Snakebite prevalence and risk factors in a nomadic population in Samburu County, Kenya: A community-based survey.

INTRODUCTION: Snakebite is an important public health concern, especially in tropical areas, but the true burden remains unclear due to sub-optimal reporting and over-reliance on health facility-based data. METHODS: A community-based cross-sectional survey was conducted in Samburu County, Kenya from December 2019 to March 2020. Geospatial techniques were used to create a sampling frame of all households in Samburu County and a multistage cluster sampling strategy to select households and recruit study participants. Five year prevalence and mortality rates were estimated, the characteristics and circumstances of snakebite were described, and multilevel logistic regression models were built to identify independent risk factors for snakebite. RESULTS: We recruited 3,610 individuals living in 875 households from 30 clusters. The 5-year prevalence of snakebite was 2.2% (95% CI 1.4%-3.4%), and the 5-year mortality rate was 138 (95% CI 44-322) deaths per 100,000 inhabitants, resulting in an estimated 1,406 snakebites and 88 deaths from snakebites per year in Samburu County. Snakebite incidents often occurred at night between 9pm and 6 am (44%, n = 36), and the participants were mostly walking/playing outdoors (51%, n = 41) or sleeping (32%, n = 27) when they were bitten. Lower household socioeconomic status and smaller numbers of people per house were significant independent risk factors. CONCLUSION: Samburu County has a high snakebite burden and the most victims are bitten while sleeping or walking outdoors at night. Snakebite prevention and health promotion programs in Samburu County, and other endemic regions, need to be contextualised and consider the geographic, seasonal, and temporal specificities found in our study. Our findings also have implications for health care delivery, especially identification of the need for night-time staffing with expertise in snakebite management and antivenom availability to better manage patients and thereby improve outcomes.

Correspondence: The African snakebite Alliance.

The goal to reduce the burden of snakebite envenoming is challenged by the gaps in evidence for clinical care and public health. These evidence gaps and the absence of a strong network are illustrated by bibliometrics. The African Snakebite Alliance is a multidisciplinary group focusing on research themes which will generate evidence needed to shape policy and practice.

Stakeholder perspectives from 15 countries in Africa on barriers in snakebite envenoming research and the potential role of research hubs.

Snakebite envenoming is a debilitating neglected tropical disease disproportionately affecting the rural poor in low and middle-income countries in the tropics and sub-tropics. Critical questions and gaps in public health and policy need to be addressed if major progress is to be made towards reducing the negative impact of snakebite, particularly in the World Health Organisation (WHO) Africa region. We engaged key stakeholders to identify barriers to evidence-based snakebite decision making and to explore how development of research and policy hubs could help to overcome these barriers. We conducted an electronic survey among 73 stakeholders from ministries of health, health facilities, academia and non-governmental organizations from 15 countries in the WHO Africa region. The primary barriers to snakebite research and subsequent policy translation were limited funds, lack of relevant data, and lack of interest from policy makers. Adequate funding commitment, strong political will, building expert networks and a demand for scientific evidence were all considered potential factors that could facilitate snakebite research. Participants rated availability of antivenoms, research skills training and disease surveillance as key research priorities. All participants indicated interest in the development of research and policy hubs and 78% indicated their organization would be willing to actively participate. In conclusion, our survey affirms that relevant stakeholders in the field of snakebite perceive research and policy hubs as a promising development, which could help overcome the barriers to pursuing the WHO goals and targets for reducing the burden of snakebite.

Conducting epidemiological studies on snakebite in nomadic populations: A methodological paper.

