A Unified Framework for the Infection Dynamics of Zoonotic Spillover and Spread.

A considerable amount of disease is transmitted from animals to humans and many of these zoonoses are neglected tropical diseases. As outbreaks of SARS, avian influenza and Ebola have demonstrated, however, zoonotic diseases are serious threats to global public health and are not just problems confined to remote regions. There are two fundamental, and poorly studied, stages of zoonotic disease emergence: 'spillover', i.e. transmission of pathogens from animals to humans, and 'stuttering transmission', i.e. when limited human-to-human infections occur, leading to self-limiting chains of transmission. We developed a transparent, theoretical framework, based on a generalization of Poisson processes with memory of past human infections, that unifies these stages. Once we have quantified pathogen dynamics in the reservoir, with some knowledge of the mechanism of contact, the approach provides a tool to estimate the likelihood of spillover events. Comparisons with independent agent-based models demonstrates the ability of the framework to correctly estimate the relative contributions of human-to-human vs animal transmission. As an illustrative example, we applied our model to Lassa fever, a rodent-borne, viral haemorrhagic disease common in West Africa, for which data on human outbreaks were available. The approach developed here is general and applicable to a range of zoonoses. This kind of methodology is of crucial importance for the scientific, medical and public health communities working at the interface between animal and human diseases to assess the risk associated with the disease and to plan intervention and appropriate control measures. The Lassa case study revealed important knowledge gaps, and opportunities, arising from limited knowledge of the temporal patterns in reporting, abundance of and infection prevalence in, the host reservoir.Natural Environment Research Council (project no.: NEJ001570-1), Department for International Development, Economic and Social Research Council, National Institute for Health Research, Science and Technology Directorate, Department of Homeland Security, Fogarty International Center USA, European Union FP7 (project ANTIGONE (contract number 278976)), Royal Society (Wolfson Research Merit Award), Alborada Trust, US National Institute of Health (P20GM103501, BAANIAID-DAIT-NIHQI2008031, HHSN272201000022C, HHSN272200900049C, 1U19AI109762, 1R01AI104621, 2R44AI088843), USAID/NIH PEER Health grant.This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pntd.000495

Using modelling to disentangle the relative contributions of zoonotic and anthroponotic transmission: the case of lassa fever.

BACKGROUND: Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions. METHODOLOGY/PRINCIPAL FINDINGS: Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost [Formula: see text] of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals ('super-spreaders'), as we found only [Formula: see text] of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) [Formula: see text], with a maximum value up to [Formula: see text]. CONCLUSIONS/SIGNIFICANCE: This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection.This work for the Dynamic Drivers of Disease in Africa Consortium, NERC project no. NE-J001570-1, was funded with support from the Ecosystem Services for Poverty Alleviation (ESPA) programme. The ESPA programme is funded by the Department for International Development (DFID), the Economic and Social Research Council (ESRC) and the Natural Environment Research Council (NERC). See more at: http://www.espa.ac.uk/about/identity/acknowledging-espafunding# sthash.UivKPObf.dpuf. GL, JLNW, AAC, CTW and EFC also benefit from the support of the small mammal disease working group, funded by the Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directorate, Department of Homeland Security, and Fogarty International Center, USA. JLNW and AC were also supported by the European Union FP7 project ANTIGONE (contract number 278976). AAC is supported by a Royal Society Wolfson Reearch Merit Award. JLNW is also supported by the Alborada Trust. JSS, LM, RG, and JGS were supported by the US National Institute of Health (JSS: NIH grant P20GM103501; LM, RG, JGS: NIH grant BAA-NIAID-DAIT-NIHQI2008031).This is the final published version. It first appeared at http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0003398

Lassa Fever Induced Hearing Loss: The Neglected Disability of Hemorrhagic Fever.

