Case-area targeted preventive interventions to interrupt cholera transmission: Current implementation practices and lessons learned.

BACKGROUND: Cholera is a major cause of mortality and morbidity in low-resource and humanitarian settings. It is transmitted by fecal-oral route, and the infection risk is higher to those living in and near cholera cases. Rapid identification of cholera cases and implementation of measures to prevent subsequent transmission around cases may be an efficient strategy to reduce the size and scale of cholera outbreaks. METHODOLOGY/PRINCIPLE
FINDINGS: We investigated implementation of cholera case-area targeted interventions (CATIs) using systematic reviews and case studies. We identified 11 peer-reviewed and eight grey literature articles documenting CATIs and completed 30 key informant interviews in case studies in Democratic Republic of Congo, Haiti, Yemen, and Zimbabwe. We documented 15 outbreaks in 12 countries where CATIs were used. The team composition and the interventions varied, with water, sanitation, and hygiene interventions implemented more commonly than those of health. Alert systems triggering interventions were diverse ranging from suspected cholera cases to culture confirmed cases. Selection of high-risk households around the case household was inconsistent and ranged from only one case to approximately 100 surrounding households with different methods of selecting them. Coordination among actors and integration between sectors were consistently reported as challenging. Delays in sharing case information impeded rapid implementation of this approach, while evaluation of the effectiveness of interventions varied.
CONCLUSIONS/SIGNIFICANCE: CATIs appear effective in reducing cholera outbreaks, but there is limited and context specific evidence of their effectiveness in reducing the incidence of cholera cases and lack of guidance for their consistent implementation. We propose to 1) use uniform cholera case definitions considering a local capacity to trigger alert; 2) evaluate the effectiveness of individual or sets of interventions to interrupt cholera, and establish a set of evidence-based interventions; 3) establish criteria to select high-risk households; and 4) improve coordination and data sharing amongst actors and facilitate integration among sectors to strengthen CATI approaches in cholera outbreaks.

Introduction

Cholera remains a significant cause of mortality and morbidity, particularly in low-resource, fragile, and humanitarian settings.[1,2] Cholera, an acute bacterial diarrhea, is transmitted by the fecal-oral route and can be prevented with access to safe water, improved sanitation, and protective hygiene practices.[3] Because of both person-to-person and environmental transmission pathways, the risk of cholera infection is higher to those living in or near the case household.[4,5] To interrupt cholera transmission in high-risk environments, preventive water, sanitation, and hygiene (WASH), health, and surveillance interventions are implemented via various delivery models. One approach is termed case-area targeted interventions (CATI), which are spatially and temporally focused and intended to be delivered to the case household and immediate neighbors as soon as possible after case identification. CATIs are often implemented through rapid intervention mechanisms in response to an increase in cholera cases in a given area and are intended to contain cholera outbreaks and are aligned with recommendations in Ending Cholera–A Global Roadmap to 2030.[3] While CATIs are used to interrupt cholera outbreaks, differing implementation practices can affect effectiveness including surveillance mechanisms to trigger a CATI, included interventions, methods of determining coverage area, timeliness, and coordination between the implementing actors.

To comprehensively study the CATI implementation process in different settings, we employed a mixed-methods design including reviews of peer-reviewed and grey literature and retrospective case studies where the CATI approach was utilized to control cholera. As the terms CATI and Rapid Response Teams (RRT) were interchangeably used, and at the time CATI approaches were used, but the term itself was not used, we used a broad definition of CATI to examine the evidence: cholera case targeted interventions to interrupt transmission of the disease at the household and/or community level. This flexible definition allowed us to capture evidence of CATIs irrespective of implementation mechanism by the CATI team visiting case households or case and neighboring households) and included interventions (e.g. health, WASH, surveillance). RRT articles that did not employ cholera case targeted response teams or cholera case targeted interventions were not included in this review. In this manuscript, the varied CATI implementation processes were reviewed, and lessons learned presented about context and other implementation factors that affect cholera responses.

Methods

A mixed-methods approach to study CATI implementation was employed, including: 1) reviews of peer-reviewed journal publications and grey literature published between January 2009 and November 2019; and 2) four retrospective case studies of cholera outbreaks in the Democratic Republic of the Congo (DRC) (2017–2020), Haiti (2010–2019), Yemen (2016–2020), and Zimbabwe(2018–2019).

Literature review

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines were used to guide the review.[6] A systematic search of grey and peer-reviewed literature was conducted using a combination of controlled vocabulary and keywords for cholera and rapid response interventions (S1 Table).

The search was limited to publications between January 2009 and November 2019; English language publications were included in both searches, in addition to French and Spanish publications in the grey literature search. The grey literature search used key word searches as well as review of various organizational websites including organizations involved in implementing and funding cholera responses and technical and coordinating bodies. In addition, key documents already known to the authors, including those identified by the READY Initiative,[7]. and forward citation tracking were used to ensure the review was as inclusive as possible.

The screening process for peer-reviewed literature was managed using Covidence software.[8] Titles and abstracts were independently screened by two reviewers; in cases of disagreement, a third reviewer was used as a tiebreaker. Eligibility of full texts were assessed by a single reviewer, and if excluded, the reason recorded. For inclusion, articles had to include primary data or be a systematic review and discuss cholera rapid response intervention(s). Grey literature documents were screened by one reviewer and classified as primary (evaluation reports, after action reviews, and case study reports) or secondary (website posts or blogs in which an organization provided a project update). Primary documents were advanced to full data extraction, while secondary documents were only used to map outbreaks.

Both the included peer and grey literature were categorized as reporting on CATI or other rapid response interventions and only CATI interventions were included in this review. Data extraction used a Microsoft Excel template with fields organized under the following categories: outbreak information, rapid response activation, team composition and equipment/supplies, activities implemented, cross-sectoral integration, coordination, data collected, performance/results, and challenges/limitations. Following initial data extraction key articles and documents were re-reviewed and additional data extracted around particular themes during results synthesis.

Case studies

Retrospective case studies were used to investigate CATI implementation in DRC (2017–2020), Haiti (2010–2019), Yemen (2016–2020), and Zimbabwe (2018–2019) where the approach was implemented to control cholera outbreaks. Locations were selected in consultation with a strategic advisory group that included members from United Nations Children’s Fund (UNICEF), World Health Organization (WHO), and United States Agency for International Development. Personal contacts, referrals, and snowball sampling were used to identify potential key informants; the DRC, Haiti, and Yemen case studies had eight to nine key informants, whilst Zimbabwe had four.

A semi-structured interview guide was developed that included outbreak background; decision-making; response actors; flow of information; interventions; coordination and integration of WASH, health, and surveillance activities; change in interventions over time; challenges; and lessons learned. The interviews lasted approximately one hour, and follow-up interviews/correspondence were undertaken as needed; participants were also requested to share relevant documentation (DRC = 8, Haiti = 6, Yemen = 0, and Zimbabwe = 1). After completing interviews, results were compiled by topic and country-level reports prepared; drafts were shared with key informants and feedback incorporated as appropriate in final versions. A non-human subject’s research determination was received from the Johns Hopkins Bloomberg School of Public Health Institutional Review Board for the case study component.

