Rabies and the pandemic: lessons for One Health

This article examines the impact of coronavirus disease 2019 (COVID-19) on dog-mediated rabies, a neglected tropical disease that remains endemic in >65 countries. A globally agreed strategy for rabies elimination is underpinned by a One Health approach, coordinating human and animal health sectors and engaging communities. We present data on the scale and nature of COVID-19 disruption to rabies control programmes and the wider learning for One Health implementation. We argue that the global shift in health priorities caused by the pandemic, and consequent side-lining of animal health, will have broader ramifications for One Health implementation and preparedness for future emergent zoonoses

The need to improve access to rabies post-exposure vaccines: Lessons from Tanzania

Background Rabies is preventable through prompt administration of post-exposure prophylaxis (PEP) to exposed persons, but PEP access is limited in many rabies-endemic countries. We investigated how access to PEP can be improved to better prevent human rabies. Methods Using data from different settings in Tanzania, including contact tracing (2,367 probable rabies exposures identified) and large-scale mobile phone-based surveillance (24,999 patient records), we estimated the incidence of rabies exposures and bite-injuries, and examined health seeking and health outcomes in relation to PEP access. We used surveys and qualitative interviews with stakeholders within the health system to further characterise PEP supply and triangulate these findings. Results Incidence of bite-injury patients was related to dog population sizes, with higher incidence in districts with lower human:dog ratios and urban centres. A substantial percentage (25%) of probable rabies exposures did not seek care due to costs and limited appreciation of risk. Upon seeking care a further 15% of probable rabies exposed persons did not obtain PEP due to shortages, cost barriers or misadvice. Of those that initiated PEP, 46% did not complete the course. If no PEP was administered, the risk of developing rabies following a probable rabies exposure was high (0.165), with bites to the head carrying most risk. Decentralized and free PEP increased the probability that patients received PEP and reduced delays in initiating PEP. No major difficulties were encountered by health workers whilst switching to dose-sparing ID administration of PEP. Health infrastructure also includes sufficient cold chain capacity to support improved PEP provision. However, high costs to governments and patients currently limits the supply chain and PEP access. The cost barrier was exacerbated by decentralization of budgets, with priority given to purchase of cheaper medicines for other conditions. Reactive procurement resulted in limited and unresponsive PEP supply, increasing costs and risks to bite victims. Conclusion PEP access could be improved and rabies deaths reduced through ring-fenced procurement, switching to dose-sparing ID regimens and free provision of PEP

Rapid in-country sequencing of whole virus genomes to inform rabies elimination programmes.

Genomic surveillance is an important aspect of contemporary disease management but has yet to be used routinely to monitor endemic disease transmission and control in low- and middle-income countries. Rabies is an almost invariably fatal viral disease that causes a large public health and economic burden in Asia and Africa, despite being entirely vaccine preventable. With policy efforts now directed towards achieving a global goal of zero dog-mediated human rabies deaths by 2030, establishing effective surveillance tools is critical. Genomic data can provide important and unique insights into rabies spread and persistence that can direct control efforts. However, capacity for genomic research in low- and middle-income countries is held back by limited laboratory infrastructure, cost, supply chains and other logistical challenges. Here we present and validate an end-to-end workflow to facilitate affordable whole genome sequencing for rabies surveillance utilising nanopore technology. We used this workflow in Kenya, Tanzania and the Philippines to generate rabies virus genomes in two to three days, reducing costs to approximately £60 per genome. This is over half the cost of metagenomic sequencing previously conducted for Tanzanian samples, which involved exporting samples to the UK and a three- to six-month lag time. Ongoing optimization of workflows are likely to reduce these costs further. We also present tools to support routine whole genome sequencing and interpretation for genomic surveillance. Moreover, combined with training workshops to empower scientists in-country, we show that local sequencing capacity can be readily established and sustainable, negating the common misperception that cutting-edge genomic research can only be conducted in high resource laboratories. More generally, we argue that the capacity to harness genomic data is a game-changer for endemic disease surveillance and should precipitate a new wave of researchers from low- and middle-income countries

The potential effect of improved provision of rabies post-exposure prophylaxis in Gavi-eligible countries: a modelling study