OBJECTIVE: Lassa fever (LF) a hemorrhagic fever endemic to Western has an incidence of approximately 500,000 cases per year. Here, we evaluate hearing loss and other sequelae following LF. METHODS: This case-control study enrolled laboratory confirmed LF survivors, non-LF Febrile controls and Matched Community controls with no history of LF or recent hospitalization for a febrile illness. Study participants completed a symptom questionnaire. Pure-tone audiometry was completed by a subset of participants. RESULTS: One hundred forty-seven subjects were enrolled aged from 3-66 years (mean = 23.3). LF survivors were significantly more likely to report balance difficulties (55% vs 20%, p < 0.001), hair loss (32% vs 7%, p < 0.001), difficulty speaking (19% vs 1%, p < 0.001), social isolation (50% vs 0%, p < 0.001), and hearing loss (17% vs 1%, p = 0.002) in comparison to Matched-Community Controls. Similar trends were noted in comparison to Febrile Controls, although these findings were non-significant. Fifty subjects completed audiometry. Audiometry found that LF survivors had significantly more bilateral hearing loss in comparison to Matched-Community Controls (30% vs 4%, p = 0.029). CONCLUSION: This study characterizes the sequelae of LF and highlights the need for increased access to hearing care in West Africa

Long-Term Complications of Ebola Virus Disease: Prevalence and Predictors of Major Symptoms and the Role of Inflammation

Background Cohort studies have reported a high prevalence of musculoskeletal, neurologic, auditory, and visual complications among Ebola virus disease (EVD) survivors. However, little is known about the host- and disease-related predictors of these symptoms and their etiological mechanisms. Methods The presence and patterns of 8 cardinal symptoms that are most commonly reported following EVD survival were assessed in the 326 EVD survivors who participated in the ongoing longitudinal Liberian EVD Survivor Study. At quarterly study visits, symptoms that developed since acute EVD were recorded and blood was collected for biomarkers of inflammation and immune activation. Results At baseline (mean 408 days from acute EVD), 75.5% of survivors reported at least 1 new cardinal symptom since surviving EVD, which in 85.8% was rated as highly interfering with life. Two or more incident symptoms were reported by 61.0% of survivors, with pairings of joint pain, headache, or fatigue the most frequent. Women were significantly more likely than men to report headache, while older age was significantly associated with musculoskeletal and visual symptoms. In analyses adjusted for multiple comparisons, no statistically significant association was found between any symptom and 26 markers of inflammation and immune activation. Symptom frequency remained largely unchanged during study follow-up. Conclusions Post-EVD complications occur in a majority of survivors and remain present more than 4 years after acute infection. An association between markers of inflammation and immune activation and individual symptoms was not found, suggesting an alternative etiology for persistent post-EVD symptomatology

Boosting understanding of Lassa Fever virus epidemiology: Field testing a novel assay to identify past Lassa Fever virus infection in blood and oral fluids of survivors and unexposed controls in Sierra Leone.

BACKGROUND: Despite identification 50 years ago, the true burden of Lassa Fever (LF) across Africa remains undefined for reasons including research focus on hospitalised patients, lack of validated field-feasible tools which reliably identify past infection, and the fact that all assays require blood samples making large-scale surveys difficult. Designated a priority pathogen of epidemic potential requiring urgent research by the World Health Organisation, a better understanding of LF sero-epidemiology is essential to developing and evaluating new interventions including vaccines. We describe the first field testing of a novel species-neutral Double Antigen Binding Assay (DABA) designed to detect antibodies to LF in plasma and oral fluid. METHODOLOGY/PRINCIPAL FINDINGS: Paired plasma and oral fluid were collected in Sierra Leone from survivors discharged from Kenema Government Hospital Lassa Fever Unit between 1980 and 2018, and from controls recruited in Freetown in 2019. Epidemiological sensitivity and specificity of the DABA measured against historical diagnosis in survivors and self-declared non-exposed controls was 81.7% (95% CI 70.7%- 89.9%) and 83.3% (72.7%- 91.1%) respectively in plasma, and 71.8% (60.0%- 81.9%) and 83.3% (72.7%- 91.1%) respectively in oral fluid. Antibodies were identified in people infected up to 15 years and, in one case, 40 years previously. Participants found oral fluid collection easy and painless with 80% happy to give an oral fluid sample regularly. CONCLUSIONS/SIGNIFICANCE: Given the difficulties of assay validation in a resource-limited setting, including unexpected exposures and diagnostics of varying accuracy, the new assay performed well in both plasma and oral fluid. Sensitivity and specificity are expected to be higher when case/control ascertainment is more definitive and further work is planned to investigate this. Even at the performance levels achieved, the species-neutral DABA has the potential to facilitate the large-scale seroprevalence surveys needed to underpin essential developments in LF control, as well as support zoonotic investigations

Dengue and chikungunya seroprevalence among Qatari nationals and immigrants residing in Qatar.

