Tropical Medicine and Infectious Disease Systematic Review Reactive Case Detection Strategy for Malaria Control and Elimination: A 12 Year Systematic Review and Meta-Analysis from 25 Malaria-Endemic Countries Ebenezer Krampah Aidoo 1,*, Frank Twum Aboagye 2 , Felix Abekah Botchway 1, George Osei-Adjei 1 , Michael Appiah 1, Ruth Duku-Takyi 1, Samuel Asamoah Sakyi 3 , Linda Amoah 4, Kingsley Badu 5 , Richard Harry Asmah 6, Bernard Walter Lawson 5 and Karen Angeliki Krogfelt 7,8,* 1 Department of Medical Laboratory Technology, Accra Technical University, Accra GP 561, Ghana; felixbotchway@yahoo.com (F.A.B.); gosei-adjei@atu.edu.gh (G.O.-A.); mappiah@atu.edu.gh (M.A.); rduku-takyi@atu.edu.gh (R.D.-T.) 2 Biomedical and Public Health Research Unit, Council for Scientific and Industrial Research-Water Research Institute, Accra AH 38, Ghana; frankaboagye71@gmail.com 3 Department of Molecular Medicine, Kwame Nkrumah University of Science & Technology, University Post Office, Kumasi AK 039, Ghana; samasamoahsakyi@yahoo.co.uk 4 Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra LG 581, Ghana; lamoah@noguchi.ug.edu.gh 5 Department of Theoretical & Applied Biology, Kwame Nkrumah University of Science & Technology, University Post Office, Kumasi AK 039, Ghana; kingsbadu@gmail.com (K.B.); bwalterlawson@yahoo.com (B.W.L.) 6 Department of Biomedical Sciences, School of Basic and Biomedical Science, University of Health & Allied Sciences, Ho PMB 31, Ghana; rasmah@uhas.edu.gh 7 Department of Science and Environment, Unit of Molecular and Medical Biology, The PandemiX Center, Roskilde University, 4000 Roskilde, Denmark 8 Department of Virus and Microbiological Special Diagnostics, Statens Serum Institut, 2300 Copenhagen, Denmark * Correspondence: ekaidoo@atu.edu.gh (E.K.A.); karenak@ruc.dk (K.A.K.) Citation: Aidoo, E.K.; Aboagye, F.T.; Botchway, F.A.; Osei-Adjei, G.; Abstract: Reactive case detection (RACD) is the screening of household members and neighbors Appiah, M.; Duku-Takyi, R.; Sakyi, S.A.; Amoah, L.; Badu, K.; Asmah, of index cases reported in passive surveillance. This strategy seeks asymptomatic infections and R.H.; et al. Reactive Case Detection provides treatment to break transmission without testing or treating the entire population. This Strategy for Malaria Control and review discusses and highlights RACD as a recommended strategy for the detection and elimination Elimination: A 12 Year Systematic of asymptomatic malaria as it pertains in different countries. Relevant studies published between Review and Meta-Analysis from 25 January 2010 and September 2022 were identified mainly through PubMed and Google Scholar. Malaria-Endemic Countries. Trop. Search terms included “malaria and reactive case detection”, “contact tracing”, “focal screening”, Med. Infect. Dis. 2023, 8, 180. https:// “case investigation”, “focal screen and treat”. MedCalc Software was used for data analysis, and the doi.org/10.3390/tropicalmed8030180 findings from the pooled studies were analyzed using a fixed-effect model. Summary outcomes were Academic Editor: Peter A. Leggat then presented using forest plots and tables. Fifty-four (54) studies were systematically reviewed. Of these studies, 7 met the eligibility criteria based on risk of malaria infection in individuals living Received: 1 February 2023 with an index case < 5 years old, 13 met the eligibility criteria based on risk of malaria infection Revised: 23 February 2023 in an index case household member compared with a neighbor of an index case, and 29 met the Accepted: 9 March 2023 Published: 18 March 2023 eligibility criteria based on risk of malaria infection in individuals living with index cases, and were included in the meta-analysis. Individuals living in index case households with an average risk of 2.576 (2.540–2.612) were more at risk of malaria infection and showed pooled results of high variation heterogeneity chi-square = 235.600, (p < 0.0001) I2 = 98.88 [97.87–99.89]. The pooled results showed Copyright: © 2023 by the authors. that neighbors of index cases were 0.352 [0.301–0.412] times more likely to have a malaria infection Licensee MDPI, Basel, Switzerland. relative to index case household members, and this result was statistically significant (p < 0.001). This article is an open access article The identification and treatment of infectious reservoirs is critical to successful malaria elimination. distributed under the terms and Evidence to support the clustering of infections in neighborhoods, which necessitates the inclusion of conditions of the Creative Commons neighboring households as part of the RACD strategy, was presented in this review. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Trop. Med. Infect. Dis. 2023, 8, 180. https://doi.org/10.3390/tropicalmed8030180 https://www.mdpi.com/journal/tropicalmed Trop. Med. Infect. Dis. 2023, 8, 180 2 of 25 Keywords: reactive case detection; infection reservoir; index cases; passive surveillance; malaria control and elimination 1. Introduction Malaria, a vector-borne disease, remains a major public health problem. Globally, 84 countries with malaria endemicity recorded an estimated 247 million cases of the disease in 2021, up from 245 million in 2020, with most of this rise occurring in countries in the World Health Organization African Region [1]. However, the malaria elimination effort is gathering momentum in many countries. The total number of malaria-endemic countries that counted fewer than 100 malaria cases increased from 6 in 2000 to 27 in 2021 [1]. During the same period, the number of countries that recorded fewer than 10 indigenous cases rose from 4 to 25 [1]. Over the years, milestones such as these have hinged on vector-control strategies such as periodic indoor residual spraying (IRS), distribution of long-lasting insecticide nets (LLINs), increased funding, strengthening of health systems, seasonal malaria chemopre- vention in children, preventive chemotherapies (e.g., intermittent preventive treatment in infants and pregnant women), and improved case reporting and surveillance [2]. Today, the recommendation by the WHO on the use of the RTS, S malaria vaccine for the prevention of Plasmodium falciparum malaria in children living in moderate- to high-transmission areas, as described by the WHO [1], will further complement these existing interventions. Some countries focus their malaria prevention strategies on the above-mentioned interventions together with malaria control programs that aim at a decline in the disease burden until it ceases to be a public health problem. Other countries with fewer than 10,000 malaria cases work towards elimination to guarantee sustained zero local transmission of malaria in the population within a specified geographic area through enhanced surveillance systems. Asymptomatic malaria infections have existed for many years, and finding and treat- ing individual asymptomatic infections, which comprise 60% of the infected population, remains a challenge [3]. An infected asymptomatic individual can become an important reservoir of transmission to healthy individuals under suitable conditions [4] and present an obstacle to the elimination of the disease. In hypoendemic areas moving towards malaria elimination, asymptomatic malaria must be scrutinized within the wider context of sustainable malaria control and elimination strategies. In addition to an increasing use of more sensitive molecular diagnostic methods to achieve elimination and prevent resurgence, surveillance systems will hinge on which strategy is best suited to identify these asymptomatic infections. Reactive case detection, whereby household members, neighbors, and other contacts of index cases are screened for infection and treated with antimalarial drugs [3], is a strategy recommended by the WHO. Despite the WHO’s recommendation of RACD [5] and its use, knowledge gaps still exist in its implementation. These include questions to do with standard metrics on the coverage of screening needed to affect transmission, optimal target populations, timing, and frequency. Among the Asia Pacific Malaria Elimi- nation Network (APMEN) partner countries, some countries have reported using a specific screening radius (maximum of 2.5 km) around index cases [6]. Procedures to determine neighboring households for investigation have included screening individuals residing within a particular radius of the index case and choosing a definite number of neighbors or households for follow-up [7]. Another study recommended the use of tablets loaded with satellite images from study sites to determine the proportion of households that should be tested [8]. At the individual country level, limited practical know-how exists to inform control programs. RACD can, however, be better executed when operational experiences from different countries are brought together to inform country-specific needs. Hence, the objective of this review is to discuss and highlight RACD as a recommended strategy for the detection and elimination of asymptomatic malaria as it pertains in different countries. Trop. Med. Infect. Dis. 2023, 8, 180 3 of 25 Few RACD reviews and meta-analyses that include research published up to the year 2022 currently exist. Newby et al. [9] and Perera et al. [10] reviewed the literature up to 2018 and 2019, respectively. Subsequently, a review by Stresman et al. [11] and a meta-analysis by Deen et al. [12] (confined to the Greater Mekong Sub-region) up to 2019 and 2021, respectively, were undertaken. A review and meta-analysis will expand the frontiers of current knowledge for programs geared towards malaria elimination by this strategy. 