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Ebola: lessons learned
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Ebola: lessons learned
since the virus was identified in 1976. Detailed data are not available for most outbreaks, which typically involve a few hundred cases, and occur in rural African settings. However the most recent West African Ebola epidemic, which lasted a little over 2 years from the end of 2013 until the beginning of 2016, has been extensively studied, providing insights that have significantly furthered our knowledge of this complex disease. The more than 28,000 cases of the disease were spread predominantly across three West African nations (Guinea, Sierra Leone and Liberia). This epidemic caught the world off guard and demonstrated the importance of rapid action to contain epidemic diseases in our increasingly interconnected world. Children accounted for approximately 20% of cases during the West African epidemic, despite children under 15 years making up more than 40% of the population in each of the three heavily affected countries. The relative sparing of children in this context remains unclear. It has been hypothesised that children may have been less susceptible to the disease. This is not supported by the mortality rates, which demonstrated children under five having some of the highest mortality rates of the epidemic (in excess of 70%). The other suggestion, and perhaps the more likely one, is that children were protected from infection either by community strategies to remove children from homes where there may be an infected individual, or because children generally were less likely to care for a sick relative, teenagers being an exception to this. Another possibility is that prior to the introduction of widespread screening of dead bodies, many children who died of Ebola were diagnosed with other acute febrile illnesses.
Nathalie MacDermott JA Herberg
Abstract Ebola virus disease (EVD) is a viral haemorrhagic fever caused by the filovirus, Ebola virus. In humans clinical disease results from infection with any of four species of Ebola virus (Zaire, Sudan, Bundibugyo, Tai Forest). EVD recently held the world’s attention as the international community united to tackle the largest Ebola virus epidemic in history. Focussed in West Africa and caused by the Makona strain of Zaire ebolavirus, there were over 28,000 cases with over 11,000 deaths. This article provides an overview of the epidemiology, pathophysiology and clinical signs and symptoms of EVD, with emphasis on the data arising from the 2013e2016 West African epidemic. Paediatric features, experimental therapies, survivor sequelae and preventive strategies are highlighted providing further information for the clinician on approaches to managing this disease either as individual cases or in an epidemic setting.
Keywords Ebola virus disease; epidemic; EVD; favipiravir; filovirus; intensive care; rVSV-ZEBOV vaccine; viral haemorrhagic fever; ZMAPP
Ebola virus disease (EVD) is caused by infection with Ebola virus, from the family Filoviridae. It is known to cause a severe haemorrhagic fever, with mortality rates between 25 and 90%. There are five species of Ebola virus e Zaire, Sudan, Bundibugyo, Tai Forest and Reston. Zaire, Sudan and Bundibugyo have been associated with several large outbreaks in Africa. Reston only causes symptomatic disease in animals.
Pathophysiology of EVD The Ebola virus targets a range of host tissues, including myeloid and lymphoid lineage leukocytes, endothelial, hepatic, renal and adrenal cells. Cell entry is mediated by binding to leptins and other cell surface receptors. On mast cells and Tcells, cell entry is thought to involve the TIM-1 receptor. Once endocytosed into the cell the Niemann Pick C1 receptor appears essential for viral entry into the cell cytoplasm, where replication occurs. Ebola virus uses multiple mechanisms to evade the host immune response. It sheds its glycoprotein coating to mop up circulating antibody. Efficient production of specific antibodies is inhibited by interruption of T lymphocyte signalling to B cells, as infected antigen presenting cells up-regulate T-cell inhibitory molecules and down-regulate T-cell stimulatory molecules. Early T-cell apoptosis and aberrant cytokine release depletes the cellular immune response, whilst promoting production of pro-inflammatory cytokines and inhibiting production of anti-inflammatory cytokines. The excessive proinflammatory cytokine production results in end organ damage, alongside the direct cytopathic effect of the virus which spreads widely and invades the liver, spleen, and adrenal glands, resulting in concomitant hepatic and adrenal failure. Acute kidney injury is also sustained through several potential mechanisms including, the direct cytopathic effect of the virus, acute tubular necrosis or as a direct result of hypovolaemia and deposition of microthrombi. Invasion of the endothelial lining by virus further amplifies the inflammatory cascade and leads to endothelial leakage and haemorrhagic tendencies. The latter
Epidemiology While the disease is rare, sporadic outbreaks occur in countries where the virus is present in certain mammals. The mammals identified so far include fruit bats, non-human primates and forest antelope. See Figure 1 for regions of the world known to be at risk of EVD epidemics. While Ebola virus disease is considered a zoonosis, as it must cross from its animal host into a human host for initial human disease to occur, this appears to be a sporadic event with ongoing transmission then maintained person to person (Figure 2). Healthcare workers are at particularly high risk and nosocomial transmission is common at the beginning of an outbreak when the disease may not yet be suspected in clinical settings.
