Lyndsey Castle

Bio: Lyndsey Castle is an academic researcher from University of Oxford. The author has contributed to research in topics: Ebola virus & Outbreak. The author has an hindex of 6, co-authored 9 publications receiving 256 citations. Previous affiliations of Lyndsey Castle include Wellcome Trust Centre for Human Genetics.

Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

Abstract: Background: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. Methods and Findings: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. Conclusions: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. Trial registration: Pan African Clinical Trials Registry PACTR201501000997429 © 2016 Dunning et al.

Experimental Treatment of Ebola Virus Disease with Brincidofovir

Abstract: Background The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic. Methods and Findings In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD. Conclusions Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients.

Global outbreak research: harmony not hegemony

Abstract: [ ]perhaps it is self-evident that harmonisation of clinical investigation during outbreaks is desirable In 2016, the ISARIC/WHO CCP was implemented in Brazil in response to the emergence of Zika virus and chikungunya virus in Latin America, facilitating studies of viral shedding and serology 2 The CCP was also used for the establishment of cohort studies of critically ill patients with Middle East respiratory syndrome 3 At present, the Uganda Virus Research Institute (Entebbe, Uganda) is using the protocol to study severe acute febrile illness and severe influenza 4 The value of this approach is becoming apparent in the age of COVID-19 The original reports on clinical findings in COVID-19 used harmonised data collection 5,6 46 countries have registered to record clinical data using the ISARIC/WHO CCP Case Report Form and investigators in many countries are planning to use the CCP biological sampling protocol to coordinate studies of transmission, prognostication, pathogenesis, and diagnostics (appendix)

Clinical assessment is a neglected component of outbreak preparedness: evidence from refugee camps in Greece

Abstract: Refugees may have an increased vulnerability to infectious diseases, and the consequences of an outbreak are more severe in a refugee camp. When an outbreak is suspected, access to clinical information is critical for investigators to verify that an outbreak is occurring, to determine the cause and to select interventions to control it. Experience from previous outbreaks suggests that the accuracy and completeness of this information is poor. This study is the first to assess the adequacy of clinical characterisation of acute medical illnesses in refugee camps. The objective is to direct improvements in outbreak identification and management in this vulnerable setting. We collected prospective data in 13 refugee camps in Greece. We passively observed consultations where patients presented with syndromes that might warrant inclusion into an existing syndromic surveillance system and then undertook a structured assessment of routine clinical data collection to examine the extent to which key clinical parameters required for an outbreak response were ascertained and then documented. A total of 528 patient consultations were included. The most common presenting condition was an acute respiratory illness. Clinicians often made a comprehensive clinical assessment, especially for common syndromes of respiratory and gastrointestinal conditions, but documented their findings less frequently. For fewer than 5% of patients were a full set of vital signs ascertained and so the severity of patient illnesses was largely unknown. In only 11% of consultations was it verified that a patient who met the case criteria for syndromic surveillance reporting based on an independent assessment was reported into the system. Opportunities exist to strengthen clinical data capture and recording in refugee camps, which will produce a better calibrated and directed public health response. Information of significant utility for outbreak response is collected at the clinical interface and we recommend improving how this information is recorded and linked into surveillance systems.

Tocilizumab for treatment of mechanically ventilated patients with COVID-19.

Abstract: Background Severe coronavirus disease 2019 (COVID-19) can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is an approved treatment.

Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China.

Abstract: A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain, providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s).

The role of nanotechnology in the treatment of viral infections.

Abstract: Infectious diseases are the leading cause of mortality worldwide, with viruses in particular making global impact on healthcare and socioeconomic development. In addition, the rapid development of ...