Zika virus: causality, open science and risk of emerging infectious diseases

The Zika virus (ZIKV) outbreak in the Americas between 2015 and 2017 took the world by surprise. Within two years, over 1.5 million suspected or confirmed cases were reported. However, the true incidence is likely much higher, due to under-reporting and asymptomatic infections that are undetected. As of July 2019, 87 countries had reported ongoing or past circulation of ZIKV. ZIKV infection results generally in mild and transient symptoms. The disease caused by ZIKV is often asymptomatic or mild. However, infection during pregnancy can result in severe adverse congenital outcomes with microcephaly as most prominent. This was first noted in clusters of infants born with disabilities linked to ZIKV infection in Brazil in 2015, making ZIKV a disease with a serious public health impact. In this thesis, I explore different aspects of the ZIKV epidemic. I use different epidemiological methods to provide insight in the Zika virus as a cause of adverse outcomes, ZIKV as a sexually transmitted disease and the risk of future ZIKV outbreaks. In Chapter 1, I provide an introduction to the history of emerging infections and the emergence of ZIKV specifically. I describe the investigation of causality, the use and accumulation of evidence during disease outbreaks, and how disease transmission can be investigated using mathematical models. In Chapter 2, I provide insight in how evidence accumulates during an outbreak and more in general during new causal questions. Case reports and case series were the first studies to appear, followed by basic research (in vivo and in vitro studies). It took more than a year after the onset of the ZIKV outbreak for robust epidemiological studies to be published. Establishing early public health guidance thus requires a broad approach taking into account all evidence available. We have to make do with the low quality evidence. To minimize further delays, evidence should be accessible as soon as it becomes available through rapid and open access dissemination. In Chapter 3, I extend a systematic review that was conducted earlier, and turn it into a living systematic review. I introduce the concept and implementation of living systematic reviews in the context of an emerging disease. I assess the evidence on the causal relation between ZIKV infection and adverse congenital and auto-immune neurological outcomes, published between May 30, 2016 and January 18, 2017, using a framework based on the causality dimensions of Bradford Hill. During this period, the evidence expanded that ZIKV was indeed a cause of congenital abnormalities and Guillain-Barré syndrome (GBS). I provide a proof of concept for the use of living systematic reviews to synthesize evidence about an emerging pathogen such as ZIKV. In Chapter 4, I assess the evidence published between January 18, 2017 and July 1, 2019. I quantify the strength of association of the relation between maternal ZIKV infection and congenital adverse outcomes and between ZIKV infection and GBS. I found that the strength of association between ZIKV infection and adverse outcomes from case-control studies differs according to whether exposure to ZIKV is assessed in the mother (odds ratio (OR) 3.8, 95% CI: 1.7–8.7, I2=19.8%) or the foetus/infant (OR 37.4, 95% CI: 11.0–127.1, I2=0%). In cohort studies, the risk of congenital abnormalities was 3.5 times higher after ZIKV infection (95% CI: 0.9–13.5, I2=0%). The strength of association between ZIKV infection and GBS was higher in studies that enrolled controls from hospital (OR: 55.8, 95% CI: 17.2-181.7, I2=0%) than in studies that enrolled controls at random from the same community or household (OR: 2.0, 95% CI: 0.8–5.4, I2=74.6%). The heterogeneity between the studies could be partly explained by the heterogeneity in methods and sampled populations. Studies suffered from bias and uncontrolled residual confounding. In Chapter 5, I present a framework to systematically assess the evidence for ZIKV as a sexually transmitted disease. I reviewed all available literature and concluded that the risk of sexual transmission of ZIKV is likely small, but relevant for certain risk groups. I found that in semen viral RNA could be detected for a median period of 34 days (95% CI: 28–41 days) and 35 days (no CI given) based on two cohort studies. Aggregated data about detection of ZIKV RNA from 37 case reports and case series indicate a median duration of 40 days (95% CI: 30–49 days) and a maximum duration of 370 days in semen. In human vaginal fluid, the median duration was 14 days (95% CI: 7–20 days) and the maximum duration was 37 days. Infectious virus in human semen was detected for a median duration of 12 days (95% CI: 1–21 days) and a maximum of 69 days. I highlight the poor quality of the evidence and the need for systematic observational studies that evaluate the risk of sexual transmission of ZIKV. In Chapter 6, I present predictions on the future risk of ZIKV, based on data from Managua, Nicaragua, using mathematical modelling. The risk of a new outbreak in the next decades is low due to herd immunity. However, a next outbreak will disproportionally hit people in the young reproductive age hardest (age 15–29 years). Vaccination could curb this risk: Early introduction of vaccination in 15-year-old girls has the capacity to extend the herd immunity and be of benefit to the whole population. Introduction of a vaccine needs to happen within a decade after the 2016 outbreak to achieve this protection. The duration of immunity following ZIKV infection has impact on the speed at which outbreaks will reoccur. In Chapter 7, I present an overview of the main findings and I discuss the interpretation and implications of these results. I discuss the strengths and limitations of the work, and outline follow-up questions emerging from the work. In this thesis, I establish and use different frameworks and methods that help to make sense of the limited evidence that is available during disease outbreaks. ZIKV has been introduced on the American continent, and it is likely there to stay, thus we have to accept that ZIKV will continue to re-emerge. At the same time, due to the climate change, the European temperate region also becomes more suitable for vector-borne disease such as ZIKV. With the ZIKV epidemic on the wane, we now have time to consolidate findings and implement the lessons learnt. We need to be prepared for the re-emergence of ZIKV but also for the emergence of new diseases. The tools and methods I present in this thesis, will help us to be more prepared for a next outbreak