Prevalence Epidemics of EVD are relatively rare, there have been approximately 23 known Ebola epidemics, occurring every few years Nathalie MacDermott BSc MBBCH is a Clinical Research Fellow in the Section of Paediatrics at Imperial College, London, UK. Conflict of interest: no competing/conflicts of interest to declare. J A Herberg MBBCH PhD is a Clinical Senior Lecturer in the Section of Paediatrics at Imperial College, London, UK. Conflict of interest: no competing/conflicts of interest to declare.
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Figure 1. Regions of the world at risk of Ebola virus disease.
Figure 2. Ebola Virus Ecology and Transmission courtesy of the Centers for Disease Control and Prevention, USA.
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is further exacerbated by thrombocytopaenia and depletion of coagulation factors through hepatic failure.
WHO EVD case definition in epidemic situations (http://www.who.int/csr/resources/publications/ebola/ebola-casedefinition-contact-en.pdf )
Clinical course
SUSPECTED CASE: Any person, alive or dead, suffering or having suffered from a sudden onset of high fever and having had contact with:
EVD initially presents in a similar fashion to many febrile infectious diseases and then progresses relatively rapidly, with death ensuing approximately 7e12 days following symptom onset. In those who survive, recovery usually follows approximately 14e21 days following onset of symptoms. While fever is a predominant feature in presentation, data from the West African epidemic reveal that up to 18% of patients did not have a fever at the time of their presentation to an Ebola treatment facility. In children under 5 years of age the data suggest this was as high as 25%. The clinical course usually commences with mild nonspecific symptoms such as fever, headache, myalgia and arthralgia and then progresses to symptoms such as abdominal pain and profuse diarrhoea. Haemorrhage follows in a proportion of patients (10e30%) a few days later, including haemorrhagic conjunctivitis, melaena/haemorrhagic diarrhoea, metrorrhagia, bleeding from venepuncture sites and bleeding from the nose and gums. Profuse and catastrophic haemorrhage as a terminal event occurs in only a small proportion of those with haemorrhagic symptoms. Clinical presentations most associated with death in the West African epidemic were those which included high fever, diarrhoea, hiccups, haemorrhagic symptoms or end organ damage. In most case series for those with overt gross haemorrhagic symptoms, the disease was invariably fatal. Children often presented with less well defined illness, making diagnosis all the more challenging, particularly in younger children. Some young infants presented in a collapsed state with a history of minimal symptoms over the preceding 24 hours. The mortality rates in children under 1 were close to 90% and for those in the neonatal period mortality was almost 100%. Teenagers on the other hand had the highest survival rates of any age group in the West African epidemic and often presented with milder symptomatology.