Background: Tens of thousands of people die from dog-mediated rabies annually. Deaths can be prevented through post-exposure prophylaxis for people who have been bitten, and the disease eliminated through dog vaccination. Current post-exposure prophylaxis use saves many lives, but availability remains poor in many rabies-endemic countries due to high costs, poor access, and supply. Methods: We developed epidemiological and economic models to investigate the effect of an investment in post-exposure prophylaxis by Gavi, the Vaccine Alliance. We modelled post-exposure prophylaxis use according to the status quo, with improved access using WHO-recommended intradermal vaccination, with and without rabies immunoglobulin, and with and without dog vaccination. We took the health provider perspective, including only direct costs. Findings: We predict more than 1 million deaths will occur in the 67 rabies-endemic countries considered from 2020 to 2035, under the status quo. Current post-exposure prophylaxis use prevents approximately 56 000 deaths annually. Expanded access to, and free provision of, post-exposure prophylaxis would prevent an additional 489 000 deaths between 2020 and 2035. Under this switch to efficient intradermal post-exposure prophylaxis regimens, total projected vaccine needs remain similar (about 73 million vials) yet 17·4 million more people are vaccinated, making this an extremely cost-effective method, with costs of US$635 per death averted and$33 per disability-adjusted life-years averted. Scaling up dog vaccination programmes could eliminate dog-mediated rabies over this time period; improved post-exposure prophylaxis access remains cost-effective under this scenario, especially in combination with patient risk assessments to reduce unnecessary post-exposure prophylaxis use. Interpretation: Investing in post-exposure vaccines would be an extremely cost-effective intervention that could substantially reduce disease burden and catalyse dog vaccination efforts to eliminate dog-mediated rabies. Funding: World Health Organization

Malignant Mesothelioma Manifesting in an Elderly Female without Occupational Asbestos Exposure

Case Presentation: A 71-year-old Caucasian female with a history of SARS-CoV-2 pneumonia, chronic obstructive pulmonary disease (COPD) and 50 pack-years smoking presented with dyspnea, cough, fever, anorexia, and 12-pound weight loss over two weeks. She had three recent hospitalizations for COPD exacerbation and pneumonia. She was noted to be hypoxic despite five liters/minute of supplemental oxygen. Laboratory studies revealed leukocytosis, hypernatremia, and elevated brain natriuretic peptide. Urine streptococcal and legionella antigens, and respiratory viral panel were negative. Chest radiograph [Figure 1] revealed lobulated left-sided pleural masses, which were confirmed on computed tomography (CT) scan of the chest [Figure 2]. CT-guided pleural biopsy was performed, and the diagnosis of malignant mesothelioma (MM) was established. Positron emission tomography revealed avidity of the pleural masses [Figure 3]. The patient denied occupational asbestos exposure, however she reported routinely laundering her husband's clothing who worked extensively with asbestos. She elected to pursue hospice care.Sarah Steenson (1), Tarang Pankaj Patel (1), Satish Kalanjeri (2), Jeremy Carl Johnson (2) ; 1. Division of Pulmonary, Critical Care and Environmental Medicine, University of Missouri School of Medicine. 2. Division of Pulmonary, Critical Care and Environmental Medicine, Harry S Truman Veterans Affairs Hospital, University of Missouri School of Medicine.Includes bibliographical reference

The impact of the first year of the COVID-19 pandemic on canine rabies control efforts: a mixed-methods study of observations about the present and lessons for the future

