An intersectoral approach to enhance surveillance and guide rabies control and elimination programs

Rabies is a viral zoonotic disease causing horrific neurological symptoms inevitably leading to death without prompt administration of post-exposure prophylaxis (PEP) to prevent infection. While any mammal can be infected by and transmit rabies, almost 99% of the estimated 59,000 human deaths per year are due to bites from rabid dogs, with the vast majority occurring in Asia and Africa. Through mass dog vaccinations starting in the 1920s, rabies has been successfully eliminated from domestic dog populations in practically all high-income countries. Yet, many lowand middle-income countries (LMICs) are still endemic and face extensive challenges controlling rabies and achieving elimination. Strengthening surveillance through integrated intersectoral methods has been an important component of the Zero by 30 global strategy to eliminate human deaths from dog-mediated rabies by 2030. Similar to other neglected tropical diseases, only a small percentage of human and animal rabies cases are captured in surveillance at the local level, then go on to be reported in official national and international statistics. This lack of detection and underreporting has resulted in suboptimal data quality that conceals the true magnitude of the burden of rabies, leading to a cycle of neglect by reducing advocacy, funding, and stakeholder engagement. Hence, surveillance must be sufficiently enhanced to monitor, evaluate, and inform rabies control efforts to support LMICs to achieve elimination. This thesis aims to critically review and evaluate the One Health approach, Integrated Bite Case Management (IBCM), as a cost-effective method to enhance rabies surveillance and guide control and elimination programs in LMICs, with a particular focus on a case study of IBCM implementation in the Philippines. The thesis is presented in a series of five chapters, starting with a general introduction (Chapter 1), followed by three standalone data chapters (Chapters 2, 3 & 4), and concluding with a general discussion (Chapter 5). IBCM is a current gold standard surveillance method advocated by WHO and other international organizations. Yet, as a relatively novel One Health approach, there is still little understood about the implementation of IBCM in practice. In Chapter 2, I examined how IBCM is conceptualized by experts in the field, exploring variation in its operationalization in different epidemiological and geographical contexts. Findings from this study highlighted the diversity of how IBCM can be organized within existing government systems/sectors and demonstrated it is not a one-sizefits-all approach. Contextual features of each location influenced the success of delivery and the potential impact of IBCM, with the issue of sustainability identified as one of the greatest challenges. For successful development and implementation of IBCM programs, this study recommends that more guidance is provided for health workers receiving bite patients on assessing rabies-risk, and for stakeholders and practitioners on how to tailor IBCM to fit the local context. In Chapter 3, I explored this topic in more depth through the evaluation of a threeyear (January 2020 to December 2022) implementation study of IBCM in Oriental Mindoro province, Philippines. Using a mixed methods process evaluation, I assessed the feasibility and fidelity of effective delivery of IBCM, and how protocols were adapted to the context over the course of the study. The evaluation showed that the initial protocols envisioning trained government staff would uptake IBCM activities were not feasible due to implementation barriers. However, following adaptations made by the project team and participants, including adjustments for the COVID-19 pandemic, IBCM was delivering more effectively in 2021 and 2022. The findings concluded that, if implemented effectively, IBCM showed great promise as a strategy to enhance rabies surveillance in the Philippines, with evidence from the study providing key lessons for the adaptation and scale-up of IBCM to additional provinces in the Philippines. In Chapter 4, I used data collected from enhanced IBCM surveillance in Oriental Mindoro province from the implementation study discussed in Chapter 3. This quantitative data was used to develop an adapted probabilistic decision tree model used to estimate the burden of rabies, evaluate surveillance performance, and assess the impact of current rabies prevention practices. Results from this study estimated a high incidence of bite patient presentations to health facilities (1,160/100,000 persons/year), with <2% deemed high-risk for rabies exposures (<25/100,000 persons/year) and an average of 71.4% of probable rabies-exposed patients seeking PEP. Routine surveillance confirmed <1% of circulating animal cases, whereas IBCM resulted in a fivefold increase in detection. The model estimated that between 275 to 838 dogs developed rabies; 18 to 28 deaths were averted by PEP; and total costs of over $535,385 USD per year, i.e.$16,730-38,240 USD per death averted, in Oriental Mindoro province. These findings highlight that current PEP practices in the Philippines are not cost-effective without concurrent strengthened risk-based surveillance to reduce the indiscriminate use of PEP. The study concludes that integrating IBCM into national policy has the potential to guide PEP administration to reduce unnecessary expenditure on PEP and inform rabies control measures. Overall, this thesis exemplifies the value of enhancing rabies surveillance using a One Health approach to achieve Zero by 30 rabies elimination goals. Yet, the development and implementation of IBCM must be carefully considered and planned to ensure the effective delivery of IBCM activities leading to desired outputs and outcomes. With more guidance provided by international organizations to streamline protocols and procedures, the IBCM approach has the potential to be a key component of national strategies to monitor and evaluate the progress of rabies control efforts, verify elimination, and promptly detect incursion events

Implementing a One Health approach to rabies surveillance: lessons from integrated bite case management