C C
OR: any person with sudden onset of high fever and at least three of the following symptoms: C headaches C anorexia/loss of appetite C lethargy C aching muscles or joints C breathing difficulties C vomiting C diarrhoea C stomach pain C difficulty swallowing C hiccup OR: any person with inexplicable bleeding OR: any sudden, inexplicable death. PROBABLE CASE: Any suspected case evaluated by a clinician OR: Any deceased suspected case (where it has not been possible to collect specimens for laboratory confirmation) having an epidemiological link with a confirmed case LABORATORY CONFIRMED CASE: Any suspected or probable cases with a positive laboratory result. Laboratory confirmed cases must test positive for the virus antigen, either by detection of virus RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), or by detection of IgM antibodies directed against Ebola. Box 1
Diagnosis
of EVD, the Public Health England (PHE) Imported Fever Service should be contacted. They will provide guidance as to the level of personal protective equipment required on the basis of the risk assessment. Basic observations and assessment of a patient’s hydration status are essential. Palpation of the abdomen may reveal other possible diagnoses. Caution should be applied in diagnosing an acute surgical abdomen and ruling out the diagnosis of EVD on this premise, as patients in the later stages of EVD may present with a picture consistent with an acute abdomen. There have also been reports of patients developing a gram negative sepsis during their illness. Due to the current limitations of personal protective equipment it is often not possible to auscultate the chest and heart sounds unless an electronic stethoscope with sound amplification external to the ear pieces is available.
History Patients most commonly present with a several day history of fever and symptoms common to many other infections, such as myalgia, arthralgia, headache, vomiting and diarrhoea. For this reason careful history taking is essential to elucidating suspicion of EVD amongst the many potential differential diagnoses. Suspicion of infection with Ebola virus is based on a history of contact with a confirmed or suspect case or travel to a region where there is an on-going epidemic. In regions where there is an on-going epidemic, suspicion should be heightened even in the absence of a clear history of contact. The World Health Organisation (WHO) case definition for EVD is shown below in Box 1, and Box 2 provides a list of symptoms and signs. Examination Examination of a patient meeting the case definition of a suspect case of EVD should not be undertaken other than in an isolation room with the clinician wearing full personal protective equipment. To determine risk in a potential imported case
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a suspected, probable or confirmed Ebola a dead or sick animal
Investigations The gold standard test for confirming a diagnosis of Ebola virus disease is a real-time reverse transcription polymerase chain
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In the context of a suspected case of EVD, all blood tests should be obtained with the patient in isolation and the healthcare worker wearing full PPE. Samples should be triple-contained and the laboratory notified in advance of their high-risk nature, to ensure they are handled in the appropriate manner or sent to a laboratory with appropriate containment.
Symptoms and signs of EVD Systemic Fever Weakness/fatigue/lethargy/ prostration Features of shock Lymphadenopathy (rare) Skin/Ocular Rash e maculopapular or petechial Injected conjunctivae/haemorrhagic conjunctivitis Respiratory Sore throat Cough Respiratory distress Neurological Headache Acute confusion/unresponsive Neurological signs/seizures (rare)
Musculoskeletal Myalgia Arthralgia
Differential diagnosis A list of potential differential diagnoses is available in Box 3.
Gastrointestinal Anorexia Abdominal pain Nausea/vomiting Diarrhoea Hiccups Features of acute abdomen Hepatomegaly (rare)
Management Management of patients with confirmed EVD in the UK should occur only in the context of a high level isolation unit, or if overseas, in a designated Ebola treatment facility. This is to ensure the safety of healthcare workers and other patients. Design of such treatment facilities is key to the optimum management of patients and the protection of staff. Management of EVD can be complicated both by the need for full personal protective equipment or isolation tents and by the multi-organ dysfunction that can evolve. Some patients with EVD present with only mild symptoms, with little deterioration, and go on to make a full recovery. Other patients may require full intensive care support with mechanical ventilation and renal dialysis, which entails a balance of benefit between public health and individual patient benefit, which has been widely debated. Where facilities are available and the risk to healthcare workers can be minimised, intensive care support has led to good recovery in infected international healthcare workers and should be given due consideration. The essential principles of managing EVD at present are largely supportive. They involve maintenance of fluid balance, in the face of at times extremely high gastro-intestinal losses, electrolyte replacement where necessary, stabilisation of coagulation abnormalities and minimisation of end organ damage. Where multi-organ failure ensues and facilities permit, intensive care support may be required.
