An investigation of genetic factors in Ebola virus disease

Introduction The West African Ebola epidemic was the largest Ebola epidemic to date with over 28,000 cases. The large number of cases permitted assessment of different disease phenotypes and outcomes of Ebola virus disease (EVD). Given the variety of disease phenotypes in EVD, a genetic predisposition to disease phenotype and outcome was hypothesised. Methods Samples from 325 deceased patients and 174 surviving patients were provided through the Sierra Leone Ministry of Health-Public Health England Ebola Biobank. Additionally, 1021 household contacts, 1004 community controls and 504 Ebola survivors were recruited in Sierra Leone. Participants provided a saliva sample for DNA extraction and an oral fluid sample for anti-EBOV IgG antibodies. Exome sequencing was undertaken on 250 extreme phenotype cases and genome wide genotyping was undertaken on 2153 Ebola patients, household contacts and community controls. Data analysis of the exome data included within family segregation studies, gene burden testing and pathway analysis. The genotyped data was interrogated through a genome wide association study comparing deceased and surviving cases. Results Of the household contacts, 3.5% were positive for anti-EBOV IgG. Seropositivity correlated with risk exposure level, with the highest risk level demonstrating seropositivity rates of 15.6%. Ebola survivors with more severe acute disease demonstrated lower levels of anti-EBOV IgG antibodies (p=0.01), as did those with more severe post-Ebola syndrome, although this was not significant. Exome sequencing revealed multiple protective mutations within cholesterol metabolism pathways. A key finding was a protective variant in the PCSK9 gene (p=0.002). Preliminary GWAS analysis of deceased versus surviving Ebola patients identified a genome wide significant (p=2.9x10-8) SNP in the Carbonic Anhydrase 5a gene. Conclusions The study established different extreme phenotypes of EVD, including highly exposed antibody negative and asymptomatic antibody positive individuals. Genetic factors affect both susceptibility to and severity of Ebola virus disease; with rare deleterious mutations in genes within cholesterol metabolism pathways, and common polymorphisms determining outcome of exposure to Ebola virus.Open Acces

In the wake of the pandemic: preparing for Long COVID

COVID-19 can cause persistent ill-health. Around a quarter of people who have had the virus experience symptoms that continue for at least a month but one in 10 are still unwell after 12 weeks. This has been described by patient groups as “Long COVID”.Our understanding of how to diagnose and manage Long COVID is still evolving but the condition can be very debilitating. It is associated with a range of overlapping symptoms including generalized chest and muscle pain, fatigue, shortness of breath, and cognitive dysfunction, and the mechanisms involved affect multiple system and include persisting inflammation, thrombosis, and autoimmunity. It can affect anyone, but women and health care workers seem to be at greater risk.Long COVID has a serious impact on people’s ability to go back to work or have a social life. It affects their mental health and may have significant economic consequences for them, their families and for society.Policy responses need to take account of the complexity of Long COVID and how what is known about it is evolving rapidl

Recommendations for the recognition, diagnosis, and management of long COVID: a Delphi study

Background In the absence of research into therapies and care pathways for long COVID, guidance based on ‘emerging experience’ is needed. Aim To provide a rapid expert guide for GPs and long COVID clinical services. Design and setting A Delphi study was conducted with a panel of primary and secondary care doctors. Method Recommendations were generated relating to the investigation and management of long COVID. These were distributed online to a panel of UK doctors (any specialty) with an interest in, lived experience of, and/or experience treating long COVID. Over two rounds of Delphi testing, panellists indicated their agreement with each recommendation (using a five-point Likert scale) and provided comments. Recommendations eliciting a response of ‘strongly agree’, ‘agree’, or ‘neither agree nor disagree’ from 90% or more of responders were taken as showing consensus. Results Thirty-three clinicians representing 14 specialties reached consensus on 35 recommendations. Chiefly, GPs should consider long COVID in the presence of a wide range of presenting features (not limited to fatigue and breathlessness) and exclude differential diagnoses where appropriate. Detailed history and examination with baseline investigations should be conducted in primary care. Indications for further investigation and specific therapies (for myocarditis, postural tachycardia syndrome, mast cell disorder) include hypoxia/desaturation, chest pain, palpitations, and histamine-related symptoms. Rehabilitation should be individualised, with careful activity pacing (to avoid relapse) and multidisciplinary support. Conclusion Long COVID clinics should operate as part of an integrated care system, with GPs playing a key role in the multidisciplinary team. Holistic care pathways, investigation of specific complications, management of potential symptom clusters, and tailored rehabilitation are needed

COVID-19 Pandemic Preparedness in a UK Tertiary and Quaternary Children's Hospital:Tales of the Unexpected

We describe the adaptive coping strategies required in the management of a heterogeneous group of SARS-CoV-2 paediatric patients. The diverse range of presentations, presenting in distinct phenotypic waves, exemplified the importance of preparedness for the unknown. Lessons learned will be essential in planning for a likely second wave of SARS-CoV-2

Clinical Manifestations and Modes of Death among Patients with Ebola Virus Disease, Monrovia, Liberia, 2014

Although the high case fatality rate (CFR) associated with Ebola virus disease (EVD) is well documented, there are limited data on the actual modes of death. We conducted a retrospective, observational cohort study among patients with laboratory-confirmed EVD. The patients were all seen at the Eternal Love Winning Africa Ebola Treatment Unit in Monrovia, Liberia, from June to August 2014. Our primary objective was to describe the modes of death of our patients and to determine predictors of mortality. Data were available for 53 patients with laboratory-confirmed EVD, with a median age of 35 years. The most frequent presenting symptoms were weakness (91%), fever (81%), and diarrhea (78%). Visible hemorrhage was noted in 25% of the cases. The CFR was 79%. Odds of death were higher in patients with diarrhea (odds ratio = 26.1, P &lt; 0.01). All patients with hemorrhagic signs died (P &lt; 0.01). Among the 18 fatal cases for which clinical information was available, three distinct modes of death were observed: Sudden death after a moderate disease process (44%), profuse hemorrhage (33%), and encephalopathy (22%). We found that these modes of death varied by age (P = 0.04), maximum temperature (P = 0.43), heart rate on admission (P = 0.04), time to death from symptom onset (P = 0.13), and duration of hospitalization (P = 0.04). Although further study is required, our findings provide a foundation for developing treatment strategies that factor in patients with specific disease phenotypes (which often require the use of aggressive hydration). These findings provide insights into underlying pathogenic mechanisms resulting in severe EVD and suggest direction for future research and development of effective treatment options.</p

Proceedings Of The 23Rd Paediatric Rheumatology European Society Congress: Part Two

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