As part of the ‘Zero by 30’ strategy to end human deaths from dog-mediated rabies by 2030, international organizations recommend a One Health framework that includes Integrated Bite Case Management (IBCM). However, little is understood about the implementation of IBCM in practice. This study aims to understand how IBCM is conceptualized, exploring how IBCM has been operationalized in different contexts, as well as barriers and facilitators to implementation. Semi-structured interviews were conducted with seventeen practitioners and researchers with international, national, and local expertise across Africa, Asia, and the Americas. Thematic analysis was undertaken using both inductive and deductive approaches. Four main themes were identified: 1) stakeholders’ and practitioners’ conceptualization of IBCM and its role in rabies elimination; 2) variation in how IBCM operates across different contexts; 3) barriers and facilitators of IBCM implementation in relation to risk assessment, PEP provisioning, animal investigation, One Health collaboration, and data reporting; and 4) the impact of the COVID-19 pandemic on IBCM programs. This study highlights the diversity within experts’ conceptualization of IBCM, and its operationalization. The range of perspectives revealed that there are different ways of organizing IBCM within health systems and it is not a one-size-fits-all approach. The issue of sustainability remains the greatest challenge to implementation. Contextual features of each location influenced the delivery and the potential impact of IBCM. Programs spanned from highly endemic settings with limited access to PEP charged to the patient, to low endemicity settings with a large patient load associated with free PEP policies and sensitization. In practice, IBCM was tailored to meet the demands of the local context and level of rabies control. Thus, experts’ experiences did not necessarily translate across contexts, affecting perceptions about the function, motivation for, and implementation of IBCM. To design and implement future and current programs, guidance should be provided for health workers receiving patients on assessing the history and signs of rabies in the biting animal. The study findings provide insights in relation to implementation of IBCM and how it can support programs aiming to reach the Zero by 30 goal

Haptoglobin gene diversity and incidence of uncomplicated malaria among children in Iganga, Uganda

Background Haptoglobin (Hp) is an acute phase protein that takes part in systemic regulation of haem during Plasmodium falciparum infections. Numerous genotypes of haptoglobin have been reported in malaria endemic populations. In this study, the relationship between haptoglobin genotypes and incidence of uncomplicated malaria in a cohort of children living in a malaria-endemic area of Uganda was determined. Methods This is an extension of a longitudinal study comprising of 423 children aged between six months and nine years, who were actively followed up for one year. Malaria episodes occurring in the cohort children were detected and the affected children treated with national policy drug regimen. Haptoglobin genotypes were determined by an allele-specific PCR method and their frequencies were calculated. A multivariate negative binomial regression model was used to estimate the impact of haptoglobin genotypes on incidence of uncomplicated malaria in the children’s cohort. In all statistical tests, a P–value of &lt; 0.05 was considered as significant. Results The prevalence of the Hp 1–1, Hp 2–1 and Hp 2–2 genotypes in the children’s cohort was 41%, 36.2% and 22.9%, respectively. The overall frequency for the Hp 1 allele was 59%, while Hp 2 allele occurred at a frequency of 41%. After adjustment of incidence rates for age, insecticide treated bed net (ITN) use and malaria history, the incidence of uncomplicated malaria for children carrying the Hp 2–2 genotype and those with the Hp 2–1 genotype was statistically similar (P = 0.41). Also, no difference in the incidence of uncomplicated malaria was observed between children carrying the Hp 1–1 genotype and those having the Hp 2–1 genotype (P = 0.84) or between Hp 2–2 Vs Hp 1–1 genotypes (P = 0.50). Conclusions This study showed that the Hp 1–1 and Hp 2–1 genotypes each occur in nearly 4 in 10 children and the Hp 2–2 genotype occurs in 2 of every 10 children. No association with incidence of uncomplicated malaria was found. Additional studies of influence of haptoglobin genotypes on P. falciparum malaria severity are needed to understand the role of these genotypes in malarial protection.De två sista författarna delar sistaförfattarskapet</p

Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda

Background: Host genetics play an important role in Plasmodium falciparum malaria susceptibility. However, information on host genetic factors and their relationships with malaria in the vaccine trial site of Iganga, Uganda is limited. The main objective of this study was to determine the prevalence of selected host genetic markers and their relationship to malaria incidence in the vaccine trial site of Iganga, Uganda. In a 1-year longitudinal cohort study, 423 children aged below 9 years were recruited and their malaria episodes were investigated. Host genetic polymorphisms were assessed by PCR-RFLP, haemoglobin electrophoresis and DNA sequencing. Using a multivariate negative binomial regression model, estimates of the impact of human genetic polymorphisms on malaria incidence were performed. In all statistical tests, a P value of &lt; 0.05 was considered as significant. Results: The prevalences of sickle cell haemoglobin trait, G6PD c. 202 G &gt; A (rs 1050828) and NOS2 -954 G &gt; C (rs 1800482) variants were 26.6, 22.7 and 17.3%, respectively. Inducible nitric oxide synthase 2 (NOS2 -954 G&gt;C; rs 1800482) heterozygosity was associated with lower incidence of malaria in all age groups {Adjusted incident rates ratio (aIRR) 0.59; 95% CI [0.386-0.887]; P = 0.012)}. About 4% of study subjects had co-existence of sickle cell Hb trait and G6PD deficiency. Sickle cell Hb heterozygotes (Hb AS) aged less than 1 year experienced significantly more malaria episodes annually than children with normal haemoglobin (Hb AA) {aIRR = 1.98; 95% CI [1.240-3.175]; P = 0.004}. There was no significant influence of the sickle cell trait on malaria incidence among older children of 1-9 years. Conclusions: Mutation (NOS2 -954 G &gt; C; rs 1800482) of nitric oxide synthase 2 gene promoter was associated with a lower incidence of acute malaria. The normal haemoglobin (wild genotype; HbAA) was associated with reduced malaria incidence rates during the first year of life. More understanding of the interplay between host genetics and malaria susceptibility is required