Results

Results from literature review and case studies were synthesized to prepare a comprehensive description of the CATI implementation process and present common implementation challenges. In the systematic review, 1,281 peer-reviewed articles were identified, and 16 peer-reviewed articles were ultimately retained, of which 11 reported on CATIs (10 from direct search result and one from forward citation tracking) and five on other rapid response interventions as outlined in the PRISMA diagram (Fig 1). In the grey literature search, 101 documents were identified and 57 were classified as primary documents. Cholera rapid response interventions were described in 29 grey literatures documents and eight reported on or mentioned CATI implementation. Additionally, one document was included during the peer-review process following one of the reviewer’s suggestion. The combined peer-reviewed and grey literature searches yielded 74 documents that were included in the review, of which 20 specifically documented CATIs. A total of 30 key informants from UN agencies (47% of the respondents), non-governmental organizations (NGOs) (23%), government (20%), and academics (10%) involved with the CATI implementation were interviewed between July and October 2020.

Fig 1

PRISMA flow diagram.

Outbreaks

A total of 15 outbreaks of varying durations in 12 countries were identified, including four from DRC,[9] two from Zimbabwe,[10] and one each from Cameroon,[11] Kenya,[12] Nigeria,[13] Sierra Leone,[14,15] Guinea,[15] South Sudan,[16] Yemen,[10,13,17-21] Haiti,[10,13,22-24] Bangladesh,[25,26] Nepal (Table 1).[27]

Table 1

Included cholera outbreak locations and reporting dates.

	Peer-reviewed*	Grey literature*	Case study*
African Region
DRC		Eastern Provinces (2017)[9]	Four outbreaks (2017–2020)
Cameroon	Douala (2004)[11]
Guinea	National (2012)[15]
Kenya	Nyanza Province (2008)[12]
Nigeria		National (2017–2018)[13]
Sierra Leone		National (2012)[14,15]
South Sudan	Juba (2015)[16]	National (2017–2018)[13] †
Zimbabwe		National (2008–2009),[28] Harare (2018–2019)[10]	Harare (2018–2019)
Eastern Mediterranean Region
Yemen	National (2016–2018),[17] Hodeidah (2016–2017)[18]	National[10,13,17,19,21,29]	National (2016–2020)
Region of the Americas
Haiti	National (2013–2017),[23] Centre (2015–2017),[22] Port au Prince (2010–2011)[24]	National[10,13]	National (2010–2019)
South-East Asia Region
Bangladesh	Dhaka (2013–2014)[25,26]
Nepal	Kathmandu Valley (2016)[27]

*Reporting duration is not the same as outbreak duration.

† The report included description of cholera specific RRT, however, they have not responded to a cholera outbreak.

Most literature documents focused on a single outbreak with only two addressing multiple outbreaks. Within our literature search period, CATIs were first reported in the 2004 Douala, Cameroon outbreak and use continued through 2020 in the ongoing cholera outbreaks DRC and Yemen case studies.[11,30] The size of outbreaks where CATIs were employed varied widely, ranging from 169 confirmed cases in Kathmandu Valley, Nepal to more than 2.3 million suspected cases in Yemen.[27,31] Additionally, outbreak duration ranged from one month in Juba, South Sudan to over eight years in Haiti;[16] the entire duration and extent of outbreaks was not consistently reported. In Bangladesh, Cameroon, DRC (some of the outbreaks), Kenya, Sierra Leone, and Zimbabwe, cholera occurred in the absence of a humanitarian emergency, whereas in DRC, Nigeria, South Sudan, and Yemen conflict was ongoing and outbreaks in Haiti and Nepal occurred several months after the earthquakes during earthquake recovery. CATIs were implemented in urban settings in Bangladesh, Cameroon, Guinea, and Nepal, and rural settings in Kenya; in the other countries, epidemics occurred in both settings.

Interventions

CATIs typically included a combination of preventive WASH, health, and surveillance activities to interrupt cholera transmission. We observed that interventions varied across the outbreaks and temporally within the same outbreak, particularly in multi-year outbreaks (Table 2).

Table 2

List of WASH, health, and surveillance interventions implemented in CATIs.

	DR Congo	Haiti	Yemen	Zimbabwe	Bangladesh	Nepal	Cameroon	Kenya	Sierra Leone	South Sudan	Nigeria	Guinea
Household Interventions
WASH
Household disinfection	X	X	X	X			X					X
Latrine disinfection	X	X	X	X			X
Hygiene education session	X	X	X	X	X	X	X	X	X	X	X	X
Chlorine tablet distribution	X	X	X	X	X	X		X		X		X
Water storage container distribution	X	X	X	X	X	X
Water collection container/jerrican	X		X	X
Water quality testing	X	X	X	X		X
Hygiene promotion flyer		X			X	X
Soap distribution	X	X	X	X		X		X		X		X
Health
Antibiotic chemoprophylaxis	X	X					X
Oral rehydration salt distribution	X	X	X									X
Oral cholera vaccine										X
Surveillance
Case identification at treatment center	X	X	X	X								X
Active case finding		X	X			X
Referrals to CTC		X	X	X								X
Community and health facility-based interventions
WASH
Health promotion	X	X	X	X		X			X			X
Point-of-use disinfection product distribution				X
Bucket chlorination	X	X
Chlorination at water point	X	X							X			X
Latrine construction in public areas	X										X
Water point rehabilitation	X	X									X	X
Safe burials		X										X
Community volunteer training		X
Health
Antibiotic chemoprophylaxis		X	X	X
ORT* through mobile clinics		X	X	X					X

Note: Interventions are reported as implemented in a country if conducted at least in one outbreak, or for a period of time in the case of long outbreak). Therefore, variability within country over space and time is not captured in this table.

* ORT = oral rehydration therapy; CTC = cholera treatment center

From the peer-reviewed literature, CATIs either encompassed WASH only (n = 6) or both health and WASH activities (n = 5); there were no CATI teams delivering health interventions alone. All WASH CATIs included water disinfection at the household or community level and/or hygiene education along with distribution of water treatment supplies. Other interventions provided in only some locations included safe water storage (Haiti and Bangladesh); soap provision (Haiti, Bangladesh, South Sudan, Kenya); and oral rehydration salts (Haiti). Health interventions delivered by CATI teams included antibiotic chemoprophylaxis for case households in Haiti (doxycycline for non-pregnant adults, though delivery was inconsistent) and for both case and adjacent households in Cameroon (doxycycline for the general population and amoxicillin for children and pregnant/lactating women). Oral cholera vaccine (OCV) was delivered as part of CATIs in South Sudan, where there was surplus stock from a previous vaccination campaign. Grey literature contained relatively little information about specific interventions. All documents reported on WASH interventions, including household disinfection, hygiene education, water chlorination, water quality testing, sanitation assessment, and waste management. Health interventions were described in four documents, including antibiotic chemoprophylaxis distribution in Haiti, health education in Sierra Leone and Yemen, health counseling and referrals in Yemen, and case investigation. Variation in CATI implementation was also observed in the four case study countries where WASH interventions were reported in all locations and health and surveillance interventions were reported in DRC, Haiti, and Yemen but not Zimbabwe.