Seroprevalence and associated risk factors of brucellosis, Rift Valley fever and Q fever among settled and mobile agro-pastoralist communities and their livestock in Chad.

Brucellosis, Rift Valley fever (RVF) and Q fever are zoonoses prevalent in many developing countries, causing a high burden on human and animal health. Only a few studies are available on these among agro-pastoralist communities and their livestock in Chad. The objective of our study was to estimate brucellosis, RVF and Q fever seroprevalence among Chadian agro-pastoralist communities and their livestock, and to investigate risk factors for seropositivity. We conducted a multi-stage cross-sectional serological survey in two rural health districts, Yao and Danamadji (966 human and 1041 livestock (cattle, sheep, goat and equine) samples)). The true seroprevalence were calculated applying a Bayesian framework to adjust for imperfect diagnostic test characteristics and accounting for clustering in the study design. Risk factors for each of the zoonotic diseases were estimated using mixed effects logistic regression models. The overall prevalence for brucellosis, Q fever and RVF combined for both regions was estimated at 0.2% [95% credibility Interval: 0-1.1], 49.1% [%CI: 38.9-58.8] and 28.1% [%CI: 23.4-33.3] in humans, and 0.3% [%CI: 0-1.5], 12.8% [%CI: 9.7-16.4] and 10.2% [%CI: 7.6-13.4] in animals. Risk factors correlating significantly with the respective disease seropositivity were sex for human brucellosis, sex and Q fever co-infection for animal brucellosis, age for human Q fever, species and brucellosis co-infection for animal Q fever, age and herd-level animal RVF seroprevalence within the same cluster for human RVF, and cluster-level human RVF seroprevalence within the same cluster for animal RVF. In Danamadji and Yao, Q fever and RVF are notably seroprevalent among agro-pastoralist human and animal communities, while brucellosis appears to have a low prevalence. Correlation between the seroprevalence between humans and animals living in the same communities was detected for RVF, highlighting the interlinkage of human and animal transmissible diseases and of their health, highlighting the importance of a One Health approach

How to update a living systematic review and keep it alive during a pandemic: a practical guide.

BACKGROUND The covid-19 pandemic has highlighted the role of living systematic reviews. The speed of evidence generated during the covid-19 pandemic accentuated the challenges of managing high volumes of research literature. METHODS In this article, we summarise the characteristics of ongoing living systematic reviews on covid-19, and we follow a life cycle approach to describe key steps in a living systematic review. RESULTS We identified 97 living systematic reviews on covid-19, published up to 7th November 2022, which focused mostly on the effects of pharmacological interventions (n = 46, 47%) or the prevalence of associated conditions or risk factors (n = 30, 31%). The scopes of several reviews overlapped considerably. Most living systematic reviews included both observational and randomised study designs (n = 45, 46%). Only one-third of the reviews has been updated at least once (n = 34, 35%). We address practical aspects of living systematic reviews including how to judge whether to start a living systematic review, methods for study identification and selection, data extraction and evaluation, and give recommendations at each step, drawing from our own experience. We also discuss when it is time to stop and how to publish updates. CONCLUSIONS Methods to improve the efficiency of searching, study selection, and data extraction using machine learning technologies are being developed, their performance and applicability, particularly for reviews based on observational study designs should improve, and ways of publishing living systematic reviews and their updates will continue to evolve. Finally, knowing when to end a living systematic review is as important as knowing when to start

Outbreaks of publications about emerging infectious diseases: the case of SARS-CoV-2 and Zika virus.

BACKGROUND: Outbreaks of infectious diseases generate outbreaks of scientific evidence. In 2016 epidemics of Zika virus emerged, and in 2020, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic of coronavirus disease 2019 (COVID-19). We compared patterns of scientific publications for the two infections to analyse the evolution of the evidence. METHODS: We annotated publications on Zika virus and SARS-CoV-2 that we collected using living evidence databases according to study design. We used descriptive statistics to categorise and compare study designs over time. RESULTS: We found 2286 publications about Zika virus in 2016 and 21,990 about SARS-CoV-2 up to 24 May 2020, of which we analysed a random sample of 5294 (24%). For both infections, there were more epidemiological than laboratory science studies. Amongst epidemiological studies for both infections, case reports, case series and cross-sectional studies emerged first, cohort and case-control studies were published later. Trials were the last to emerge. The number of preprints was much higher for SARS-CoV-2 than for Zika virus. CONCLUSIONS: Similarities in the overall pattern of publications might be generalizable, whereas differences are compatible with differences in the characteristics of a disease. Understanding how evidence accumulates during disease outbreaks helps us understand which types of public health questions we can answer and when

Living systematic review on adverse outcomes of Zika - Figures and Table

Living systematic review on adverse outcomes of Zika - Figures and Tabl

Zika virus infection as a cause of congenital brain abnormalities and Guillain-Barré syndrome: A living systematic review [version 1; peer review: 2 approved].