2. Materials and Methods 2.1. Data Sources and Search Strategy A systematic review and meta-analysis of RACD strategies for malaria control and elimination was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. Search terms (combined free text and keywords) included “malaria and reactive case detection”, “contact tracing”, “focal screening”, “case investigation” and “focal screen and treat”. Relevant studies published between January 2010 and September 2022 were identified mainly through PubMed and Google Scholar. The retrieved studies were manually screened to identify the relevant studies. 2.2. Study Selection Eligibility for inclusion was determined according to the following selection criteria: reported results of the RACD strategy (including number of cases followed, number of persons traced, number of new cases detected). The following information (Table 1) was extracted: (1) year of publication; (2) country of study; and (3) time period. Studies restricted to simulation, modeling, resampling algorithms, and articles that did not discuss RACD specifically were excluded. Review articles were also excluded from the analysis. Fifty-four (54) studies were systematically reviewed. Of these studies, 7 met the eligibility criteria based on risk of malaria infection in individuals living with an index case < 5 years old, 13 met the eligibility criteria based on risk of malaria infection in an index case household member compared with a neighbor of an index case, and 29 met the eligibility criteria based on risk of malaria infection in individuals living with index cases, and were included in the meta-analysis. A summary of the RACD strategies and outcomes, including the timing of the RACD, the baseline study participant characteristics, the RACD households, and the screening radius are shown in Table 1 and Supplementary Table S1. Trop. Med. Infect. Dis. 2023, 8, 180 4 of 25 Table 1. Summary of included studies. RACD Response Study, Country Time/Period Malaria Source of Index Trigger and RACD ResponseTransmission Main spp. Cases Malaria Test Spatial Extent Per Protocol in Real Time(Reality) Dharmawardena 2015–2016 Index case in et al., 2022 [14], Sri (months not Low transmission Pf and Cases imported by health facility Lanka stated) Pv AMC (test not Not reported Not reported Not reported reported) Index case Index case Okebe et al., 2021 June2016–December Seasonal Pf reported by village reported by village Index case Within 5 days of [15], Gambia transmission health work- health workers household Not reported index case being2018 ers/community (test not reported) reported November Index case in 50 other at-risk Within 7 days of Mainly withinRoh et al., 2021 [16], Thailand 2017–September Seasonal Pf and 1 health persons associated transmission Pv facility health facility with the index case being 7 days (6% 2018 (RDT) reported involved withinindex case 10 days) Meredith et al., August Low transmission Pf 6 health Index case in Index case 2021 [17], Kenya 2018–October 2019 facilities health facilities(RDT) household Not reported Not reported Within 2 days in Within 2 days in Index case vicinity of index vicinity of index Gunasekera et al., 2017–2019 Index case in household and case (primary case (primary 2021 [18], Sri (months not No indigenous Not reported Public and privatetransmission health facilities health facility neighboring RACD); 3–4 weeks RACD); 3–4 weeksLanka stated) (microscopy) households within in neighboring in neighboring 1 km radius households households (secondary RACD) (secondary RACD) Index case in mobile malaria Stratil, et al., 2021 January Co-travellers of [19], Cambodia 2018–December Low transmission Pf Mobile malaria post reported by posts mobile malaria confirmed index Not reported Not reported2020 workers (test not case reported) Trop. Med. Infect. Dis. 2023, 8, 180 5 of 25 Table 1. Cont. RACD Response Study, Country Time/Period MalariaTransmission Main spp. Source of Index Trigger and Cases Malaria Test Spatial Extent RACD Response Per Protocol in Real Time(Reality) Index