Team composition

CATI team composition varied across outbreaks and within the same outbreak in Haiti and Yemen. The teams were comprised of staff from NGOs, governments, and community volunteers. Teams were most commonly comprised of four to seven members with a mixed set of skills, including WASH, health/nursing, hygiene promotion, surveillance, and drivers. Teams with only WASH staff were reported in case study interviews in Yemen, Zimbabwe, and during the early response in Haiti;[23] health CATI teams were reported in Yemen.[30] The skill sets included depended upon the type of interventions delivered. For instance, a nurse accompanied CATI teams in Haiti to administer antibiotics and vaccinators were CATI members in South Sudan to provide OCV. Additionally, the Haiti case study showed that before establishing the mixed teams, comprised of health and WASH staff, the NGO WASH teams would often include a nurse to accompany them.

Implementation

CATI implementation was a multi-faceted process involving numerous steps and multiple organizations typically beginning with an alert of a suspected/confirmed cholera case(s) (Fig 2). In Nepal,[27] Bangladesh,[26] and South Sudan,[16] CATIs were implemented in response to rapid diagnostic test (RDT) or culture confirmed positive cases; both were used at different times in Yemen. [17]However, in Cameroon,[11] DRC,[10] and Zimbabwe,[32] CATIs were implemented for suspected cases that presented for care at a cholera treatment center. RDT was used in Haiti during 2013 and discontinued afterward because of delays to obtain results and reliability concerns. Specific CATI activation alert systems were not reported in Nigeria, Kenya, and Sierra Leone. The common source of information to generate an alert was the shared line list from the health treatment facility.[13,20-23] Additionally, suspected cases reported by community health workers, media reports, and other informal surveillance mechanisms also triggered alerts in DRC,[9] Haiti, and Yemen.[13] The time between the identification of a suspected case and the trigger of an alert was critical for rapid implementation of CATIs and community level alert systems were used to prioritize response.[23] Delays in sharing case information with CATI teams were frequently reported.[13,20-23] For instance, in Yemen, cholera case line lists had to be approved by central authorities before being shared[13,17] and in Haiti, case information was shared only on a weekly basis during the initial response which delayed the CATI activation. In Nepal, delays occurred as CATIs were implemented only after receiving a positive stool culture, which took an average of 3.9 days following hospital admission.[27] In Bangladesh, DRC, and Haiti, after establishing daily line lists access, and in South Sudan and Zimbabwe, the CATI teams were able to respond more quickly than in the aforementioned locations[16,22,25,26] as they had rapid access to the case information. In instances when the number of suspect/confirmed cases exceeded the capacity of the CATI teams, a set of prioritization criteria were used, including number of cases from one location (Haiti, Zimbabwe), areas without recent cases (Haiti, Zimbabwe), if a case was RDT/culture positive (Yemen), and case severity status/death (Haiti). [13,22,23]

Fig 2

Common steps in the CATI implementation process.

When CATI teams had difficultly locating case households, assistance was often sought from community members. The selection process and the number of surrounding households to be included in the CATI varied greatly across outbreaks, and depended on the density and arrangement of houses, implementation strategy, capacity, and resource availability. For instance, in Bangladesh and South Sudan, only household contacts received the interventions whereas the early WASH CATIs in Yemen included about 100 households and in the later Yemen response and Haiti a 50–100 meter radius for household selection was reported;[13] in the Zimbabwe case study, the entire apartment level was included when responding in urban settings.[30] As mentioned earlier, a combination of preventive WASH, health, and surveillance activities are used to interrupt cholera transmission, with the same or different interventions provided to case and neighboring households. For example, in Haiti antibiotic chemoprophylaxis was only administered to household contacts;[22] and latrine disinfection was conducted only at case households in Haiti, Zimbabwe, and in Cameroon.[11] In addition to case- and neighbor-targeted household-specific interventions, CATIs in DRC,[9] Sierra Leone and Guinea,[15] Yemen,[18] and Zimbabwe (case study) included community-level activities such as water point repair, WASH risk factor assessment, testing of communal water sources, construction of communal sanitation facilities, and awareness raising.

Implementation challenges

Several common difficulties were identified including: 1) implementation in logistically challenging contexts[13,17,23,27] and poor access to targeted populations;[9,12,16] 2) cholera cases exceeding the limited capacity to implement all CATIs;[10,13,22,27] 3) coordination among actors and integration of WASH, health, and surveillance activities;[10,13,15,19] 4) timely access to case information to rapidly implement CATI;[10,23] and 5) limited funding to adequately implement the interventions.[9] The grey literature review and all four case studies reported coordination between WASH and health actors as hard to achieve, at times resulting in duplication of activities by the WASH and health CATI teams. Aspects such as access to case data as well as coordination among partners gradually improved over time, which enhanced response timeliness in Haiti[23] as well as in Yemen.[30]

Evaluation measures

Multiple measures were used to evaluate different aspects of CATI performance including: 1) timeliness (e.g. time between case presentation/confirmation and CATI start or time between outbreak declaration/index case confirmation and start of the first CATI); 2) coverage; 3) cost of the intervention; 4) household’s knowledge and practice of measures aiming to interrupt cholera transmission; 5) outputs (items distributed during intervention); and 6) impact (incidence of cases). While the Bangladesh and Haiti studies reported about the complete CATI approach, none of the documents reviewed evaluated the effect of individual interventions (e.g. only chlorine tablet distribution or only awareness session) in reducing the number of new cases or interrupting the cholera transmission pathways.

Timeliness of intervention delivery was reported in four peer-reviewed[16,22,23,27] and two grey literature documents.[10,13] The elapsed time between case admission and the start of CATIs varied across outbreaks, and usually CATI teams based at cholera treatment facilities were able to initiate interventions faster than separate organizations not based in the facilities. In Cameroon,[11] DRC,[33] Haiti,[24] and Bangladesh[26] the interventions started at case admission or discharge where antibiotic prophylaxis and hygiene kits were distributed to the case’s household. In South Sudan, Nepal, and Zimbabwe, interventions at the case household began between one and four days after case identification. In Nepal, delivery started on average 1.7 days after culture result and 3.9 days after admission,[27] and in Zimbabwe, the intervention started within 48 hours of the presentation of a suspected case at the treatment center,[9] and in South Sudan, CATIs occurred 1–6 days after the suspected case was presented at the health facility with an average delay of 3.4 days.[16]