Background: The Zika virus (ZIKV) caused a large outbreak in the Americas leading to the declaration of a Public Health Emergency of International Concern in February 2016. A causal relation between infection and adverse congenital outcomes such as microcephaly was declared by the World Health Organization (WHO) informed by a systematic review structured according to a framework of ten dimensions of causality, based on the work of Bradford Hill. Subsequently, the evidence has continued to accumulate, which we incorporate in regular updates of the original work, rendering it a living systematic review. Methods: We present an update of our living systematic review on the causal relation between ZIKV infection and adverse congenital outcomes and between ZIKV and GBS for four dimensions of causality: strength of association, dose-response, specificity, and consistency. We assess the evidence published between January 18, 2017 and July 1, 2019. Results: We found that the strength of association between ZIKV infection and adverse outcomes from case-control studies differs according to whether exposure to ZIKV is assessed in the mother (OR 3.8, 95% CI: 1.7-8.7, I 2=19.8%) or the foetus/infant (OR 37.4, 95% CI: 11.0-127.1, I 2=0%). In cohort studies, the risk of congenital abnormalities was 3.5 times higher after ZIKV infection (95% CI: 0.9-13.5, I 2=0%). The strength of association between ZIKV infection and GBS was higher in studies that enrolled controls from hospital (OR: 55.8, 95% CI: 17.2-181.7, I 2=0%) than in studies that enrolled controls at random from the same community or household (OR: 2.0, 95% CI: 0.8-5.4, I 2=74.6%). In case-control studies, selection of controls from hospitals could have biased results. Conclusions: The conclusions that ZIKV infection causes adverse congenital outcomes and GBS are reinforced with the evidence published between January 18, 2017 and July 1, 2019

Canine leptospirosis in Switzerland—A prospective cross-sectional study examining seroprevalence, risk factors and urinary shedding of pathogenic leptospires

Leptospirosis is an important worldwide zoonosis. While human leptospirosis remains rare in Switzerland, the incidence of canine leptospirosis is unusually high compared to other European countries. The aims of this cross-sectional study were to determine the exposure of asymtomatic dogs to pathogenic Leptospira in Switzerland, to characterise risk factors associated with seropositivity and to determine the prevalence of urinary shedding. Sampling was stratified to cover the whole of Switzerland. Sera were tested by microscopic agglutination test for antibodies against a panel of 12 serovars. Urine was tested for pathogenic Leptospira using a LipL32 real-time PCR. Of 377 sera, 55.7% (95%CI 51.2-60.7) showed a reciprocal MAT titre of ≥1:40 and 24.9% (95%CI 20.7-29.4) of ≥1:100 to at least one serovar. Seropositivity (MAT ≥1:100) was most common to serovars Australis (14.9%; 95% CI 11.4-18.6) and Bratislava (8.8%; 95%CI 6.1-11.7), followed by Copenhageni (6.1%; 95%CI 3.7-8.5), Canicola (5%; 95%CI 2.9-7.4), Grippotyphosa (4.5%; 95%CI 2.7-6.9), Pomona (4%; 95%CI 2.1-6.1), Autumnalis (2.7%; 95%CI 1.3-4.2) and Icterohaemorrhagiae (1.6%; 95%CI 0.5-2.9). In unvaccinated dogs (n = 84) the prevalence of a MAT titre ≥100 was 17.9% (95%CI 10.7-26.2), with a similar distribution of reactive serovars. Variables associated with seropositivity (≥1:40) to any serovar included age (OR 1.29/year; 95%CI: 1.1-1.5) and bioregion with higher risks in the regions Northern Alps (OR 14.5; 95%CI 2.2-292.7), Central Plateau (OR 12.3; 95%CI 2.0-244.1) and Jura (OR 11.2; 95%CI 1.7-226.7) compared to Southern Central Alps. Dogs living with horses were significantly more likely to have antibodies to serovar Bratislava (OR 4.68;95%CI 1.2-17.2). Hunting was a significant risk factor for seropositivtiy to serovar Grippotyphosa (OR 8.03; 95%CI 1.6-30.8). Urine qPCR positivity was uncommon (1/408 dogs; 0.2%; 95% CI0-0.7). These results demonstrate that dogs in Switzerland are commonly exposed to pathogenic Leptospira; however, the risk of dogs contributing to the spread of Leptospira in the environment appears low