case in Mkali et al., 2021 August 189 public and [20], Tanzania 2012–December Seasonal transmission Not reported 124 private health health facility Index case (RDT and household Not reported Not reported2019 facilities microscopy) Vilakati et al., 2021 September 287 public or Index case in health facility households within Within 7 days (at [21], Eswatini Low transmission Pf private health 500 m of index Not reported most 5 weeks) of (Swaziland) 2015–August 2017 facilities (RDT and case household index casemicroscopy) presentation 3 km around Morales et al., 2021 April Index case in households of [22], Ecuador 2019–February Low transmission Pv Health facilities health facility index cases Not reported Not reported2020 (microscopy) involving 6 neighborhoods Index case Index case A day after the Searle, et al., 2021 March 2016– July Community reported by household and [23], Zambia 2018 Low transmission Pf health worker community health neighboring Not reported notification visit to the index case worker (RDT) households within250 m household Index case Tessema et al., October Pf and Index case in household, Within 2 days of 2020 [24], Ethiopia 2016–December Low transmission Pv 2 health posts2016 health post (RDT) 6 nearest Not reported the index case neighbors, and being reported controls RACD is triggered 2011–2015 Index case in Index case if the index case Bridges et al., 2020 (months not Seasonal Pf 27 health facilities health facility household and Within 1 week of 9 closest the index case does not report a[25], Zambia stated) transmission (RDT ormicroscopy) neighboring being reported travel history households within theprevious month Trop. Med. Infect. Dis. 2023, 8, 180 6 of 25 Table 1. Cont. Malaria Source of Index Trigger and RACD Response RACD ResponseStudy, Country Time/Period Transmission Main spp. Cases Malaria Test Spatial Extent Per Protocol in Real Time(Reality) Index case in Index case The mean number health post and household and of days between Conner et al., 2020 October Health2014–December Low transmission Pf posts/community reported by 5 closest index case [26], Senegal 2014 health workers community health neighboring Not reported detection and the workers (test not households within start of the reported) 100 m radius household visitswas 1.3 Index case household, Within 1 day forcase classification Grossenbacher June 2017–August 16 public and 8 Index case in 4 nearest health facility neighbors, and and within 3 days Within 3 days ofet al., 2020 [27], 2018 Low transmission Pf private health (RDT or 5 households for treatment of index case beingTanzania facilities microscopy) within 200 m of infected reported the index case household household members Index case Daniels et al., 2020 September Index case in household and Within 3 days of [28], Senegal 2012–December Low transmission Pf Health facility health facility 5 closest Not reported index case being2015 (RDT) neighboring reported households Index case and Canavati et al., September Seasonal Pf and Pv (tested Index case in neighbors from 2020 [29], Vietnam 2016–October 2016 transmission for but none Health centers health center (RDT forest and farm Not reported Not reportedfound) or microscopy) huts within 500 m of the index cases. Index case Hsiang et al., 2020 January Index case in household and Within 7 days to Within 5 weeks of [30], Namibia 2017–December Low transmission Pf 11 health facilities health facility neighboring 5 weeks of the the index case 2017 (RDT or households within index case being being reportedmicroscopy) 500 m reported Trop. Med. Infect. Dis. 2023, 8, 180 7 of 25 Table 1. Cont. Study, Country Time/Period Malaria Main spp. Source of Index Trigger and RACD Response Transmission Cases Malaria Test Spatial Extent RACD Response Per Protocol in Real Time(Reality) Testing of Index case in co-travellers, health index case Kheang et al., 2020 July 2015–January Village malariaLow transmission Pf and Pv workers or health facility/reported household, and Within 7 days of Within 3 days of [31], Cambodia. 