Laboratory parameters: Deranged electrolytes Thrombocytopaenia Coagulation abnormalities
Haematological Bleeding from: Nose/gums Venepuncture sites Gastrointestinal (e.g. melena) Womb (e.g. metrorrhagia)
Box 2
reaction (RT-PCR). Outside of the acute disease, serological tests are available. In West Africa the application of further investigations was greatly limited, but in a high-income setting this is not the case. Certain investigations are precluded given the infection risk, for example imaging techniques such as MRI or CT, however investigations for other potential causes of symptoms should be considered depending on the patient’s presentation, such as a malaria or sepsis screen. If a viral haemorrhagic fever is suspected then PCR for Lassa fever, CrimeaneCongo haemorrhagic fever and other VHF’s should be considered. These should be discussed with PHE’s Rare and Imported Pathogens Lab. Monitoring of patients’ blood biochemistry, renal and liver function, haematology and coagulation parameters should be performed, where available. Electrolyte derangement is common in patients with profuse diarrhoea, although it appeared to be less frequent in one study of children with EVD. Renal, adrenal and hepatic dysfunction is seen, reflecting the pattern of tissue infectivity, although cytopathy is only one of several mechanisms for tissue damage. Thrombocytopenia may also develop together with coagulation abnormalities, resembling disseminated intravascular coagulation. Early identification and correction of these abnormalities may prevent development of fulminant haemorrhagic disease in those predisposed to this disease phenotype.
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Experimental therapies The West African Ebola epidemic provided an opportunity to study potentially beneficial therapies for EVD. Many of these arrived late to the epidemic due to either delays in
Potential differential diagnosis of EVD Malaria Other VHF (Lassa, CrimeaneCongo haemorrhagic fever, Marburg, arenaviruses) Gastroenteritis (bacterial/viral) Sepsis Typhoid Influenza Measles Dengue/Dengue haemorrhagic fever Yellow fever Leptospirosis Rickettsial diseases Hantavirus (pulmonary or renal syndromes) Box 3
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epidemic knowledge of post-Ebola sequelae, recrudescent disease and virus persistence in survivor’s bodily fluids was limited.
implementation of study procedures or non-availability of the study drug. Consequently, most studies were unable to demonstrate a clinically significant impact of the medication concerned. A study in Guinea which looked at favipiravir (oral, 6000 mg D0, 2400 mg D1-9), a drug developed for influenza, was able to determine that it was safe to use and straightforward to administer, but was not able to determine its efficacy. A post hoc analysis of the data suggested it was beneficial and potentially improved survival in those patients who received it when they had low viral loads. However it appeared to have no benefit in patients who had high viral loads. A trial of brincidofovir was terminated by the manufacturers early due to a scarcity of cases, and the TKM-Ebola trial was terminated mid-way by an interim review panel due to lack of efficacy. A trial of convalescent/immune plasma demonstrated no significant benefit. The most promising medication was the monoclonal antibody mixture known as ZMAPP (3 doses e D0, D3, D6). Although the ZMAPP study failed to recruit optimum numbers to demonstrate statistical significance, it showed good promise with mortality rates 40% lower in the treatment arm than the standard care arm (22% vs 37% respectively). Another medication, currently referred to as GS-5734, did not make it to clinical trials but has been shown to be highly effective in Rhesus macaque models. It was used in a few acute patients on compassionate care grounds, and is currently being trialled in Ebola survivors with virus persistence.