Intervention coverage was reported in 10 peer-reviewed articles and four grey literature reports, though different indicators were used. For example, 51% cases in South Sudan[16] and 92% in DRC received interventions;[9] whereas 17% and 30% of households and communities, respectively, received interventions in Nepal.[27] In Haiti, coverage was reported in terms of responded cholera alerts (49%),[23] identified outbreaks responded (53% in Centre department)[22] and cases admitted to cholera treatment centers in Carrefour Haiti (65%).[24] The two Bangladesh research studies reported 100% coverage of the admitted cases, which is not typical in most outbreak responses. One peer-reviewed article and two grey literature documents reported CATI cost information using different metrics. In Sierra Leone the per capita cost was US$2.32 (and was compared with a previous outbreak response in Zimbabwe where the cost was US$2.85)[14] and in Bangladesh the cost was US$45.5 per household.[26] UNICEF’s global review of cholera rapid response teams reported monthly per team costs of $10,234 in Haiti and $2,400 (urban) to $3,000 (rural) in Yemen.[13]

A range of different effectiveness measures were reported in peer-reviewed articles. Behavior change measures, such as knowledge of cholera prevention, treatment, and hygiene practices;[12,25] and use of appropriate hygiene practices and/or items distributed in hygiene kits[26,27] were commonly reported. Only the Bangladesh study and the Haiti Central department study reported evaluated differences in cholera incidence between the households that received a timely CATI and those that did not.[22,26] For instance, in Kenya, a significant difference in respondent-reported water treatment as compared to controls (56% vs 37%, p<0.001) was reported, however, cholera knowledge (7/7 indicators) and behaviors (5/6 indicators) were similar between the two groups.[12] In Bangladesh, as compared to a control group, the intervention group had significantly higher odds of handwashing (odds ratio = 14.7, CI: 8.3–25.9); was more likely to have soap present in cooking areas (98% vs. 15%, p<0.001) and latrine areas (98% vs 13%, p< 0.0001); stored drinking water was more likely to have adequate concentrations of free chlorine (94% vs 1%, p<0.0001) and less likely to be contaminated with V. Cholerae (0% vs 6%, p = 0.06); and there was a 47% lower incidence of V. cholerae infection (symptomatic and asymptomatic) in intervention group case contacts during the intervention period.[25,26] In Nepal, 30.2% of surveyed households reported hearing awareness messaging via community campaigns and 16.5% reported home visit with various types of health education messages and supplies. Individuals that received home visits were more likely to have heard of cholera (adjusted odds ratio = 2.38, p<0.05).[27] In Haiti, estimates of the effectiveness of national CATIs indicated that timely response (≤1 day after outbreak identification compared to a delayed response of >7 days) reduced new cases by 76% (CI: 59–86%) and outbreak duration by 61% (CI: 41–75%) whereas an intense response (≥1 complete CATI per week compared to a weaker response of ≤0.25 complete CATIs weekly) reduced new cases by 59% (CI: 11–81%) and outbreak duration by 73% (CI: 49–86%).[22]

Discussion

Our mixed-methods research synthesized the CATI implementation approach from 15 different outbreaks in 12 countries. We noted many ambiguities and inconsistencies regarding RRTs and CATIs in terms of definitions, interventions combinations and implementation strategies, integration, coordination, data sharing, and reporting across outbreaks. CATI approaches were used to reduce cholera transmission in different settings (e.g., urban, rural) and outbreaks of differing scale and duration. The CATI approach was used as a nationwide strategy in Haiti and Yemen, and was incorporated into the national cholera control strategy in DRC,[34] South Sudan,[35] and Nigeria.[13]

The cholera case definition (i.e. suspected, RDT positive, and culture positive) to initiate a CATI implementation varied across outbreaks based on contextual factors such as laboratory and procurement capacity, and size of the outbreak. The use of an alert system with specific mechanisms to trigger a CATI response was described in eight countries. While the specific mechanisms varied across outbreaks, the alert systems facilitated a rapid response. The use of a national case definition that considers existing surveillance and laboratory testing capacities, and links those with an alert system to trigger CATI response can strengthen early detection and quick response to contain outbreaks. The Global Task Force on Cholera Control (GTFCC) has proposed suspected and confirmed case definitions in outbreak and non-outbreak settings that can be used in the absence of national case definitions to trigger a CATI response.[3]

CATIs typically included a varied set of WASH, health, and surveillance interventions that were implemented at the case and/or neighboring households, and in affected communities (Table 2); however, the interventions were not consistently implemented across outbreaks. WASH activities such as the distribution of water disinfection supplies, water storage containers, and hygiene education predominated. While all CATIs included surveillance activities, in Bangladesh, Nepal, Kenya, Sierra Leone, and Zimbabwe health interventions at the household level were not provided. However, with the exception of the Bangladesh study, which reported three months of piloting and previous formative research to design the intentions, selection of interventions was not reported. [26] Establishing a set of specific and standardized WASH, health, and surveillance interventions according to context and that are considered to be effective to interrupt cholera transmission would support implementers in selecting activities that are relevant to the outbreak setting.

The scientific evidence of the effectiveness of CATIs in reducing cholera transmission is limited and context specific. A recent scoping review reported evidence of some interventions CATI activities such as antibiotic chemoprophylaxis, single-dose OCV, intensive hygiene promotion, and point-of-use water treatment to rapidly limit cholera transmission in the household and its high-risk radius.[36] Several measures of CATI effectiveness were identified in our study, including timeliness, completeness, coverage, and implementation cost. While these criteria provided information on strength of CATIs implementation, they did not measure impact in terms of reduced incidence of cholera. The exception were studies in Bangladesh, which reported cholera infections in control and intervention groups, and Haiti which reported the relationship between response speed and intensity and outcomes of case reduction and outbreak duration.[22,26] Additional research on the potential of CATIs to reduce cholera case incidence in different transmission settings and on the contribution of the individual interventions to case reduction would be valuable. Yet, the complexity of measuring and attributing effectiveness to one approach or one intervention during an outbreak in general and even more so in humanitarian settings should be recognized. Challenges include but are not limited to the identification of a control group; the need to adapt the response to the context, which makes comparisons difficult; delays in how rapidly research can start; and concerns around sample sizes and power of the studies. One potential alternative which would expand the breadth of evidence is strengthen monitoring systems of responding organizations to be able to better document the response, and to work towards the adoption of standardized indicators to enable comparison of evidence across outbreaks. Additionally, partnership between research institutions and emergency responders to systematically study the different components of the CATI implementation can also improve the reliability and generalizability of the evidence.

The selection criteria for households included in CATIs varied between including only case households to approximately 100 surrounding households. A recent review reported a 100m radius around the case as appropriate but proposed further study of implementation feasibility in urban settings.[36] Additionally, a study in Kinshasa, DRC reported the use of a targeted grid approach delivering WASH interventions to contain the outbreak in urban settings.[37] The feasibility of using a certain number of households as compared to a ring may depend on settings. For instance, in densely populated areas and multistoried buildings, using number of households to determine CATI coverage is easier to implement than a distance radius-based approach. While establishing fixed numbers of households or a radius is difficult considering the heterogeneity in dwelling arrangements in urban and rural settings, evidence-based guidance for neighbor household selection considering different settings could facilitate CATI delivery and potentially increase CATI effectiveness.