2017 by village malaria neighboring the index case the index casefacilities workers (RDT or households with being reported being reported microscopy) suspected malaria cases Index case Hsiang et al., 2020 261 public or Index case in [32], Eswatini September Low transmission Pf private health health facility household and Within 5 weeks of Within 2 days 2012–March 2015 (RDT or neighboring the index case of the index case(Swaziland) facilities microscopy) households within being reported being reported500 m Index case household, May 2017–January 4 nearest Stuck et al., 2020 2018 High and Low 154 public health Index case in within 3 days of [33], Tanzania and June transmissions Pf facilities or health facility neighbors, and 50 private facilities (RDT) 5 households Not reported the index case 2018–October 2018 within 200 m of being reported the index case household Index case Bhondoekhan January 2015–July 13 health centers Index case in household and within 1 week ofet al., 2020 [34], 2017 Low transmission Pf and 23 health health facility neighboring Not reported the index caseZambia posts (RDT) households within being reported 250 m Index case in 12 primary and primary school, Bekolo and April 2018–June nursery schools, nursery school, Members of index Within 1 week of Williams, 2019 High transmission Pf 4 health centers, health center, and case household Not reported the index case [35], Cameroon 2018 and 13 community community who had fever in being reported neighborhoods neighborhoods the past week (RDT) Trop. Med. Infect. Dis. 2023, 8, 180 8 of 25 Table 1. Cont. Study, Country Time/Period Malaria Main spp. Source of Index Trigger and RACD Response Transmission Cases Malaria Test Spatial Extent RACD Response Per Protocol in Real Time(Reality) Index case in Index case Melese et al., 2019 February Seasonal Pf and health facility (test household and [36], Ethiopia 2019–April 2019 transmission Pv 2 health centers not neighboring Not reported Not reported reported) households within200 m Index case compound, Aidoo et al., October 2015– Low 1 health Index case in 5 neighboring Within 7 days of 2018 [37], Kenya August 2016 transmission Pf facility health facility(microscopy) compounds, and Not reported the index case 5 control being reported compounds Deutsch Index case Feldman et al., January 2015– Low Index case in household and Within 7 days of 2018 [38], March 2016 transmission Pf Health center hospital (RDT) neighboring Not reported the index case Zambia households within being reported250 m Index case Kyaw et al., Health reported by Within 7 days of 2018 [39], January 2016– Low Pv, Pf, and Po facility and village health Within 7 days the index case December 2016 transmission community volunteers/basic Not reported of the index case being reported inMyanmar level health being reported 95.5% of staff (RDT) individuals Index case Zelman et al., May 2018 [40], 2014–December Low Pv, Pf, and Pk Health Index case in household and Within 7 days of Indonesia 2015 transmission facilities health facility neighboring Not reported the index case (microscopy) households within being reported 500 m Index case Bansil et al., October 2018 [41], 2014–February Low Pf and 213 Index case in household and Within 30 days of transmission others health health center 10 neighboring Not reported the index caseEthiopia 2015 centers (RDT) households within being reported 100 m radius Trop. Med. Infect. Dis. 2023, 8, 180 9 of 25 Table 1. Cont. RACD Response Study, Country Time/Period MalariaTransmission Main spp. Source of Index Trigger and Cases Malaria Test Spatial Extent RACD Response Per Protocol in Real Time(Reality) Locally acquired Index case Feng et al., 2018 2015 Low Pv and Community case household and Within 7 days of [42], China transmission Pm (test not reported) neighboring Not reported the index case households being reported Index case Within 7 days of Zemene et al., June Low and Pf and Index case in household and the index case2018 [43], 2016–November seasonal Pv 2 health centers health center neighboring Not reported being reportedEthiopia 2016 (microscopy) households within (typically within 200 m radius 3 days) Index case and control Naeem et al., 2018 January Pf and Index case in households in the [44], Pakistan 2015–December Low transmission Pv Military hospital hospital vicinity with Not reported Not reported2015 (microscopy) similar socio-economic status Index case contacts, such as Index case in coworkers who Zhang et al., 2018 2013–2016 travelled to the [45], China (months not Low transmission Pf and Pv Health facilities health facility stated) (RDT/Microscopy/ same area Not reported Not reported PCR) (inactive foci),family members, neighbors, and others (active foci) Rossi et al., 28 pairs of Index case 2018 [46], October 2015–May Low Pf village reported by Index case Cambodia 2017 transmission malaria village malaria household Not reported Not reported workers worker (RDT) Trop. Med. Infect. Dis. 2023, 8, 180 10 of 25 Table 1. Cont. Study, Country Time/Period Malaria Main spp. Source of Index Trigger and Spatial Extent