Sequelae and recrudescent disease Three studies from epidemics in Uganda and Democratic Republic of Congo highlighted that some survivors developed eye disease, arthralgia and headaches for months if not years following surviving the disease. The West African epidemic has now confirmed these findings and further investigation is ongoing, the largest study of which is PREVAIL III in Liberia. The most common sequelae are an acute uveitis, which left untreated goes on to cause long term visual deficit and sometimes cataract formation, chronic joint pain (from intermittent joint aches to crippling sacroiliitis), hearing impairment, headache, disordered sleep patterns and psychological problems such as depression and post-traumatic stress disorder. The list of all sequelae described (with varying incidence and in some cases just single case reports) can be found in Box 4. Not all symptoms have been demonstrated to be related to either ongoing active virus in immune privileged sites or recurrence of the virus resulting in recrudescent disease, but uveitis is thought to be related to active virus present within the eye chambers. A recent study indicates that patients who survived but had higher initial viral loads were more likely to develop uveitis and visual complications. The most dramatic recrudescent disease was documented in a healthcare worker managed in the UK who, 9 months following the onset of their symptoms, developed meningoencephalitis with evidence of virus in the cerebrospinal fluid. This may have
Prognosis The prognosis of EVD is varied. Studies from the West African epidemic demonstrate that viral load at presentation correlates with mortality risk. Death is more likely in patients with significant end organ damage/failure and those with haemorrhagic symptoms. It remains unclear why some individuals progress to end organ damage and others do not. There was no clear correlation with level of care, even for treatment facilities providing optimal intravenous replacement, or for intensive care in patients evacuated to high income-countries. It is possible that there are genetic determinants of disease susceptibility but these have not yet been identified. Different species of Ebola virus carry different reported mortality rates, Ebola Zaire has mortality rates of 40e90%, whereas Ebola Sudan is approximately 50% and Ebola Bundibugyo is approximately 25%. The most recent epidemic demonstrated that extremes of age had the highest mortality rates. Teenagers in the 10e15 year age group had the lowest overall mortality rates at approximately 40e50%. Early treatment is also key to survival and patients should be encouraged to present as soon as possible for treatment. Factors deterring prompt presentation to treatment centres in the West African epidemic included stigma, and incorrect beliefs surrounding Ebola and activities occurring at treatment centres. Initially this resulted in patients presenting in the terminal stages of the disease and subsequently significantly higher mortality rates.
Previously described sequelae associated with EVD Ophthalmic Uveitis Cataract development Visual impairment Musculoskeletal Arthralgia Sacroiliitis Neurological Headaches Meningitis New onset seizure disorders Neurodisability Sensorineural hearing loss Confusion & memory problems Sleep disturbance Endocrine Thyroid disorders Amenorrhoea
Sexual health Impotence Possible infertility Orchitis Infection Persistent fevers Possible increased susceptibility to other infections e i.e. TB, chicken pox, measles Mental health Depression Post-traumatic stress disorder Other Malnutrition Hair loss Parotitis Chronic fatigue
Follow up For the approximate 50% of patients who survive infection with EVD, there remain on-going sequelae. Prior to the West African
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Box 4
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epidemic. The recombinant vesicular stomatitis vaccine (rVSVZEBOV) was part of a ring vaccination study (a study immunising contacts of cases and contacts of contacts) undertaken in Guinea, and was then rolled out to the other two affected nations to control cluster outbreaks. The data so far for the efficacy of the vaccine is promising, however it remains unclear how long immunity may last and whether it provides cover for species of Ebola virus other than Ebola Zaire. Another vaccination with promise is the chimp adenovirus vaccine (ChAd3). This vaccine has been demonstrated to provide immunogenicity but did not reach phase three trials to demonstrate protection in an epidemic setting. The best form of prevention of EVD is to prevent epidemics reaching a significant scale. This is best done early, using appropriate containment measures. The epidemic in West Africa reached the size it did for several reasons, not least the lack of health infrastructure and trained healthcare workers in the affected nations, two of which were recovering from prolonged periods of civil war. This most recent epidemic helped to emphasise the importance of community engagement measures and sound contact tracing in the containment of epidemics. In the end, it was these measures, associated with sufficient beds in treatment facilities to isolate cases, that finally helped to turn the corner on the epidemic. Had these measures been implemented more rapidly and when the first cases started to appear it is likely the epidemic would not have reached the scale that it did. This further emphasises the significant global health need of establishing robust health infrastructures in every nation. A
