Michael Jacobs

Late Ebola virus relapse causing meningoencephalitis: a case report

Summary Background There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). Methods A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. Findings On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Interpretation Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. Funding Royal Free London NHS Foundation Trust.

Post-exposure prophylaxis against Ebola virus disease with experimental antiviral agents: A case-series of health-care workers

BACKGROUND Although a few international health-care workers who have assisted in the current Ebola outbreak in west Africa have been medically evacuated for treatment of Ebola virus disease, more commonly they were evacuated after potential accidental exposure to Ebola virus. An urgent need exists for a consensus about the risk assessment of Ebola virus transmission after accidental exposure, and to investigate the use of post-exposure prophylaxis (PEP). Experimental vaccines have occasionally been used for Ebola PEP, but newly developed experimental antiviral agents have potential advantages. Here, we describe a new method for risk assessment and management of health-care workers potentially exposed to Ebola virus and report the use of experimental antiviral therapies for Ebola PEP in people. METHODS We devised a risk assessment and management algorithm for health-care workers potentially exposed to Ebola virus and applied this to eight consecutive individuals who were medically evacuated to the UK from west Africa between January, and March, 2015. PEP with antiviral agents was given to health-care workers assessed to have had substantial risk exposures to Ebola virus. Participants were followed up for 42 days after potential exposure. FINDINGS Four of eight health-care workers were classified as having had low risk exposures and managed by watchful waiting in the community. None of these health-care workers developed Ebola virus disease. The other four health-care workers had intermediate or maximum risk exposures and were given PEP with antiviral agents. PEP was well tolerated with no serious adverse effects. None of these four health-care workers, including two with maximum risk exposures from penetrating injuries with freshly used hollow-bore needles, developed Ebola virus disease. INTERPRETATION Standardised risk assessment should be adopted and consensus guidelines developed to systematically study the efficacy and safety of PEP with experimental agents. New experimental antiviral treatments are a viable option for PEP against Ebola. FUNDING Royal Free London NHS Foundation Trust.

Antibody therapeutics for Ebola virus disease.

With the unprecedented scale of the 2014-2016 West Africa outbreak, the clinical and scientific community scrambled to identify potential therapeutics for Ebola virus disease (EVD). Passive administration of antibodies has a long successful history for prophylaxis and therapy of a variety of infectious diseases, but the importance of antibodies in EVD has been unclear and is the subject of some debate. Recent studies in non-human primates have renewed interest in the potential of antibodies to impact EVD. Currently ongoing clinical evaluation of polyclonal and monoclonal antibody therapy in EVD patients in West Africa may finally offer a definitive answer to this debate.

Thyroid dysfunction in a UK hepatitis C population treated with interferon‐α and ribavirin combination therapy

Objective  To assess the incidence of thyroid dysfunction (TD) in a UK cohort of patients with hepatitis C virus (HCV) infection treated with interferon‐α (IFNα) and ribavirin combination therapy (IFN/RBV).

Cost-effectiveness of peginterferon α-2a compared with lamivudine treatment in patients with HBe-antigen-positive chronic hepatitis B in the United Kingdom

Background Peginterferon &agr;-2a (40 kDa), a new treatment for chronic hepatitis B, produces seroconversion within 48 weeks in approximately 32% of HBeAg-positive patients. Over a defined treatment duration it offers improved efficacy over lamivudine, but at higher cost. We assessed the clinical outcomes and costs, from the perspective of the UK National Health Service, of 48 weeks of peginterferon &agr;-2a (40 kDa) vs. 4 years of lamivudine. Methods Cost-effectiveness was analysed using a state-transition Markov model simulating HBeAg-positive chronic hepatitis B natural history. Efficacy data were obtained from a large randomized trial comparing peginterferon &agr;-2a (40 kDa) with lamivudine over 48 weeks. Use of adefovir salvage treatment for lamivudine-resistant patients was also evaluated. Long-term lamivudine efficacy, treatment durability, disease progression, cost, and quality-of-life estimates were derived from the literature. One-way and probabilistic sensitivity analyses evaluated uncertainty. Results Treatment with peginterferon &agr;-2a (40 kDa) for 48 weeks resulted in higher discounted total healthcare costs (£3100), but an increase of 0.3 discounted quality-adjusted life years compared with long-term lamivudine, giving an incremental cost-effectiveness ratio of £10 400 per quality-adjusted life year gained (£8300–£15 400 in one-way sensitivity analyses). The cost-effectiveness acceptability curve showed intervention was below the £30 000/QALY threshold in over 95% of the simulations. When adefovir was included for patients with lamivudine resistance, peginterferon &agr;-2a (40 kDa) had an incremental cost of £6100/QALY gained. Conclusions Treatment with peginterferon &agr;-2a (40 kDa) for a defined duration of 48 weeks, although more expensive than lamivudine therapy, provides improvement in health outcomes, with a cost-effectiveness ratio well below the current UK cost-effectiveness threshold.