RACD Response RACD Response Transmission Cases Malaria Test Per Protocol in Real Time(Reality) Index case Larsen et al., Community 2017 [47], 2012–2013 Low Pf health Community health household and Within 7 days of transmission workers and worker/clinics neighboring the index case Not reportedZambia clinics (RDT) households within being reported140 km Wang et al., January Low and Index case in Within 7 days of 2017 [48], China 2012–December high Not reported 12 Index case 2014 transmission hospitals hospital (test not household Not reported the index casereported) being reported Within Index case 2 weeks to Smith et al., January Low and Health Index case in compound, Within 2 days 2 months of the2017 [49], Namibia 2013–August 2014 seasonal Pf facilities in health facility 4 neighboring index case Namibia (RDT) compounds, and of the index casebeing reported being reportedselected controls Molina Gómez Index case in Index case et al., 2017 [50], Not reported Seasonal Pf andtransmission Pv 1 hospital hospital (test not household and 4 neighboring Not reported Not reportedColombia reported) households Index case Tejedor-Garavito et al., 2017 [51], January 2010–June Index case in household and Within 5 weeks of Within 7 days of 2014 Low transmission Pf Health facilities health facility neighboring the index case the index caseSwaziland (RDT) households within being reported being reported 1 km Hamze et al., 2016 [52], Democratic November2013–January 2014 High transmission Pf 1 clinic Index case in clinic Index case Republic of Congo (RDT) household Not reported Not reported Trop. Med. Infect. Dis. 2023, 8, 180 11 of 25 Table 1. Cont. RACD Response Study, Country Time/Period MalariaTransmission Main spp. Source of Index Trigger and Spatial Extent RACD ResponseCases Malaria Test Per Protocol in Real Time(Reality) Index case in Index case Hustedt et al., health facility and compound,May 2013–March Low Pf and Health community 5–10 neighboring Within 3 days of2016 [53], 2014 transmission Pv facility and reported by compounds, and Not reported the index caseCambodia community village malaria 5 control being reported workers (RDT) compounds Index case compound, Fontoura et al., January 2013–July Low Index case in clinic 5 neighboring Within 6 months 2016 [54], Brazil 2013 transmission Pv 1 clinic (mi-croscopy/qPCR) compounds, and Not reported of the index case 5 control being reported compounds Index case Chihanga et al., October Index case in household and Within 2 days of 2016 [55], 2012–December Seasonal Pf Health facilities health facility neighboring the index case Not reported Botswana 2014 transmission (RDT ormicroscopy) households within being reported100 m 1 hospital, Index case Donald et al., 2016 2013–2014 Pf and 11 dispensaries, Index case in household and Within 5 days of [56], Vanuatu (months not Low transmission Pv 4 health centers, health facility neighboring Not reported the index casestated) and 28 aid posts (RDT) households within being reported 500 m Index case Herdiana et al., June 5 sub-district level Index case in household and Within 7 days of 2016 [57], 2014–December Low transmission Pv, Pf, and Pk primary health primary health neighboring Not reported the index case Indonesia 2015 centers (PHCs) center(microscopy) households within being reported500 m Trop. Med. Infect. Dis. 2023, 8, 180 12 of 25 Table 1. Cont. Malaria Source of Index Trigger and RACD Response RACD ResponseStudy, Country Time/Period Transmission Main spp. Cases Malaria Test Spatial Extent Per Protocol in Real Time(Reality) Index case reported by Index caseSearle et al., 20 rural household and Within 7 days of 2016 [58], January 2014–June Low Pf health community2014 transmission health neighboring the index case Not reportedZambia centers worker/rural households within being reported health post (RDT) 140 km Index case Index case Index case household household 91.6% van Eijk et al., household, screened within screened 2016 [59], January 2014– Low and Pf and 1 urban Index case in clinic contacts in same 1–7 days, contacts within 1 week, Chennai January 2015 seasonal Pv clinic (microscopy) apartment block, in same apartment contacts in same (India) and block and other apartment block households within households and other 0.2 km screened within households 64.8% 14 days screened within2 weeks Index case Index case Index case household household 84.4% van Eijk et al., household, screened within screened 2016 [59], March Low and Pf and 1 urban Index case in clinic contacts in same 1–7 days, contacts within 1 week, 2014–September