INTRODUCTION: Research on snakebite has mostly been conducted on settled populations and current risk factors and potential interventions are therefore most suited for these populations. There is limited epidemiological data on mobile and nomadic populations, who may have a higher risk of snakebite. METHODS AND RESULTS: We conducted a scoping review to gather evidence on survey methods used in nomadic populations and compared them with contemporary survey methods used for snakebite research. Only 16 (10.5%) of 154 articles reportedly conducted on pastoralist nomadic populations actually involved mobile pastoralists. All articles describing snakebite surveys (n = 18) used multistage cluster designs on population census sampling frames, which would not be appropriate for nomadic populations. We used geospatial techniques and open-source high-resolution satellite images to create a digital sampling frame of 50,707 households and used a multistage sampling strategy to survey nomadic and semi-nomadic populations in Samburu County, Kenya. From a sample of 900 geo-located households, we correctly identified and collected data from 573 (65.4%) households, of which 409 were in their original locations and 164 had moved within 5km of their original locations. We randomly sampled 302 (34.6%) households to replace completely abandoned and untraceable households. CONCLUSION: Highly mobile populations require specific considerations in selecting or creating sampling frames and sampling units for epidemiological research. Snakebite risk has a strong spatial component and using census-based sampling frames would be inappropriate in nomadic populations. We propose using open-source satellite imaging and geographic information systems to improve the conduct of epidemiological research in these populations.

Uniting behind a common goal: Collaboration between traditional healers and allopathic health care workers to improve rural snakebite care.

Snakebite envenoming is an acute medical emergency which affects hundreds of thousands of people worldwide, primarily in remote rural areas of low-and middle income countries in the Global South. A considerable proportion of snakebite patients turn to traditional healers (THs) for help, driven by a number of push and pull factors. These include socio-cultural factors, geographical proximity, and the absence or inaccessibility of overstretched and often costly allopathic healthcare services. Although traditional healers and allopathic healthcare staff share a common focus -the recovery and well-being of their patients- both systems operate largely in parallel to each other with collaborations being an exception rather than the rule. This is to the detriment of snakebite patients, who frequently find themselves being caught-up in the dualism between the two separate systems. Given the right circumstances, snakebite patients could benefit from elements of care from both modalities. Here, we have reviewed the role of THs in snakebite care and explored how their integration into the formal healthcare system could improve the implementation and outcome of care. The effective recruitment of THs to aid in disease control and treatment efforts in diseases other than snakebite underscores the potential benefits of this strategy. Carefully devised proof of concept studies are needed to test our hypothesis that collaborations between the formal healthcare sector and THs are feasible and improve outcomes in snakebite care.

Profiling the Murine Acute Phase and Inflammatory Responses to African Snake Venom: An Approach to Inform Acute Snakebite Pathology.

Snake envenoming causes rapid systemic and local effects that often result in fatal or long-term disability outcomes. It seems likely that acute phase and inflammatory responses contribute to these haemorrhagic, coagulopathic, neurotoxic, nephrotoxic and local tissue destructive pathologies. However, the contributory role of acute phase/inflammatory responses to envenoming is under-researched and poorly understood-particularly for envenoming by sub-Saharan African venomous snakes. To provide data to help guide future studies of human patients, and to explore the rationale for adjunct anti-inflammatory medication, here we used an in vivo murine model to systematically assess acute phase and inflammatory responses of mice to ten African snake venoms. In addition to investigating snake species-specific effects of venom on the cardiovascular system and other key organs and tissues, we examined the response to intravascular envenoming by acute phase reactants, including serum amyloid A, P-selectin and haptoglobin, and several cytokines. Venoms of the spitting (Naja nigricollis) and forest (N. melanoleuca) cobras resulted in higher acute phase and inflammatory responses than venoms from the other cobras, mambas and vipers tested. Naja nigricollis venom also stimulated a 100-fold increase in systemic interleukin 6. Thin blood films from venom-treated mice revealed species-specific changes in red blood cell morphology, indicative of membrane abnormalities and functional damage, lymphopenia and neutrophil leukocytosis. Our ex vivo assays with healthy human blood treated with these venoms identified that N. nigricollis venom induced marked levels of haemolysis and platelet aggregation. We conclude that African snake venoms stimulate very diverse responses in this mouse model of acute systemic envenoming, and that venoms of the African cobras N. nigricollis and N. melanoleuca, in particular, cause marked inflammatory and non-specific acute phase responses. We also report that several African snake venoms cause haemolytic changes. These findings emphasise the importance of understanding acute responses to envenoming, and that further research in this area may facilitate new diagnostic and treatment approaches, which in turn may lead to better clinical outcomes for snakebite patients.

