventions to households of admitted suspected cases occurred from 2017 onwards only. Overall, 74 factors affecting implementation were identified across reports including delayed supplies of materials, insufficient quantities of materials were delivered for effective programme delivery and limited or lack of coordination with local government or other agencies. Based on this review, the following recommendations are made to improve cholera prevention and control efforts: conduct rigorous and structured evaluations of cholera response programmes; explore improved models for epidemic preparedness, including rapid mobilisation of supplies and deployment of trained staff; invest in and strengthen partnerships with national and local government and other agencies as part of epidemic preparedness activities; and to standardise reporting templates within and across countries to provide consistent and accessible data by internal and external staff and collate learnings.

Based on this review, the following recommendations are made to improve cholera prevention and control efforts: conduct rigorous and structured evaluations of cholera response programmes; explore improved models for epidemic preparedness, including rapid mobilisation of supplies and deployment of trained staff; invest in and strengthen partnerships with national and local government and other agencies as part of epidemic preparedness activities; and to standardise reporting templates within and across countries to provide consistent and accessible data by internal and external staff and collate learnings.

Background

Globally, the risk of small-scale cholera outbreaks propagating rapidly and enlarging extensively remains substantial. As opposed to relying on mass, community-wide approaches, cholera control strategies could focus on proactively containing the first clusters. Case-area targeted interventions (CATI) are based on the premise that early cluster detection can trigger a rapid, localised response in the high-risk radius around one or several households to reduce transmission sufficiently to extinguish the outbreak or reduce its spread. Current evidence supports a high-risk spatiotemporal zone of 100 to 250 meters around case-households for 7 days.

We hypothesize that the prompt application of CATI will reduce household transmission and transmission in the wider ring. This will result in reduced incidence in the ring and reduced clustering of cases. The local focus of CATI will enable active case-finding and sustained uptake of interventions. This will result in prompt access to care for detected cases, and reduced mortality and community transmission.

Methods

We propose to evaluate the effectiveness of a CATI strategy using an observational study design during an acute cholera epidemic, with clearly-defined measures of the effectiveness of the CATI package. In addition, we intend to evaluate the feasibility, costs, and process of implementing this approach. The CATI package delivered by Médecins Sans Frontières’ (MSF) will incorporate key transmission-reducing interventions (including household-level water, sanitation, and hygiene measures, active case-finding, antibiotic chemoprophylaxis, and, single-dose oral cholera vaccination (OCV)) which aim to rapidly reduce the risk of infection in the household and in the ring around the primary case household. MSF will decide on the contents of the CATI package used, the radius of intervention and the prioritization strategy used if the caseload is higher than the operational capacity, based on national policies, the local context, and operational considerations. In scenarios where preventative vaccination has been recently conducted or is planned, CATI and its evaluation will focus on implementation before and during the mass campaign, or in areas where vaccination coverage was sub-optimal.

The study design is based on comparing the effects of CATIs that rapidly provide protection in averting later generations of cases when compared with progressively-delayed CATIs. A regression analysis will be used to model the observed incidence of enriched RDT-positive cholera as a function of the delay to intervention (in days). The delay will reflect the inverse strength of rapid response. Groups, as a function of their delays to intervention, will serve as internal controls.

Case-area targeted interventions (CATI) are based on the premise that early cluster detection can trigger a rapid, localised response in the high-risk radius around one or several households to reduce transmission sufficiently to extinguish the outbreak or reduce its spread.

We propose to evaluate the effectiveness of a CATI strategy using an observational study design during an acute cholera epidemic, with clearly-defined measures of the effectiveness of the CATI package. In addition, we intend to evaluate the feasibility, costs, and process of implementing this approach. The CATI package delivered by Médecins Sans Frontières’ (MSF) will incorporate key transmission-reducing interventions (including household-level water, sanitation, and hygiene measures, active case-finding, antibiotic chemoprophylaxis, and, single-dose oral cholera vaccination (OCV) ) which aim to rapidly reduce the risk of infection in the household and in the ring around the primary case household.

CATI has been highlighted as a major component of the GTFCC’s global research agenda. Therefore, conducting a rigorous prospective evaluation of the effectiveness of CATI, which includes OCV and explains the pathway to impact, is an important and timely question for outbreak control.