been an isolated case in an individual with a very high initial viral load, who survived in part due to advanced medical technologies in the UK. Anecdotal reports however, suggest there may also have been cases in West Africa. Virus persistence Previous epidemics indicated that the virus might persist in the semen of male survivors up to 3 months after the onset of symptoms. The most recent epidemic has revealed that in just over a quarter of male survivors, virus persists in semen beyond 9 months. In some cases this may extend to 18 months. While viral genetic material has been identified in semen, culture of live virus has not been consistently demonstrated, and the risk of sexual transmission remains unclear. However, there have been a small number of cases of defined sexual transmission of Ebola virus from male survivors to their partners, which have largely been responsible for the cluster outbreaks seen in the three affected West African nations following the nations being declared Ebola free. Use of condoms should be advocated for all male Ebola survivors until such time as they have had serial semen samples (a minimum of two samples at least 48 hours apart) test negative for the virus on RT-PCR. Further care considerations for EVD survivors For the reasons noted above, regular follow up of EVD survivors is essential during the first year, and thereafter if there are on-going physical complaints. All EVD survivors should be provided with psychological support during their disease and also following their survival. Close attention must be paid to the potential development of psychiatric conditions. Interim guidance from the WHO is available for the care of EVD survivors. Providing care to EVD survivors must be done in a manner which provides optimal treatment, while minimising risk to healthcare workers and preventing development of undue stigma. In the UK all Ebola survivors are assigned to a designated infectious diseases unit for routine follow up and advice. Should a survivor become acutely unwell they should first contact their designated infectious disease unit for advice and risk assessment. In the event of an emergency where this may not be possible and EVD survivors present with symptoms consistent with described post-EVD syndromes, EVD relapse should be considered and patients should be isolated, and EVD infection prevention and control precautions applied. As soon as possible following admission contact should be made with the designated infectious disease unit or Imported Fever Service at Public Health England to facilitate an appropriate risk assessment. Based on this risk assessment, healthcare workers collecting or handling biological specimens from these patients may be advised to wear full EVD personal protective equipment. Appropriate precautions would also be recommended for attending to deliveries of women who were infected with Ebola virus while pregnant and performing surgical procedures.
FURTHER READING Bah EI, Lamah M-C, Fletcher T, et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N Engl J Med 2015; 372: 40e7. http://dx.doi.org/10.1056/NEJMoa1411249. Centers for Disease Control and Prevention. Communication Resources - Ebola virus ecology and transmission 2016. https://www. cdc.gov/vhf/ebola/resources/virus-ecology.html”. Deen GF, Knust B, Broutet N, et al. Ebola RNA persistence in semen of Ebola virus disease survivors e preliminary report. N Engl J Med 2015; http://dx.doi.org/10.1056/NEJMoa1511410. Henao Restrepo AM, Longini IM, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 2015; 386: 857e66. http://dx.doi. org/10.1016/S0140-6736(15)61117-5. Hunt L, Gupta-Wright A, Simms V, et al. Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. Lancet Infect Dis 2015; http://dx.doi.org/10.1016/ S1473-3099(15)00144-9. Jacobs M, Rodger A, Bell DJ, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet 2016; http://dx.doi.org/ 10.1016/S0140-6736(16)30386-5. Leligdowicz A, Fischer WA, Uyeki TM, et al. Ebola virus disease and critical illness. Crit Care 2016; 20: 217. http://dx.doi.org/10.1186/ s13054-016-1325-2. Mattia JG, Vandy MJ, Chang JC, et al. Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. Lancet Infect
Prevention Research is currently underway for potential vaccines to prevent EVD. Two candidates reached clinical trials during the recent
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Please cite this article in press as: MacDermott N, Herberg JA, Ebola: lessons learned, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.11.007
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Dis 2016; 16: 331e8. http://dx.doi.org/10.1016/S1473-3099(15) 00489-2. Mate SE, Kugelman JR, Nyenswah TG, et al. Molecular evidence of sexual transmission of Ebola virus. N Engl J Med 2015; 373: 2448e54. http://dx.doi.org/10.1056/NEJMoa1509773. MacDermott NE, Bausch DG. Virus persistence and recrudescence after Ebola virus disease: what are the risks to healthcare workers? J Hosp Infect 2016; http://dx.doi.org/10.1016/j.jhin. 2016.07.004. Schieffelin JS, Shaffer JG, Goba A, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med 2014; 371: 2092e100. http://dx.doi.org/10.1056/NEJMoa1411680. Shah T, Greig J, van der Plas LM, et al. Inpatient signs and symptoms and factors associated with death in children aged 5 years and younger admitted to two Ebola management centres in Sierra Leone, 2014: a retrospective cohort study. The Lancet Glob Health 2016; 4: e495e501. http://dx.doi.org/10.1016/S2214-109X(16) 30097-3. Sissoko D, Laouenan C, Folkesson E, et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med 2016; 13: e1001967. http://dx.doi.org/10.1371/journal.pmed. 1001967. van Griensven J, Edwards T, de Lamballerie X, et al. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med 2016; 374: 33e42. http://dx.doi.org/10.1056/NEJMoa1511812. Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola virus in ocular fluid during convalescence. N Engl J Med 2015; 372: 2423e7. http://dx.doi.org/10.1056/NEJMoa1500306.