Delays, fears and training needs: Perspectives of health workers on clinical management of snakebite revealed by a qualitative study in Kitui County, Kenya.

Key aims of the WHO Strategy to halve snakebite morbidity and mortality include health system strengthening and training of health workers. This requires knowledge of local health system needs and capacity, health worker training needs, and factors influencing health worker decision-making in snakebite management. This study explored health worker experiences and perceptions of snakebite management, both individually and in the context of their local health system. We used a qualitative study design with semi-structured interviews (n = 14) and focus group discussions (n = 4). We employed a combination of sampling strategies aiming to achieve maximum variation among key informants within resource limitations. We recruited health workers (n = 33) of varying roles from purposively selected tier 2, 3 and 4 health facilities (n = 12) and the community (tier 1) in four sub-counties in Kitui County, Kenya. We conducted inductive thematic analysis of all transcripts. The results identified that health workers recognised snake envenoming as a time-critical emergency in which delay in care seeking, sometimes exacerbated by health system referral delays, was a major barrier to effective management of patients. Clinicians strongly voiced a need for training in snakebite management, diagnosis and antivenom administration. Unexpressed needs for training were demonstrated in traditional remedy ineffectiveness, syndromic management, and critical appraisal of treatment effectiveness. Under-resourcing in antivenom, other medication, equipment, infrastructure and staffing also challenged management. Fear of snakebite and fear of antivenom, both linked to past experiences, influenced clinical decision-making. Our findings clearly indicate a need in Kitui County for training programmes that equip health workers for clinical decision-making in snakebite management. We further identify community intervention needs to facilitate prompt presentation to healthcare, including practical affordable transport solutions, and systematic health system resourcing needs. In addition, we recommend supportive supervision and further research in response to the emotional stress resulting from managing difficult cases in under-resourced settings.

Correction: Preclinical antivenom-efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa.

[This corrects the article DOI: 10.1371/journal.pntd.0005969.].

Impact of the Levonorgestrel-Releasing Intrauterine System on the Progression of Chlamydia trachomatis Infection to Pelvic Inflammatory Disease in a Baboon Model.

Background: Understanding the relationship between the levonorgestrel (LNG)-releasing intrauterine system (IUS) and sexually transmitted infections (STIs) is increasingly important as use of the LNG-IUS grows to include women at higher risk for STIs. This study assessed the impact of the LNG-IUS on development of Chlamydia trachomatis pelvic inflammatory disease, using a baboon model. Methods: Baboons with and those without the LNG-IUS were cervically inoculated with C. trachomatis and monitored daily, and cervical and fallopian tube swab specimens were collected weekly for C. trachomatis quantitation by nucleic acid amplification testing and culture. Vaginal swab specimens were collected for cytokine analysis, and serum samples were obtained for detection of C. trachomatis antibodies. Results: The LNG-IUS resulted in an increased C. trachomatis burden in the cervix, with the bacterial burden in the LNG-IUS group diverging from that in the non-LNG-IUS group by 6 weeks after infection. One of 7 baboons in the non-LNG-IUS group and 2 of 6 in the LNG-IUS group developed pelvic inflammatory disease, while 3 animals in each group met criteria suggestive of pelvic inflammatory disease. LNG-IUS increased baseline interleukin 8 levels but failed to further upregulate interleukin 8 during infection. In LNG-IUS recipients, early perturbations in the interleukin 1ß axis corresponded to decreased C. trachomatis clearance and increased T-helper type 2 immune responses. Conclusion: LNG-IUS use results in delayed clearance of C. trachomatis and might alter the reproductive tract immune environment.

Preclinical antivenom-efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa.