Achieving zero human deaths from dog-mediated rabies has been set as a global target for 2030. However, the COVID-19 pandemic has disrupted essential health services across the world, with disproportionate impacts on Neglected Tropical Diseases. Through a mixed-method study using stakeholder questionnaires and in-depth interviews, we examined the scale and nature of disruption from the first year of the pandemic to rabies control programs, and reflected on lessons for the future. Study participants included practitioners and policymakers working in government, academia, international organizations, and the pharmaceutical industry across 48 countries, mainly in Africa and Asia. Mass dog vaccination, essential to rabies control, was most heavily impacted and in 2020, was carried out as planned in just 5% of surveyed countries. Access to post-exposure prophylaxis (PEP) also decreased due to fear of COVID-19 infection and difficulties in reaching health care centers. Dog vaccination and PEP delivery suffered from disruptions to the importation and distribution of vaccines. School closures affected rabies awareness activities and, when public events moved online, they could not reach the most disadvantaged groups. Surveillance, already weak, was severely disrupted by movement restrictions which, together with reduced demand for PEP, exacerbated under-reporting. Participants reported growing complaints around free-roaming dogs, with numbers likely to have increased in some settings. In some countries, dog rabies outbreaks and human rabies cases were already ascribed to the pandemic, but further impacts are likely still to be realized. Meanwhile, decreased demand for PEP from COVID-19 constraints could lead to reduced procurement in future. In the wake of post-COVID-19 demands on health services, there is an opportunity for veterinary services to show leadership in progressing the Zero by 30 agenda, particularly in scaling up mass dog vaccination within and across countries, as well as potential to make better use of community-based vaccinators. Countries must further secure stable procurement of dog and human vaccines, classifying them as essential goods prioritized for import and where needed, through sharing of stocks. Dedicated telemedicine services also show promise, for example through fostering participatory disease surveillance, including Integrated Bite Case Management, and delivering up-to-date instructions on the closest sources of PEP

Transcutaneous carbon dioxide monitoring could reduce physical contact with COVID-19 patients

Background: Transcutaneous carbon di-oxide (TcCO2) monitoring can be valuable to allow non-invasive monitoring of plasma carbon dioxide (PaCO2) levels in patients with acute respiratory failure including those with novel coronavirus disease 2019 (COVID-19). Methods: A pilot retrospective chart review was performed on critically-ill, adult patients admitted to the medical intensive care unit to assess correlation between TcCO2 and PaCO2 values. Obtained demographics, diagnoses, acute physiology, and chronic health evaluation II score (APACHE II), and Charlson co-morbidity index. TcCO2 values compared with corresponding blood gas PaCO2 values - including patients requiring inotropic agents. Microsoft Excel 2016 and IBM SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, N.Y., USA) used for statistical analysis. Results: Cohort consisted of 53 patients with acute respiratory failure from a variety of documented overlapping diagnoses. Thirty-one (58.4%) needed invasive mechanical ventilation, 20 (37.7%) required non-invasive ventilation with impending need for intubation and 2 patients (3.8%) who did not require oxygen delivery beyond high flow nasal cannula. Forty patients provided 121 instances of paired measurements of TcCO2 and PaCO2 where values were strongly correlated, r(121)=.90, p[less than]0.001, including 54 instances where patients received one or more inotrope infusions at time of measurement. In the paired measurement cohort, the sum of instances per overlapping diagnosis accounted for 47[38.8%] COVID-19, 20[16.5%] interstitial lung disease, 69[57%] pneumonia, 74[61.2%] septic shock, 23[19%] acute exacerbation of chronic obstructive lung disease, 8[6.6%] pulmonary embolism, 13[10.7%] aspiration pneumonia, 7[5.8%] severe pulmonary hypertension, 10 [8.3%] cardiac arrest, 24[19.8%] congestive heart failure, 1[0.8%] each for neuromuscular respiratory failure and angioedema and 13[10.4%] stroke. Conclusions: Continuous TcCO2 monitoring correlates well with PaCO2 offering opportunities to reduce the need for physical patient contact for frequent arterial punctures and arterial line placement among critically-ill patients with acute respiratory failure. It is a valuable addition to non-invasive monitoring of PaCO2 especially those with COVID-19 and irrespective of shock states.James Carrington, DO (1); Tinashe Maduke, MD, MPH (2); Sarah Steenson, DO (2); Nurjahan Khatun, MD (1); Troy Whitacre, RRT (3); Mohammed Alnijoumi, MD (2), Hariharan Regunath, MD (2,4) ; 1. Department of Medicine, University of Missouri. 2. Department of Medicine – Division of Pulmonary, Critical Care and Environmental Medicine, University of Missouri. 3. Respiratory Therapy Services, University of Missouri Hospital and Clinics. 4. Department of Medicine– Division of Infectious Diseases, University of Missouri.Includes bibliographical reference