The objective of this study is to characterize the seroprevalence of anti-dengue (DENV) and anti-chikungunya (CHIKV) antibodies among blood donors residing in Qatar who are Middle East and North Africa (MENA) nationals and non-nationals. Sera were collected from adult blood donors in Qatar from 2013 to 2016 and tested for anti-DENV and anti-CHIKV IgG using commercial microplate enzyme-linked immunosorbent assays. Age-specific seroprevalence was summarized by region/nationality: Asia (India, Philippines), Middle East (Iran, Jordan, Lebanon, Pakistan, Palestine, Syria, Yemen), North Africa (Egypt, Sudan), Qatar. The adjusted odds of anti-DENV and anti-CHIKV IgG seropositivity was estimated by logistic regression. Among 1,992 serum samples tested, Asian nationals had higher adjusted odds of being seropositive for anti-DENV antibodies compared to nationals of the Middle East (aOR 0.05, 95% CI 0.04-0.07), North Africa (aOR 0.14, 95% CI 0.10-0.20), and Qatar (aOR 0.01, 95% CI 0.01-0.03). Asian nationals also had higher adjusted odds of being seropositive for anti-CHIKV antibodies compared to those from the Middle East (aOR 0.14, 95% CI 0.07-0.27), North Africa (aOR 0.50, 95% CI 0.26-0.96), and Qatar (aOR 0.38, 95% CI 0.15-0.96). The adjusted odds of being anti-DENV seropositive was higher among anti-CHIKV seropositive adults, and vice versa (aOR 1.94, 95% CI 1.09-3.44), suggesting co-circulation of these viruses. DENV and CHIKV exposure is lower in Qatar and MENA nationals compared to Asian nationals suggesting a lower burden of DENV and CHIKV disease in the MENA. Antibodies to both viruses were detected in nationals from most MENA countries, supporting the need to better understand the regional epidemiology of these viruses.This work was supported by Qatar University student grants [QUST-1-CHS-2018-3/4, received by ESA, MMH, SSO, DMA, HGE] and the Qatar National Research Fund [UREP19-013-3- 001, received by LJA and GKN]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Being Ready to Treat Ebola Virus Disease Patients

As the outbreak of Ebola virus disease (EVD) in West Africa continues, clinical preparedness is needed in countries at risk for EVD (e.g., United States) and more fully equipped and supported clinical teams in those countries with epidemic spread of EVD in Africa. Clinical staff must approach the patient with a very deliberate focus on providing effective care while assuring personal safety. To do this, both individual health care providers and health systems must improve EVD care. Although formal guidance toward these goals exists from the World Health Organization, Medecin Sans Frontières, the Centers for Disease Control and Prevention, and other groups, some of the most critical lessons come from personal experience. In this narrative, clinicians deployed by the World Health Organization into a wide range of clinical settings in West Africa distill key, practical considerations for working safely and effectively with patients with EVD

Outcomes of World Health Organization–defined Severe Respiratory Distress without Shock in Adults in Sub-Saharan Africa

Sepsis is the leading cause of global mortality and is most often attributed to lower respiratory tract infections and subsequent acute respiratory distress syndrome (ARDS) (1). The greatest burden of sepsis rests on sub-Saharan Africa, where lower respiratory tract infections account for approximately 390,000 adult deaths each year (2). However, patients from sub-Saharan Africa are underrepresented in sepsis and ARDS research (3). ARDS is difficult to diagnose in low-income countries because it requires often unavailable imaging, mechanical ventilation to set positive end-expiratory pressure and deliver a reliable fraction of inspired oxygen, and arterial blood gases to identify hypoxemia (4). To mitigate this gap, the World Health Organization (WHO) pragmatically defined severe respiratory distress without shock (SRD) in adults as oxygen saturation of less than 90% or a respiratory rate of more than 30 breaths per minute, and a systolic blood pressure over 90 mm Hg in the setting of infection and in the absence of clinical cardiac failure (5). The natural history of SRD has not been fully described; accordingly, we aimed to evaluate the prevalence, characteristics, and outcomes of SRD in hospitalized patients in sub-Saharan Africa

Implementation of the Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) study: Lessons learned for vision health systems strengthening in Sierra Leone.