First confirmed case of Crimean-Congo haemorrhagic fever in the UK

In October, 2012, a 38-year-old Afghan man presented to an emergency department in Glasgow, UK, 2 h after returning on a fl ight from Kabul via Dubai, after a 3 week stay in Afghanistan, where he had attended a wedding in Samangan Province. His symptoms had started 5 days before presentation and included fever, epigastric pain, bloody diarrhoea, and haematemesis. On examination he was languid but orientated, with physical observations within normal limits. Conjunctival suff usion was present and a haematoma rapidly developed at the site of venepuncture. Initial blood results showed transaminitis and thrombocytopenia (appendix). The patient was transferred to the Brownlee Centre for Infectious Diseases, Glasgow, and isolated in a negative-pressure room. Formal viral haemorrhagic fever risk assessment was implemented according to the 2012 guidelines published by the Advisory Committee on Dangerous Pathogens (ACDP); the patient reported no contact with ticks (the vector of Crimean-Congo haemorrhagic fever [CCHF]) or with animals and was therefore classifi ed as “possibility of viral haemorrhagic fever” (appendix). Infection control measures were applied in line with ACDP guidance. He was discussed with the Rare and Imported Pathogens Department (RIPD) of the Health Protection Agency, Greater Glasgow and Clyde Public Health Department, and the High Security Infectious Diseases Unit at the Royal Free Hospital, London. Samples of blood and urine were sent by courier to the RIPD laboratory at Porton Down, UK, for rapid CCHF virus testing by PCR: laboratory con fi rmation of the diagnosis of CCHF was made within 36 h of the patient’s presentation. After diagnosis, the patient’s wife discovered that during the Afghan wedding ceremony her husband had been close to a slaughtered calf, the probable source of infection. Despite intravenous ribavirin, the patient’s condition deteriorated, with fl uctuating Glasgow Coma Scale scores, and rising respiratory rate and pulse. 60 h after initial presentation, in keeping with national guidelines, he was transported to Glasgow International Airport by the Scottish Ambulance Service Special Operations Response Team and a dedicated RAF Air Transport Isolator team, and then transferred to the Royal Free Hospital High Security Infectious Diseases Unit in an RAF Hercules and dedicated ambulance where he was managed in a modi fi ed Trexler isolator (Putlock Chimney Systems Ltd, Whitchurch, UK) which provided a sealed environment and pro tection for the staff caring for him. During the fl ight further clinical deterioration was evident including anuria, vascular leak, and a decerebrate response to pain suggesting an intracerebral haemorrhage. Over the subsequent 24 h, he deteriorated further and developed pulmonary haemorrhage. The patient died 96 h after initial presentation. Viral haemorrhagic fever is a rare diagnosis in nonendemic areas and we report the fi rst confi rmed case of CCHF in the UK. Caused by a tick-borne virus, CCHF virus is endemic to more than 30 countries in Central and south western Asia, south eastern Europe, and Africa. Human beings can be infected from tick bites, contact with body fl uid, or, as suspected in the present case, contact with tissue from viraemic livestock. After a variable incubation period (average 2–7 days), fever and myalgia develop; haemorrhagic features start around the fourth day of illness, with mortality rate up to 30%. With increasing international travel to viral haemorrhagic fever endemic areas, clinicians in all countries must maintain a high index of suspicion for cases. In this instance, following infectious diseases consultant assessment, the possibility of viral haemor rhagic fever was recognised within 6 h of presentation, and the diagnosis of CCHF confi rmed rapidly. Consequently, the patient was promptly isolated. Surveillance has not identifi ed any onward transmission. This situation contrasts with multiple previously reported incidences of CCHF where late diagnosis and gaps in infection control procedure have been associated with nosocomial outbreaks. The case also highlights the value of a collateral history and asking about contact with blood from animal carcasses. Our patient is the fi rst confi rmed case of viral haemorrhagic fever in the UK since the 2012 guidelines for management of human infectious diseases of high consequence were published.