BACKGROUND: Antivenom is the treatment of choice for snakebite, which annually kills an estimated 32,000 people in sub-Saharan Africa and leaves approximately 100,000 survivors with permanent physical disabilities that exert a considerable socioeconomic burden. Over the past two decades, the high costs of the most polyspecifically-effective antivenoms have sequentially reduced demand, commercial manufacturing incentives and production volumes that have combined to create a continent-wide vacuum of effective snakebite therapy. This was quickly filled with new, less expensive antivenoms, many of which are of untested efficacy. Some of these successfully marketed antivenoms for Africa are inappropriately manufactured with venoms from non-African snakes and are dangerously ineffective. The uncertain efficacy of available antivenoms exacerbates the complexity of designing intervention measures to reduce the burden of snakebite in sub-Saharan Africa. The objective of this study was to preclinically determine the ability of antivenoms available in Kenya to neutralise the lethal effects of venoms from the most medically important snakes in East Africa. METHODS: We collected venom samples from the most medically important snakes in East Africa and determined their toxicity in a mouse model. Using a 'gold standard' comparison protocol, we preclinically tested the comparative venom-neutralising efficacy of four antivenoms available in Kenya with two antivenoms of clinically-proven efficacy. To explain the variant efficacies of these antivenoms we tested the IgG-venom binding characteristics of each antivenom using in vitro IgG titre, avidity and venom-protein specificity assays. We also measured the IgG concentration of each antivenom. FINDINGS: None of the six antivenoms are preclinically effective, at the doses tested, against all of the most medically important snakes of the region. The very limited snake polyspecific efficacy of two locally available antivenoms is of concern. In vitro assays of the abilities of 'test' antivenom IgGs to bind venom proteins were not substantially different from that of the 'gold standard' antivenoms. The least effective antivenoms had the lowest IgG content/vial. CONCLUSIONS: Manufacture-stated preclinical efficacy statements guide decision making by physicians and antivenom purchasers in sub-Saharan Africa. This is because of the lack of both clinical data on the efficacy of most of the many antivenoms used to treat patients and independent preclinical assessment. Our preclinical efficacy assessment of antivenoms available in Kenya identifies important limitations for two of the most commonly-used antivenoms, and that no antivenom is preclinically effective against all the regionally important snakes. The potential implication to snakebite treatment is of serious concern in Kenya and elsewhere in sub-Saharan Africa, and underscores the dilemma physicians face, the need for clinical data on antivenom efficacy and the medical and societal value of establishing independent preclinical antivenom-efficacy testing facilities throughout the continent.

Blocking central pathways in the primate motor system using high-frequency sinusoidal current.

Electrical stimulation with high-frequency (2-10 kHz) sinusoidal currents has previously been shown to produce a transient and complete nerve block in the peripheral nervous system. Modeling and in vitro studies suggest that this is due to a prolonged local depolarization across a broad section of membrane underlying the blocking electrode. Previous work has used cuff electrodes wrapped around the peripheral nerve to deliver the blocking stimulus. We extended this technique to central motor pathways, using a single metal microelectrode to deliver focal sinusoidal currents to the corticospinal tract at the cervical spinal cord in anesthetized adult baboons. The extent of conduction block was assessed by stimulating a second electrode caudal to the blocking site and recording the antidromic field potential over contralateral primary motor cortex. The maximal block achieved was 99.6%, similar to findings of previous work in peripheral fibers, and the optimal frequency for blocking was 2 kHz. Block had a rapid onset, being complete as soon as the transient activation associated with the start of the sinusoidal current was over. High-frequency block was also successfully applied to the pyramidal tract at the medulla, ascending sensory pathways in the dorsal columns, and the descending systems of the medial longitudinal fasciculus. High-frequency sinusoidal stimulation produces transient, reversible lesions in specific target locations and therefore could be a useful alternative to permanent tissue transection in some experimental paradigms. It also could help to control or prevent some of the hyperactivity associated with chronic neurological disorders.