contacts in sameNadiad 2014 seasonal Pv clinic (microscopy) apartment block in same apartment (India) (100 m), and block and other apartment block households within households and other 100–1000 m screened within households 93.9% 14 days screened within2 weeks Index case Wangdi, et al., 2014–2015 Index case in household and 2016 [60], Bhutan (months not High transmission Pf and Pv Health centers health center (test not neighboring Not reported Not reportedstated) reported) households within1 km Trop. Med. Infect. Dis. 2023, 8, 180 13 of 25 Table 1. Cont. Study, Country Time/Period Malaria Main spp. Source of Index Trigger and RACD Response RACD Response Transmission Cases Malaria Test Spatial Extent Per Protocol in Real Time(Reality) Index case Larson et al., 2016 2014 (months not Not reported Not reported 173 health Index case in household and [61], Zambia stated) facilities health facility(RDT) neighboring Not reported Not reported households Pinchoff et al., Index case (RDT 2015 [62], June 2012–June Seasonal2013 transmission Pf 1 clinic and Index case microscopy) in household Not reported Not reportedZambia clinic Larsen et al., Community Index caseLow health Index case in clinic household and Within 7 days2015 [63], 2014–2015 Zambia transmission Pf workers and (RDT) 10 neighboring of the index case Not reported 20 clinics households being reported Littrell et al., Index case Within 3 days of 2013 [64] 2012 Seasonal Pf 13 clinics Index case in clinic compound and Senegal transmission (test not reported) 5 neighboring the index case Not reported compounds being reported Index case Sturrock et al., December Seasonal Health Locally acquired case household and 48.6% screened 2013 [8], 2009–June 2012 transmission Pf facilities in or imported case neighboring Not reported within 1 week, Swaziland Swaziland (test not reported) households within 87.3% screened 1 km Within 14 days. Rogawski et al., Low and Pf and 1 case in hospital Neighbors within 1 km of index After 2 weeks of2012 [65], July 2011 seasonal Pv 1 hospital (test case (fever was Not reported the index caseThailand not reported) not a criterion) being reported Stresman et al., Homestead ofJune 2009– Seasonal 4 rural Case (RDT) in index case (fever Within 2 weeks of2010 [66], August 2009 transmission Pf clinics clinic was not a the index case Not reportedZambia criterion) being reported Pm: Plasmodium malariae; Po: Plasmodium ovale; Pv: Plasmodium vivax; Pk: Plasmodium knowlesi; Pf: Plasmodium falciparum; AMC: Anti Malaria Campaign; RDT: Rapid Diagnostic Test; PCR: Polymerase Chain Reaction; qPCR: Quantitative Polymerase Chain Reaction. Trop. Med. Infect. Dis. 2023, 8, 180 14 of 25 2.3. Data Extraction and Assessment of Study Quality Duplicates were removed with EndNote Reference Library. Studies that met the eligibility criteria were included after going through careful screening and evaluation by two reviewers (EKA and FTA). Studies were initially considered depending on their titles and abstracts, and this was followed by a thorough review of the complete article for relevance. To clarify any disagreements, a third investigator (SAS) was involved. 2.4. Statistical Analysis Statistical analysis was carried out using MedCalc 20.0 (MedCalc Software Ltd., Os- tend, Belgium). The findings from the pooled studies were reported as odds ratios with their confidence intervals from a pooled fixed-effect model. A Forest plot was generated from the outcomes to graphically represent the results. Publication bias and heterogeneity were tested using Egger’s test and Higgins I2 [67], respectively. For I2, values between 25% and 50% indicated low heterogeneity, values between 50% and 75% indicated moderate heterogeneity, and values greater than 75% indicated severe heterogeneity. A p-value of ≤0.05 was considered significant in all cases. 3. Results 3.1. Search Result In all, 115 studies were identified through PubMed and 284 studies were identified though Google Scholar (Figure 1). Following the removal of duplicates, 260 studies were screened, and this left 154 studies for full assessment. Of these, 100 studies were excluded because they concerned strategies other RACD (e.g., simulation, modeling). The remaining studies were carefully evaluated in detail, resulting in a total of 54 studies for qualitative synthesis and 7, 13, and 29 studies for quantitative synthesis. 