Scaling-up the delivery of dog vaccination campaigns against rabies in Tanzania

An increasing number of countries are committing to meet the global target to eliminate human deaths from dog-mediated rabies by 2030. Mass dog vaccination is central to this strategy. To interrupt rabies transmission from dogs to humans, the World Health Organization recommends that vaccination campaigns should be carried out every year in all dog-owning communities vaccinating 70% of their susceptible dogs. Monitoring and evaluation of dog vaccination campaigns are needed to measure progress towards elimination. In this study, we measured the delivery performance of large-scale vaccination campaigns implemented in 25 districts in south-east Tanzania from 2010 until 2017. We used regression modelling to infer the factors associated with, and potentially influencing the successful delivery of vaccination campaigns. During 2010–2017, five rounds of vaccination campaigns were carried out, vaccinating in total 349,513 dogs in 2,066 administrative vaccination units (rural villages or urban wards). Progressively more dogs were vaccinated over the successive campaigns. The campaigns did not reach all vaccination units each year, with only 16–28% of districts achieving 100% campaign completeness (where all units were vaccinated). During 2013–2017 when vaccination coverage was monitored, approximately 20% of vaccination units achieved the recommended 70% coverage, with average coverage around 50%. Campaigns were also not completed at annual intervals, with the longest interval between campaigns being 27 months. Our analysis revealed that districts with higher budgets generally achieved higher completeness, with a twofold difference in district budget increasing the odds of a vaccination unit being reached by a campaign by slightly more than twofold (OR: 2.29; 95% CI: 1.69–3.09). However, higher budgets did not necessarily result in higher coverage within vaccination units that were reached. We recommend national programs regularly monitor and evaluate the performance of their vaccination campaigns, so as to identify factors hindering their effective delivery and to guide remedial action

Integrating contact tracing and whole-genome sequencing to track the elimination of dog-mediated rabies: An observational and genomic study

Background: Dog-mediated rabies is endemic across Africa causing thousands of human deaths annually. A One Health approach to rabies is advocated, comprising emergency post-exposure vaccination of bite victims and mass dog vaccination to break the transmission cycle. However, the impacts and cost-effectiveness of these components are difficult to disentangle. Methods: We combined contact tracing with whole-genome sequencing to track rabies transmission in the animal reservoir and spillover risk to humans from 2010 to 2020, investigating how the components of a One Health approach reduced the disease burden and eliminated rabies from Pemba Island, Tanzania. With the resulting high-resolution spatiotemporal and genomic data, we inferred transmission chains and estimated case detection. Using a decision tree model, we quantified the public health burden and evaluated the impact and cost-effectiveness of interventions over a 10-year time horizon. Results: We resolved five transmission chains co-circulating on Pemba from 2010 that were all eliminated by May 2014. During this period, rabid dogs, human rabies exposures and deaths all progressively declined following initiation and improved implementation of annual islandwide dog vaccination. We identified two introductions to Pemba in late 2016 that seeded re-emergence after dog vaccination had lapsed. The ensuing outbreak was eliminated in October 2018 through reinstated islandwide dog vaccination. While post-exposure vaccines were projected to be highly cost-effective ($256 per death averted), only dog vaccination interrupts transmission. A combined One Health approach of routine annual dog vaccination together with free post-exposure vaccines for bite victims, rapidly eliminates rabies, is highly cost-effective ($1657 per death averted) and by maintaining rabies freedom prevents over 30 families from suffering traumatic rabid dog bites annually on Pemba island. Conclusions: A One Health approach underpinned by dog vaccination is an efficient, cost-effective, equitable, and feasible approach to rabies elimination, but needs scaling up across connected populations to sustain the benefits of elimination, as seen on Pemba, and for similar progress to be achieved elsewhere. Funding: Wellcome [207569/Z/17/Z, 095787/Z/11/Z, 103270/Z/13/Z], the UBS Optimus Foundation, the Department of Health and Human Services of the National Institutes of Health [R01AI141712] and the DELTAS Africa Initiative [Afrique One-ASPIRE/DEL-15-008] comprising a donor consortium of the African Academy of Sciences (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA), the New Partnership for Africa’s Development Planning and Coordinating (NEPAD) Agency, Wellcome [107753/A/15/Z], Royal Society of Tropical Medicine and Hygiene Small Grant 2017 [GR000892] and the UK government. The rabies elimination demonstration project from 2010-2015 was supported by the Bill & Melinda Gates Foundation [OPP49679]. Whole-genome sequencing was partially supported from APHA by funding from the UK Department for Environment, Food and Rural Affairs (Defra), Scottish government and Welsh government under projects SEV3500 and SE0421