BACKGROUND: Following the West African Ebola virus disease (EVD) outbreak of 2013-2016 and more recent EVD outbreaks in the Democratic Republic of Congo, thousands of EVD survivors are at-risk for sequelae including uveitis, which can lead to unremitting inflammation and vision loss from cataract. Because of the known risk of Ebola virus persistence in ocular fluid and the need to provide vision-restorative, safe cataract surgery, the Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) Study was implemented in Sierra Leone. During implementation of this multi-national study, challenges included regulatory approvals, mobilization, community engagement, infection prevention and control, and collaboration between multiple disciplines. In this report, we address the multifacted approach to address these challenges and the impact of implementation science research to address an urgent clinical subspecialty need in an outbreak setting. METHODOLOGY/PRINCIPAL FINDINGS: Given the patient care need to develop a protocol to evaluate ocular fluid for Ebola virus RNA persistence prior to cataract surgery, as well as protocols to provide reassurance to ophthalmologists caring for EVD survivors with cataracts, the EVICT study was designed and implemented through the work of the Ministry of Health, Sierra Leone National Eye Programme, and international partnerships. The EVICT study showed that all 50 patients who underwent ocular fluid sampling at 19 and 34 months, respectively, tested negative for Ebola virus RNA. Thirty-four patients underwent successful cataract surgery with visual acuity improvement. Here we describe the methodology for study implementation, challenges encountered, and key issues that impacted EVD vision care in the immediate aftermath of the EVD outbreak. Key aspects of the EVICT study included defining the pertinent questions and clinical need, partnership alignment with key stakeholders, community engagement with EVD survivor associations, in-country and international regulatory approvals, study site design for infection prevention and control, and thorough plans for EVD survivor follow-up care and monitoring. Challenges encountered included patient mobilization owing to transportation routes and distance of patients in rural districts. Strong in-country partnerships and multiple international organizations overcame these challenges so that lessons learned could be applied for future EVD outbreaks in West and Central Africa including EVD outbreaks that are ongoing in Guinea and Democratic Republic of Congo. CONCLUSIONS/SIGNIFICANCE: The EVICT Study showed that cataract surgery with a protocol-driven approach was safe and vision-restorative for EVD survivors, which provided guidance for EVD ophthalmic surgical care. Ophthalmologic care remains a key aspect of the public health response for EVD outbreaks but requires a meticulous, yet partnered approach with international and local in-country partners. Future efforts may build on this framework for clinical care and to improve our understanding of ophthalmic sequelae, develop treatment paradigms for EVD survivors, and strengthen vision health systems in resource-limited settings

Neutralizing and non-neutralizing monoclonal antibodies against dengue virus E protein derived from a naturally infected patient

<p>Abstract</p> <p>Background</p> <p>Antibodies produced in response to infection with any of the four serotypes of dengue virus generally provide homotypic immunity. However, prior infection or circulating maternal antibodies can also mediate a non-protective antibody response that can enhance the course of disease in a subsequent heterotypic infection. Naturally occurring human monoclonal antibodies can help us understand the protective and pathogenic roles of the humoral immune system in dengue virus infection.</p> <p>Results</p> <p>Epstein-Barr Virus (EBV) transformation of B cells isolated from the peripheral blood of a human subject with previous dengue infection was performed. B cell cultures were screened by ELISA for antibodies to dengue (DENV) envelope (E) protein. ELISA positive cultures were cloned by limiting dilution. Three IgG1 human monoclonal antibodies (HMAbs) were purified and their binding specificity to E protein was verified by ELISA and biolayer interferometry. Neutralization and enhancement assays were conducted in epithelial and macrophage-like cell lines, respectively. All three HMAbs bound to E from at least two of the four DENV serotypes, one of the HMAbs was neutralizing, and all were able to enhance DENV infection.</p> <p>Conclusions</p> <p>HMAbs against DENV can be successfully generated by EBV transformation of B cells from patients at least two years after naturally acquired DENV infections. These antibodies show different patterns of cross-reactivity, neutralizing, and enhancement activity.</p