Abstract Background Chikungunya fever is a globally spreading mosquito-borne disease that shows an unexpected neu- rovirulence. Even though the neurological complications have been a major cause of intensive care unit admission and death, to date, there is no systematic analysis of their spectrum available. Objective To review evidence of neurological manifesta- tions in Chikungunya fever and map their epidemiology, clinical spectrum, pathomechanisms, diagnostics, therapies and outcomes. Methods Case report and systematic review of the litera- ture followed established guidelines. All cases found were assessed using a 5-step clinical diagnostic algorithm assigning categories A–C, category A representing the highest level of quality. Only A and B cases were con- sidered for further analysis. After general analysis, cases were clustered according to geospatial criteria for subgroup analysis. Results Thirty-six of 1196 studies were included, yielding 130 cases. Nine were ranked as category A (diagnosis of Neuro-Chikungunya probable), 55 as B (plausible), and 51 as C (disputable). In 15 cases, alternative diagnoses were more likely. Patient age distribution was bimodal with a mean of 49 years and a second peak in infants. Fifty per- cent of the cases occurred in patients <45 years with no reported comorbidity. Frequent diagnoses were encephali- tis, optic neuropathy, neuroretinitis, and Guillain–Barre ́ syndrome. Neurologic conditions showing characteristics of a direct viral pathomechanism showed a peak in infants and a second one in elder patients, and complications and neurologic sequelae were more frequent in these groups. Autoimmune-mediated conditions appeared mainly in patients over 20 years and tended to show longer latencies and better outcomes. Geospatial subgrouping of case reports from either India or Re ́union revealed diverging phenotypic trends (Re ́union: 88% direct viral vs. India: 81% autoimmune). ConclusionsDirect viral forms of Neuro-Chikungunya seem to occur particularly in infants and elderly patients, while autoimmune forms have to be also considered in middle-aged, previously healthy patients, especially after an asymptomatic interval. This knowledge will help to identify future Neuro-Chikungunya cases and to improve outcome especially in autoimmune-mediated conditions. The genetics of Chikungunya virus might play a key role in determining the course of neuropathogenesis. With further research, this could prove diagnostically significant.
Clinical Trials of Therapeutics for the Prevention of Congenital Zika Virus Disease: Challenges and Potential Solutionsby Alex Salam, Amanda Rojek, Jake Dunning, Peter Horby
This article evaluates the major challenges in choosing therapeutics to prevent congenital ZIKV disease and conducting clinical trials of these treatments, with a focus on preventing congenital central nervous system malformations. This article was first published in Annals of Internal Medicine.
This paper proposes a generic ordinal sequential trial design (GOST) for a randomised clinical trial comparing an experimental treatment for an emerging infectious disease with standard care. The design is intended as an off-the-shelf, ready-to-use robust and flexible option. This article was first published in PLOS.
With video. Results of the Wellcome Trust funded trial of the experimental anti-Ebola drug TKM-130803 have been published in PLoS Medicine. Using a novel approach designed to get rapid indications of a drug’s effectiveness, the trial showed that at the dose given the drug did not improve survival compared to historic controls.
Charvy Narain describes how Oxford medics found themselves on the front line
Abstract Chikungunya is an emerging arbovirus that is characterized into four lineages. One of these, the Asian genotype, has spread rapidly in the Americas after its introduction in the Saint Martin island in October 2013. Unexpectedly, a new lineage, the East-Central-South African genotype, was introduced from Angola in the end of May 2014 in Feira de Santana (FSA), the second largest city in Bahia state, Brazil, where over 5,500 cases have now been reported. Number weekly cases of clinically confirmed CHIKV in FSA were analysed alongside with urban district of residence of CHIKV cases reported between June 2014 and October collected from the municipality’s surveillance network. The number of cases per week from June 2014 until September 2015 reveals two distinct transmission waves. The first wave ignited in June and transmission ceased by December 2014. However, a second transmission wave started in January and peaked in May 2015, 8 months after the first wave peak, and this time in phase with Dengue virus and Zika virus transmission, which ceased when minimum temperature dropped to approximately 15°C. We find that shorter travelling times from the district where the outbreak first emerged to other urban districts of FSA were strongly associated with incidence in each district in 2014 (R2).
This article discusses the designs used for two such clinical trials which have recruited patients in Liberia and Sierra Leone. General principles are outlined for trial designs intended to be deployed quickly, adapt flexibly and provide results soon enough to influence the course of the current epidemic rather than just providing evidence for use should Ebola break out again. Lessons are drawn for the conduct of clinical research in future outbreaks of infectious diseases, where the sequence of events may or may not be similar to the West African Ebola epidemic. The paper was published in Clinical Trials.
This article describes the treatments tested during the recent Ebola outbreak, it was published in Science on the 31st of December 2015.
The article in The Conversation today discusses the recent NEJM publication where a consortium led by the Antwerp Institute of Tropical Medicine examined the utility of convalescent plasma in treating Ebola during the recent epidemic.
Very few treatments have been sucessful in treating Ebola. Convalescent plasma has been used sucessfully to treat a number of diseases, the Ebola Tx consortium examined the utility of using convalescent plasma to treat Ebola patients attending an Ebola Treatment Centre in Guinea.
Could scientists make history and change the way we deal with outbreaks?
In December 2013, an outbreak of Chikungunya virus (CHIKV) caused by the Asian genotype was notified in the Caribbean. The outbreak has since spread to 38 regions in the Americas. By September 2014, the first autochthonous CHIKV infections were confirmed in Oiapoque, North Brazil, and in Feira de Santana, Northeast Brazil. METHODS: We compiled epidemiological and clinical data on suspected CHIKV cases in Brazil and polymerase-chain-reaction-based diagnostic was conducted on 68 serum samples from patients with symptom onset between April and September 2014. Two imported and four autochthonous cases were selected for virus propagation, RNA isolation, full-length genome sequencing, and phylogenetic analysis. We then followed CDC/PAHO guidelines to estimate the risk of establishment of CHIKV in Brazilian municipalities. RESULTS: We detected 41 CHIKV importations and 27 autochthonous cases in Brazil. Epidemiological and phylogenetic analyses indicated local transmission of the Asian CHIKV genotype in Oiapoque. Unexpectedly, we also discovered that the ECSA genotype is circulating in Feira de Santana. The presumed index case of the ECSA genotype was an individual who had recently returned from Angola and developed symptoms in Feira de Santana. We estimate that, if CHIKV becomes established in Brazil, transmission could occur in 94% of municipalities in the country and provide maps of the risk of importation of each strain of CHIKV in Brazil. CONCLUSIONS: The etiological strains associated with the early-phase CHIKV outbreaks in Brazil belong to the Asian and ECSA genotypes. Continued surveillance and vector mitigation strategies are needed to reduce the future public health impact of CHIKV in the Americas.