This review aimed to investigate the integration of WASH, health, and surveillance activities in CATI, both in terms of level of integration as well as the possible positive effects on the overall performance of CATI. Integration was defined in terms of conducting activities from the three sectors and including different technical profiles in the same team. While in few instances only WASH interventions were delivered, we found that in most of the cases, CATI were integrated, and included WASH, health, and surveillance activities. Considering the time and resources needed to implement CATIs, it may seem more efficient in outbreak settings to integrate the interventions so that they can be implemented by one CATI team. However, the evidence on the effectiveness of integrated versus individual WASH and health CATIs is mixed. Further research on the integration of health interventions in CATIs is of strategic importance and should be further explored due to their potential to limit transmission (as demonstrated in non-CATI contexts).[36]

Operational challenges to coordinate between the actors were frequently reported, which can reduce the effectiveness of a joint intervention. CATI implementation often involved multiple actors (e.g. government, UN, NGOs) and both WASH and health sectors. Functioning coordination between the actors and sectors can improve implementation. For instance, direct access to cholera patient line lists from treatment facilities was limited and delayed in multiple responses. The usefulness of CATIs heavily relies on early detection of an outbreak and rapid response to interrupt person-to-person and environmental transmission.[4] Therefore, it is imperative for all involved actors (authorities, health facilities, and CATI implementers) to establish an effective coordination mechanism that facilitates rapid access to cholera case information for CATI teams.

Our peer-reviewed and grey literature search was limited to the past decade and peer-reviewed articles were limited to the English language. This may have reduced our capacity to identify relevant CATI literature that was published earlier; however, inclusions of documents identified via forward citation tracking, irrespective of publication date, mitigates this concern. While extensive, the grey literature did not provide the level of detail reported in the peer reviewed literature. Therefore, certain elements related to CATI implementation may not have been fully reported, especially as none of the documents focused solely on CATI. Our case studies included CATI experiences from four countries; inclusion of additional key informants, in particular government representatives, for case study countries and expanding the number of countries and contexts could have strengthened our findings and provided additional perspectives about the implementation process. Majority of the countries in the study were deemed to be fragile by the World Bank. [38] While studying the implications of countries fragility on the effectiveness of CATIs were beyond the scope of the manuscript, readers should consider this caveat when interpreting the results.

To better characterize the CATI approach and differentiate it from other response modalities, we suggest defining CATI as cholera case targeted interventions to interrupt transmission of the disease at the household and/or community level. Future studies and operational reports should provide precise intervention descriptions to differentiate CATI more easily from other rapid response mechanisms that are not focused on the individual case.

Literature search strategy summary.

(DOCX)

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3 Sep 2021

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Emily Gurley

Deputy Editor

PLOS Neglected Tropical Diseases

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Are the objectives of the study clearly articulated with a clear testable hypothesis stated? YES

-Is the study design appropriate to address the stated objectives? YES

-Is the population clearly described and appropriate for the hypothesis being tested? NO. Inclusion of studies on Rapid Response Team as equivalent to CATI was not appropriate. YES

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested? YES

-Were correct statistical analysis used to support conclusions? YES

-Are there concerns about ethical or regulatory requirements being met? YES

Reviewer #2: - Yes, the objectives of the study are clearly articulated

- Yes, the study design is appropriate

- The analyzed literature used for this study should better be described, and choice of analyzed papers and grey literature better explained (see comments bellow)

- Some key articles and reports are missing in the review (see comments bellow)

This study includes no statistics and present no experiments

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Does the analysis presented match the analysis plan? YES

-Are the results clearly and completely presented? YES

-Are the figures (Tables, Images) of sufficient quality for clarity? NO, Table need revision

Reviewer #2: - Characteristics of selected articles and reports should better be presented (see comments bellow)

- Part of the results should better be presented (see comments bellow)

- yes, figures are of sufficient quality

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Are the conclusions supported by the data presented? YES

-Are the limitations of analysis clearly described? YES

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study? YES

-Is public health relevance addressed? YES

Reviewer #2: - Part of the conclusions is not supported by the data presented (see general comments bellow)

- Limitations of the study are not addressed in the Discussion

- Yes, authors discuss how these data can be helpful, and public relevance is addressed

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: For the purpose of reviewing the contents of the manuscript, it will be more easier for the reviewers if the authors included line numbering on each of the sentences.

Reviewer #2: Abstract

- I recommend against citing the first reference from Ali et al. even if this paper has been widely cited. Indeed, it provides doubtful estimates of the global burden of cholera based on unreliable extrapolations from only 3 limited cross-sectional cholera prevalence surveys ! I suggest authors cite yearly WHO records even though they are likely underestimates.

- In their conclusion, authors write that CATI « are believed to be effective in reducing cholera outbreaks, but there is

insufficient evidence in their effectiveness ». I do not agree with this statement as

Authors Summary:

- in « Evaluation measures varied, however, few evaluated cholera transmission reduction » : remove « however » ?

Introduction:

- Authors should rather cite the number of cholera suspected cases recorded by WHO rather than this

Methods

- Rather than citing the Cochrane reference [5], authors could directly cite the PRISMA 2020 statement of the EQUATOR Network (https://www.equator-network.org/reporting-guidelines/prisma/)

- The PRISMA checklist is missing : https://www.equator-network.org/reporting-guidelines/prisma/

Results

- The process of outbreak selection is not clear to me. Did authors only select outbreaks they found CATI reports on ? Please clarify

- Similarly, I do not understand whether the references cited in Table 1 only intend to describe the listed epidemics, or the CATI implemented strategies. In the latter case, and for example for Haiti, Table 1 could directly include ref [21] and [27]

- For RDC, authors should include the report from Bompangue et al 2020 (https://doi.org/10.1186/s12879-020-4916-0).

- For Sierra Leone and Guinea in 2012, authors should include this report: https://plateformecholera.info/attachments/article/394/5-GCSL_2012_SLL_ACF_001.pdf

- A first description of cholera rapid response teams was published in 1971 by Voelkel (http://www.ncbi.nlm.nih.gov/pubmed/5576843)

- A CATI strategy was also implemented in 1998-1999 in Comoros with support of the Medecins du Monde NGO (https://devsante.org/articles/l-epidemie-de-cholera-aux-comores)

- Page 9, ref [14] was published in 2017 and does not describe 2013-2019 CATI strategy in Haiti. Authors could rather cite ref [21] or [27] , or a more recent letter (https://doi.org/10.1016/s2214-109x(20)30430-7).

- Please note that the study [20] describes a limited strategy implemented in Port-au-Prince in 2010-2011, which was not part of the nationwide CATI strategy launched in 2013. Further citations of this ref [20] are thus often ambiguous.

- page 10: please note that although the Haiti epidemic occurred 10 months after the earthquake, the disease was imported by a UN peace keeping battalion in a rural area (Mirebalais commune) and exploded 80km downstream of a highly likely contaminated river in a rice field plain, both of which had not been affected by the earthquake at all. Please modify the sentence as it wrongly suggests that cholera may have been triggered by the earthquake.