3.2. Study Characteristics and Quality Assessment All 7, 13, and 29 respective studies used for the meta-analysis involved real RACD strategies. In all, the studies included a total of 8965 index cases leading to 90,940 contacts (Supplementary Table S1). While 16 studies used only RDT to test contacts, 2 studies used RDT/PCR, 1 study used LAMP/PCR, 1 study used microscopy/PCR, 6 studies used PCR, 1 study used microscopy, 2 used studies LAMP, and 5 studies did not report the diagnostic method used (Supplementary Table S1). Index case demographics and individual study characteristics are shown in Supplementary Table S1. Although some of the included studies had a higher risk of bias than others, sensitivity analyses that excluded those studies showed significant difference. Quality assessment was independently carried out by two reviewers, and any disagreements were resolved by discussion. 3.3. Outcomes 3.3.1. Risk of Malaria Infection Amongst Persons Living with Index Cases Twenty-Nine studies met the eligibility criteria for the meta-analysis (Figure 2). The average risk of malaria infection for an individual living with an index case was 2.576 (2.540–2.612) and was statistically significant (p = 0.033). The risk of infection for an individ- ual living with an index case ranged between 0.032 and 232.545. From the pooled results, high variation heterogeneity chi-square = 235.600, (p < 0.0001) I2 = 98.88 [97.87–99.89] (assessed with Egger’s Test, intercept = 1.154, p = 0.8534; test for overall effect, Z = 2.136, (p = 0.003) was observed. Trop. Med. Infect. Dis. 2023, 8, x FOR PEER REVIEW 13 of 24 Trop. Med. Infect. Dis. 2023, 8, 180 15 of 25 1 2 Records identified through Additional records identified database searching through Google scholar 3 115 PubMed (n =284) 4 5 Records after duplicates removed (n =366) 6 7 Records screened Records excluded 8 (n =260) (n =106) 9 10 Full-text articles Records excluded because of 11 assessed for eligibility other strategies other than real (n =154) RACD (n = 100) 12 13 Studies included in q u alitative synthesis 14 (n =54) 15 16 17 18 Studies included in quantitative synthesis 19 (meta-analysis) (n = 7, 13 and 29) 20 Figure 1. PRISMA flow diagram showing schematic illustration of database searches, identification, 21 screening, and eligibility of included studies. Figure 1. PRISMA flow diagram showing schematic illustration of database searches, identification, screening, and eligibility of included studies. Included Eligibility Screening Identification innnncc ded Trop. Med. Infect. Dis. 2023, 8, x FOR PEER REVIEW 14 of 24 3.2. Study Characteristics and Quality Assessment All 7, 13, and 29 respective studies used for the meta-analysis involved real RACD strategies. In all, the studies included a total of 8965 index cases leading to 90,940 contacts (Supplementary Table S1). While 16 studies used only RDT to test contacts, 2 studies used RDT/PCR, 1 study used LAMP/PCR, 1 study used microscopy/PCR, 6 studies used PCR, 1 study used microscopy, 2 used studies LAMP, and 5 studies did not report the diagnostic method used (Supplementary Table S1). Index case demographics and indi- vidual study characteristics are shown in Supplementary Table S1. Although some of the included studies had a higher risk of bias than others, sensitivity analyses that excluded those studies showed significant difference. Quality assessment was independently car- ried out by two reviewers, and any disagreements were resolved by discussion. 3.3. Outcomes 3.3.1. Risk of Malaria Infection Amongst Persons Living with Index Cases. Twenty-Nine studies met the eligibility criteria for the meta-analysis (Figure 2). The average risk of malaria infection for an individual living with an index case was 2.576 (2.540–2.612) and was statistically significant (p = 0.033). The risk of infection for an indi- vidual living with an index case ranged between 0.032 and 232.545. From the pooled re- Trop. Med. Infect. Dis. 2023, 8, 180 sults, high variation heterogeneity chi-square = 235.600, (p < 0.0001) I2 = 98.88 [97.87–99.89] 16 of 25 (assessed with Egger’s Test, intercept = 1.154, p = 0.8534; test for overall effect, Z = 2.136, (p = 0.003) was observed. SE: Standard Error, Log(odds ratio) values with “-“ are negative values Figure 2. Risk of malaria infection amongst persons living with index cases [14,15,17–19,23–25,29– 32,3 4F–ig3u7,r4e1 2,.4 R6i,4sk7 ,o5f0 m–5a2la,r5i4a, i5n5f,e5c7ti,o6n2 –a6m4o,6n6g]s.t pSeEr:soSntas nlidvianrgd wEirthro inr,dLexo gca(osedsd [1s4r, a1t5i,o 1)7v-1a9l,u 2e3s-2w5, ith “-“ are neg2a9ti-v32e, v34a-l3u7e, s4.1, 46, 47, 50-52, 54, 55, 57, 62-64, 66]. Trop. Med. Infect. Dis. 2023, 8, x FOR PEER REVIEW 15 of 24 3.3.32..3.T2h. 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