Provision of care for Ebola

According to WHO, more than 5000 people have died from Ebola, including 240 health workers. We are deeply concerned about the devastating effect of Ebola on reproductive health in Guinea, Liberia, and Sierra Leone in the context of continuous deterioration of socioeconomic conditions and general health in aff ected countries. The indirect negative effect of Ebola on reproductive health stems mainly from the desertion of already understaffed health facilities by health-care workers who are fearful of contracting Ebola. This fear is further increased because most reproductive health life-saving interventions include handling blood or bodily fluids from patients whose Ebola status is often unknown and health staff often do not have access to appropriate protection. Most referral maternity wards in the three most affected countries (Guinea, Liberia, and Sierra Leone) do not have equipment to do real-time screening for Ebola (eg, PCR), which could lead to the denial of care for women suspected to be pregnant. Additionally, the absence of providers offering relevant services, the inability to differentiate between Ebola and other febrile diseases, and the fear of contracting Ebola at a health facility can prevent users seeking reproductive health services. Statistics from Matam maternity hospital in Conakry, Guinea, show a substantial drop in attendance between March, 2014, and September, 2014, compared with 2013 (fi gure). A decrease in paediatric or maternal admissions because of fear of contracting Ebola has also been reported by Médecins Sans Frontières in Sierra Leone. We are concerned that women in need of reproductive health care because of pregnancy, childbirth, and post-partum related complications, including haemorrhage, eclampsia, obstructed labour, and abortion, will not have necessary and even life-saving care and attention. United Nations Population Fund estimates that 15% of the 800 000 women who will give birth in the next 12 months in Guinea, Liberia, and Sierra Leone could die of complications because of inade quate emergency obstetric care, and thousands of others could develop devastating pathological conditions, such as obstetric fistula. Increased support to fight Ebola is needed in Guinea, Liberia, and Sierra Leone coupled, with specific attention to reproductive health services. Adequate measures, including health system strengthening and community mobilisation coupled with an enabling environment for provision of emergency obstetric care, need to be put in place urgently to avoid devastating short-term and long-term effects for thousands of women.

Telaprevir or boceprevir based therapy for chronic hepatitis C infection: Development of resistance-associated variants in treatment failure

The use of triple-therapy, pegylated-interferon, ribavirin and either of the first generation hepatitis C virus (HCV) protease inhibitors telaprevir or boceprevir, is the new standard of care for treating genotype 1 chronic HCV. Clinical trials have shown response rates of around 70-80%, but there is limited data from the use of this combination outside this setting. Through an expanded access programme, we treated 59 patients, treatment naïve and experienced, with triple therapy. Baseline factors predicting treatment response or failure during triple therapy phase were identified in 58 patients. Thirty seven (63.8%) of 58 patients had undetectable HCV RNA 12weeks after the end of treatment. Genotype 1a (p=0.053), null-response to previous treatment (p=0.034), the rate of viral load decline after 12weeks of previous interferon-based treatment (p=0.033) were all associated with triple-therapy failure. The most common cause of on-treatment failure for telaprevir-based regimens was the development of resistance-associated variants (RAVs) at amino acids 36 and/or 155 of HCV protease (p=0.027) whereas in boceprevir-based regimens mutations at amino acid 54 were significant (p=0.015). SVR12 rates approaching 64% were achieved using triple therapy outside the clinical trial setting, in a patient cohort that included cirrhotics.

Thromboelastography in the Management of Coagulopathy Associated With Ebola Virus Disease

Here, we describe the first use of thromboelastography (TEG) in the management of 2 cases of Ebola virus disease. Early in their illness, both patients had evidence of a consumptive coagulopathy. As this resolved, TEG demonstrated that both developed a marked hypercoagulable state, which was treated with low-molecular-weight heparin.

Diagnostics in Ebola Virus Disease in Resource-Rich and Resource-Limited Settings

The Ebola virus disease (EVD) outbreak in West Africa was unprecedented in scale and location. Limited access to both diagnostic and supportive pathology assays in both resource-rich and resource-limited settings had a detrimental effect on the identification and isolation of cases as well as individual patient management. Limited access to such assays in resource-rich settings resulted in delays in differentiating EVD from other illnesses in returning travellers, in turn utilising valuable resources until a diagnosis could be made. This had a much greater impact in West Africa, where it contributed to the initial failure to contain the outbreak. This review explores diagnostic assays of use in EVD in both resource-rich and resource-limited settings, including their respective limitations, and some novel assays and approaches that may be of use in future outbreaks.