- Similarly, are authors sure that the 2016 cholera epidemic in Nepal was influenced by the April 2015 earthquake ?

- page 13: there was no vaccinator in the CATI teams in Haiti as no OCV was administered (Table 2). Please add « respectively »

- page 13: please explain what were the mixed teams in Haiti

- page 14 : as described in ref [27], a specific weekly alert system at the communal level was initiated in Haiti in 2013 in order to help prioritize and monitor CATIs. This system preceded the generalization of case line list sharing. Authors should add this information.

- page 14: in Haiti, a nation-wide use of RDT was implemented from 2013 in order to help prioritizing CATIs. This strategy was later abandoned as RDT results were not readily available for RRTs and their results proved unreliable.

- page 14: results from stool culture were also used for CATI implementation in Haiti during the last years of the strategy: as part of the elimination process, RRTs were asked to implement a second CATI in case of positive culture

- page 15: please add references to « 4)timely access to case information to rapidly implement CATI ». For instance ref [27] was cited for the same topic on page 14.

- page 17: in Haiti, coverage was also reported as the proportion of responded cholera alerts (see ref [27] : 49% between July 2013 and June 2017).

- page 17: the UNICEF’s global review of cholera rapid response teams reports a monthly cost of $10,234 per team in Haiti (not $180!), and $2,400-3,000 in Yemen (not $1,776). Please check and correct.

- in « differences in cholera incidence between those that received a timely CATI », the term « those » is imprecise.

- page 16-18: I recommend to present behavior change results (that can be considered as CATI outcomes), before effectiveness and impact results. The global « theory of change » scheme could be used to better arrange this part of the review (see for instance http://fic.tufts.edu/assets/WASH-Systematic-Review.pdf)

Discussion

- page 19 : I do not understand the meaning of « which reported formative research to design the intentions ». I do not get the specificities of this very good study [23] on that aspect.

- page 22: considering the proposed definition of CATI, do authors consider that interventions targeting a cholera cluster (e.g. a neighborhood, a locality or even a commune) could be considered as a CATI ?

- no paragraph on the limitations of the study

References :

- ref [8]: URL does not seem to work

- ref [18]: URL does not work

- ref [19]: URL does not work

- ref [20]: URL does not work

- ref [25]: URL does not work

- ref [28]: URL does not work

- ref [31]: URL does not work

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Reviewers’ report for the manuscript PNTD-D-21-00779, Case-area targeted preventive interventions to interrupt cholera transmission: current implementation practices and lessons learned

General comment

This is well written manuscript on a valuable study that synthesizes available literature on CATI as a strategy for prevention and control of cholera outbreaks. Most importantly, the authors investigated and described weaknesses with previous implementation of CATI and give evidence based recommendation to strengthen CATI intervention implementation. The study has the potential to increase scientific knowledge on CATI. However, there are still few important weaknesses in the content that need to addressed and are essential to improve clarity of the message, remove ambiguity in the understanding by the readers and enhance the quality of the contents therein.

The major flaws with this manuscript are in the categorization and inclusion of the studies using the term RRT as synonymous to CATI interventions. Yet CATI and RRT are two distinct terms that are used differently by the cholera outbreak responders/ stakeholders. Also, given that seven out of eleven countries in this paper (table 2.) were from sub-Saharan Africa where cholera prevention is guided by the implementation of Integrated Disease Surveillance and Response (World Health Organization. Technical Guidelines for Integrated Disease Surveillance and Response in the WHO African Region THIRD EDITION. 2019. Available: https://apps.who.int/iris/bitstream/handle/10665/325015/WHO-AF-WHE-CPI-05.2019-eng.pdf) use of RRT as synonymous to CATI has to be very cautious. According to IDSR/WHO, A Rapid Response Team (RRT) is composed of experts who take the lead in conducting the initial investigation of reported and suspected cases or outbreaks so as to confirm the nature of the event under investigation. It is also the responsibility of the RRT to initiate the preliminary control/containment measures needed to prevent further spread of the disease. The same information is also articulated in the cholera prevention WHO RRT guide (World Health Organization. Guide for Rapid Response Teams (RRTs) for Cholera Outbreak investigation & initial response. 2010. Available: https://plateformecholera.info/attachments/article/672/RRT%20%20cholera%20outbreak%20investigation%20guide.pdf). In summary RRT is constituted by experts and there role is to do the initial investigation and response and can be in place before, during and after the cholera outbreak. While CATI is one of the cholera control strategy that can be used by the RRT to contain/interrupt the outbreak. Therefore, Mustafa et al, should revise manuscript and exclude studies on RRT.

Specific comments

The following comments are related to above concerns.

1. Introduction. Page 4, second paragraph, “As the terms CATI and Rapid Response Teams (RRT) were interchangeably used, and at the time CATI approaches were used, but the term itself was not used, we used a broad definition of CATI to examine the evidence: cholera case targeted interventions to interrupt transmission of the disease at the household and/or community level” according to IDSR/WHO the term CATI and RRT mean different things. This has the potential to confuse the reader who have accessed IDSR/WHO guidelines. The authors will need to revise this section and possibly exclude studies with RRT from the manuscript.

2. Method section. Page 6, second paragraph, “ Both the included peer and grey literature were categorized as reporting on CATI or other rapid response interventions). This statement is related to above on RRT. Furthermore, other rapid response interventions is open to speculation and misinterpretation. Hence, Mustafa et al, will need to revise this section to remove possible confusion of the readers.

3. Result section. Page10, Table 2. The authors use the terms health and surveillance to categorized activities of CATI. However, the activities listed in surveillance can still fit in health. The authors could therefore merge the two under one sub-heading.

4. Discussion. Page 18, first paragraph, “ We noted many ambiguities and inconsistencies regarding RRTs and CATIs in terms of definitions, interventions combinations and implementation strategies, integration, coordination, data sharing, and reporting across outbreaks”. The author appreciates that there were many ambiguities for RRTs and CATIs. However, in the subsequent discussion the authors only focus on CATIs and nothing is given on RRTs. This is yet another important reason for Mustafa et al, to revise the contents of the paper in the introduction and methodology section and focus on CATIs as reflected in the title, abstract, discussion and conclusion of this manuscript.

5. Discussion. Page 20, first paragraph, “The scientific evidence of the effectiveness of CATIs in reducing cholera transmission is limited. A recent scoping review found some evidence that antibiotic chemoprophylaxis, single-dose OCV, intensive hygiene promotion, and point-of-use water treatment to rapidly limit cholera transmission in the household and its high-risk radius”. It is clear what message the authors wanted to share. The first sentence points to lack or limited evidence while the second sentence show that there is evidence for effectiveness. Hence, the authors will need to revise this paragraph.

Other comments

Page 15, paragraph 2, “ Haiti,[20] and Bangladesh[23] the interventions started at case admission or discharge where, for example, antibody prophylaxis and hygiene..” The authors should review the highlighted word and if necessary replace it.

Page 16, some abbreviations such as CTC are not explained. The authors should review the manuscript and ensure that all abbreviations are explained to avoid misinterpretation by the readers.

End

Thank you.

Reviewer #2: In this very interesting mixed-methods study using a review of published peer-reviewed and grey literature, authors address the implementation of case-area targeted interventions against cholera.

This piece of work is important as such cholera control strategy has been implemented in several major cholera epidemic over the past decade.

The manuscript is well written, the amount of aggregated information is important, authors propose highly relevant comments and several valuable recommendations, and they should be acknowledged for this piece of work.

Nevertheless, the manuscript suffers from the absence of several important publications and reports, and from several imprecisions and discrepancies which are listed in my specific comments and should be corrected.

Besides, I do not support one aspect of the overall conclusion of this review, which on several occasions implies that CATI effectiveness has not yet been established and that promotion of CATI would so far only be a matter of expert opinion.

Authors do cite a randomized control trial of hospital-based hygiene and water treatment intervention in Bangladesh [23] which showed that distributing cholera kits in hospital to the family of cholera cases reduced secondary cases. They also cite a quasi-experimental study conducted in Haiti [21], which found that prompt and repeated CATIs were associated with a significant reduction of cholera outbreak duration and cumulative case incidence. Besides, as authors wrote in a recent report of the John Hopkins University about the same subject as the present article (http://hopkinshumanitarianhealth.org/assets/documents/RRT_CaseStudy_Report_2021.pdf), no cholera case has been confirmed in the Haiti since February 2019, which could represent a relevant proof of concept of the CATI approach, as this was implemented as a massive national strategy between 2013 and 2019, with no alternative explanation of cholera disappearance so far. Therefore, they should explain why they do not seem to consider this as as evidence of CATI effectiveness.

Following a modern science-based approach (https://sciencebasedmedicine.org/about-science-based-medicine/), I thus invite authors to consider a less stringent definition of evidence production in such epidemic contexts than the sole randomized control trials. Water disinfection, hand washing, sanitation and so on have for a long time now been shown to prevent fecal-oral diseases such as cholera.

I thus strongly believe that the state of « clinical equipoise » is not present regarding the question of conducting a CATI or not, and all cases should now be targeted. As a matter of fact, many experts, field public health actors as well as political or administrative leaders do consider that randomizing which cholera case family should or should not receive a CATI during cholera epidemics raises serious ethical issues.

Nevertheless, I strongly agree with authors that « The scientific evidence of the effectiveness of CATIs in reducing cholera transmission is limited » (page 20). I can only join them on the fact that « measuring and attributing effectiveness to one approach or one intervention during an outbreak » is highly complex. And I totally agree that « monitoring systems of responding organizations » should be strengthened: this is precisely what was performed in Haiti. Some additional evidence to optimize the composition of the CATI package, or the selection of neighboring households to be targeted is urgently needed, and I imagine that valuable randomized studies could be conducted to answer these questions.

I thus think that authors should modify several sentences using a less ambiguous wording such as :

- conclusion of the abstract: « CATIs are believed to be effective in reducing cholera outbreaks, but there is insufficient evidence in their effectiveness ».

- introduction: « CATI is conceptualized as an efficient way to interrupt cholera outbreaks… »

- Evaluation measures in results: « None of the documents reviewed evaluated the effect of individual interventions in reducing the number of new cases or interrupting the cholera transmission pathways ». This is wrong, as ref [23] demonstrated that distributing cholera kits in hospital to the family of cholera cases reduced secondary cases in Bangladesh, and ref [21] demonstrated that prompt and repeated CATIs were associated with a significant reduction of cholera outbreak duration and cumulative case incidence.

- Similarly within the same sentence « there were no prospective evaluations of CATI’s effectiveness » : ref [23] was a prospective randomized control trial. And ref [21] was a quasi-experimental evaluation of CATI’s effectiveness which could also be considered as « prospective » : although analyses were retrospective and CATIs were not randomized, both the exposition (CATIs) and outcome (cholera suspected cases) were routinely and prospectively recorded.

- Discussion: « … selection of interventions did not appear to be based on evidence of their effectiveness. »

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Reviewer #1: Yes: Godfrey Bwire, MBCHB, MPH, PhD

Reviewer #2: No

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Submitted filename: Reviewer report _ Manuscript PNTD-D-21-00779_ Godfrey Bwire.pdf

Click here for additional data file.

10 Oct 2021

Submitted filename: Response to reviewers Oct 1 2021.docx

Click here for additional data file.

8 Nov 2021

Dear Dr. Spiegel,

Thank you very much for submitting your manuscript "Case-area targeted preventive interventions to interrupt cholera transmission: current implementation practices and lessons learned" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Jade Benjamin-Chung

Guest Editor

PLOS Neglected Tropical Diseases

Emily Gurley

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Are the objectives of the study clearly articulated with a clear testable hypothesis stated? YES

-Is the study design appropriate to address the stated objectives? YES

-Is the population clearly described and appropriate for the hypothesis being tested? NO

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested? YES

-Were correct statistical analysis used to support conclusions? YES

-Are there concerns about ethical or regulatory requirements being met? NA

Reviewer #2: (No Response)

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Does the analysis presented match the analysis plan? YES

-Are the results clearly and completely presented? YES

-Are the figures (Tables, Images) of sufficient quality for clarity? YES

Reviewer #2: (No Response)

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Are the conclusions supported by the data presented? NO. There is selective use of data

-Are the limitations of analysis clearly described? NO

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study? YES

-Is public health relevance addressed? YES

Reviewer #2: (No Response)

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Thank you very much for informing the authors to include the line numberiung. This version was userfrendly to review.

Reviewer #2: (No Response)

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Reviewer’s report

Reviewer: 1

Manuscript No: PNTD-D-21-00779

Manuscript title: Case-area targeted preventive interventions to interrupt cholera transmission: current implementation practices and lessons learned

General comments

The authors have made efforts to address the issues raised with the original manuscript. This revised version is clearer and the study undoubtedly has the potential to streamline and strengthen CATI implementation due to the good recommendations listed by the authors. I applaud the authors for these well thought recommendations. However, in this updated version there are still important issues in the method section that need to be clarified to increase readability and allow for replicability of the study findings by other researchers.

Essential comments

1. Method section. Lines 105-107, “The search was limited to publications between January 2009 and November 2019; English language publications were included in both searches, in addition to French and Spanish publications in the grey literature search.” and lines 96-97, “ A mixed-methods approach to study CATI implementation was employed, including: 1) reviews of peer reviewed journal publications and grey literature published in the past ten years; .

The authors state that the study was limited to ten years however this is approximately 11 years. Furthermore, lines 164, table 1, the authors included studies in Cameroon, Duala, 2004 Reference 11 and in Kenya, Nyanza, 2008, Reference 12. This information that is not clear on the period of literature included makes it difficult for replicability of this study findings by other researchers. Therefore, the authors should revise the paper and clear inconstancies/ inaccuracies so as to make this study easily replicable by other researchers. The studies in Kenya and Cameron that are clearly out the period stated should be omitted.

2. Abstract and method sections. Lines 40-42, “ Conclusions/Significance: CATIs are believed to be effective in reducing cholera outbreaks, but there is limited and context specific evidence of their effectiveness in reducing the incidence of cholera cases and lack of guidance for their consistent implementation.”. in this statement, the author note that there is limited evidence on effectiveness of CATI yet there are other studies such that by Bompangue et al 2020, https://doi.org/10.1186/s12879-020-4916-0. are not included. Yet, lines 129-131, “Retrospective case studies were used to investigate CATI implementation in DRC (2017-2020), Haiti (2010-2019), Yemen (2016-2020), and Zimbabwe (2018-2019) where the approach was implemented to control cholera outbreaks. Locations were selected in …” included the period 2020.. Therefore to avoid misinterpretation of the selective use of literature and information, the authors should revise this manuscript and include this study or in their discussion should refer to it as new finding that have weakened/overshadowed their study findings.

3. Abstract. Lines 40-42, “ Conclusions/Significance: CATIs are believed to be effective in reducing cholera outbreaks, but there is limited and context specific evidence of their effectiveness in reducing the incidence of cholera cases and lack of guidance for their consistent implementation.”. my main concern with this conclusion is that the authors use the term “believed” where there is clear and robust study conducted by a competent team in a place (Bangladesh ) that has shapped the current knowledge on the epidemiology of cholera (Sack et al, https://doi.org/10.1093/infdis/jiab440). Therefore, the authors should revise the statement and remove the word believe since the facts are available. This revision should be carried out in the entire manuscript where the term believed is used.

4. Abstract and method sections. Abstract Lines 29-32, “ We identified 11 peer-reviewed and eight grey literature articles documenting CATIs and completed 30 key informant interviews in case studies in Democratic Republic of Congo, Haiti, Yemen, and Zimbabwe. We documented 15 outbreaks in countries where CATIs were used.”. and method section lines 128-135. All 100% of the countries listed in this statement are fragile states. Further, majority of the studies shaping the finding were from the fragile states (https://thedocs.worldbank.org/en/doc/179011582771134576-0090022020/original/FCSFY20.pdf ). Fragility is known to affect social services even when effective approaches are applied ( doi: 10.1093/heapol/czz142; https://www.usip.org/sites/default/files/resources/SR_301.pdf: http://www.gsdrc.org/docs/open/con86.pdf ). When the study in Kenya (2008) is excluded, this effect becomes even more clearer. Therefore, could it be that the observed results are due to fragile nature of the states where studies were carried out? The authors will need to explain in the discussion section the effect of this on their findings.

Other comments

1. Lines 96-99,

“A mixed-methods approach to study CATI implementation was employed, including: 1) reviews of peer reviewed journal publications and grey literature published in the past ten years; and 2) four retrospective case studies of recent cholera outbreaks in the Democratic Republic of the Congo (DRC), Haiti, Yemen, and Zimbabwe”

and lines 29-32,

“ Methodology/Principle Findings: We investigated implementation of cholera case-area targetedinterventions (CATIs) using systematic reviews and case studies. We identified 11 peer-reviewed and eight grey literature articles documenting CATIs and completed 30 key informant interviews in case studies in Democratic Republic of Congo, Haiti, Yemen, and Zimbabwe. We documented 15 outbreaks in countries where CATIs were used”

The authors use the term “recent” that is open to misinterpretation by readers and scientists interested in replicability of the study findings. Therefore, the authors should clearly specify the timeframe/period to allow for replicability of the findings.

2. In reference my earlier comment (first comment) on the original version which is not fully addressed yet. The authors interpreted rapid response team as CATI, yet this is WHO-AFRO strategy for outbreak investigation and response that is applicable to any infectious disease epidemic in WHO African region. Since most the studies are from WHO Afro region, I think that it would be important if the authors could raise this as a limitation in the interpretation of the study findings and conclusion.

END

Reviewer #2: * I sincerely acknowledge authors for their modifications and clarifications, and I believe I am now in line with the authors’ point of view.

* In the conclusion of their abstract, I however think the verb « believe » wrongly suggests that CATI effectiveness is a matter of unscientific belief. I suggest a more neutral sentence, for instance like this : « CATIs appear effective in reducing cholera outbreaks, but the available evidence remains limited and context specific, and no guidance for their consistent implementation has been released so far. »

* I understand the fact that the grey publication search was limited to the period January 2009 - November 2019. Considering the limited number of scientific publication on the subject, I really think that this period should be extended for them. In particular, the paper from Bompangue et al 2020 should really be cited in a systematic review published in 2022 and with a strong expected impact.

* I don’t understand the position of the new ref [5] (Voelkel 1971). Although it rapidly lists cholera transmission pathways, this French pioneering paper mainly describes principles of CATIs.

* I still strongly think that authors should also include the Sierra Leone and Guinea in 2012 report in their systematic review, even though it does not significantly change authors conclusions. This report provides valuable data on CATI implementation and impact, and to be systematic, this review should definitely cite this report.

* Concerning Comoros, a paper was published in 2007 describing response teams (https://www.researchgate.net/publication/229983054_Needs_for_an_Integrative_Approach_of_Epidemics_The_Example_of_Cholera/link/59e5d180a6fdcc1b1d96f21d/download), and I believe it should be included in this systematic review as well.

* Page 14: As far as I know, no reactive OCV was implemented in Haiti; and no vaccinator was member of CATI teams in Haiti. As the sentence mix Haiti and South Sudan, it is confusing.

* Concerning RDT and culture use for CATI implementation in Haiti, authors could easily complete their case study with informants already interviewed from Unicef, University of Notre Dame, or Assistance Publique Hôpitaux de Marseille.

* I am sorry I do not understand the source of the $1,776 monthly cost in Yemen, as the Unicef reference [13] states : « In Yemen, the average monthly cost range is US$1,500,000 – 1,875,000 for an average of 625 teams, with costs varying depending on rural and urban settings.43 This results in an average monthly cost of approximately US$2,400 for urban teams and US$3,000 for rural teams. » (p. 22)

* Line 284-285: it is unclear to me what « antibody prophylaxis » state for. It usually refers to the use of monoclonal antibodies for post-exposure prophylaxis against an infectious diseases (such as rabies, hepatitis B, or COVID-19). Of course, this does not exist for cholera. I think authors aimed to refer to « antibiotic prophylaxis ».

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Reviewer #1: Yes: Godfrey Bwire, MBChB, MPH, PhD

Reviewer #2: No

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Submitted filename: Reviewer report _ Manuscript PNTD-D-21-00779_Godfrey Bwire 25.10.pdf

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21 Nov 2021

Submitted filename: Response to reviewers Nov 21 2021.docx

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1 Dec 2021

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13 Dec 2021

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