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WHO Ebola Response Team, Agua-Agum J, Ariyarajah A, Blake IM, et al. Ebola virus disease in West Africaethe first 9 months of the epidemic and forward projections. N Engl J Med 2014; 371: 1481e95. http://dx.doi.org/10.1056/NEJMc1413884#SA2. WHO Ebola Response Team, Agua-Agum J, Ariyarajah A, Blake IM, et al. Ebola virus disease among children in West Africa. N Engl J Med 2015; 372: 1274e7. http://dx.doi.org/10.1056/ NEJMc1415318.
Practice points
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There is a high risk of nosocomial transmission of Ebola virus disease if appropriate personal protective measures are not applied. Early features of EVD may resemble many other infectious diseases, a high degree of suspicion is warranted. Management of EVD should only be undertaken in a high-level isolation unit or designated Ebola treatment facility. There is no proven effective treatment for EVD other than optimal supportive care, including intensive care and organ support where available and safe to provide. Ebola survivors continue to suffer sequelae for months to years following their survival and require regular monitoring and follow up. Sexual transmission of Ebola from male survivors has been documented although remains a rare occurrence.
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Please cite this article in press as: MacDermott N, Herberg JA, Ebola: lessons learned, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.11.007
Ebola: lessons learned
since the virus was identified in 1976. Detailed data are not available for most outbreaks, which typically involve a few hundred cases, and occur in rural African settings. However the most recent West African Ebola epidemic, which lasted a little over 2 years from the end of 2013 until the beginning of 2016, has been extensively studied, providing insights that have significantly furthered our knowledge of this complex disease. The more than 28,000 cases of the disease were spread predominantly across three West African nations (Guinea, Sierra Leone and Liberia). This epidemic caught the world off guard and demonstrated the importance of rapid action to contain epidemic diseases in our increasingly interconnected world. Children accounted for approximately 20% of cases during the West African epidemic, despite children under 15 years making up more than 40% of the population in each of the three heavily affected countries. The relative sparing of children in this context remains unclear. It has been hypothesised that children may have been less susceptible to the disease. This is not supported by the mortality rates, which demonstrated children under five having some of the highest mortality rates of the epidemic (in excess of 70%). The other suggestion, and perhaps the more likely one, is that children were protected from infection either by community strategies to remove children from homes where there may be an infected individual, or because children generally were less likely to care for a sick relative, teenagers being an exception to this. Another possibility is that prior to the introduction of widespread screening of dead bodies, many children who died of Ebola were diagnosed with other acute febrile illnesses.
Nathalie MacDermott JA Herberg
Abstract Ebola virus disease (EVD) is a viral haemorrhagic fever caused by the filovirus, Ebola virus. In humans clinical disease results from infection with any of four species of Ebola virus (Zaire, Sudan, Bundibugyo, Tai Forest). EVD recently held the world’s attention as the international community united to tackle the largest Ebola virus epidemic in history. Focussed in West Africa and caused by the Makona strain of Zaire ebolavirus, there were over 28,000 cases with over 11,000 deaths. This article provides an overview of the epidemiology, pathophysiology and clinical signs and symptoms of EVD, with emphasis on the data arising from the 2013e2016 West African epidemic. Paediatric features, experimental therapies, survivor sequelae and preventive strategies are highlighted providing further information for the clinician on approaches to managing this disease either as individual cases or in an epidemic setting.
Keywords Ebola virus disease; epidemic; EVD; favipiravir; filovirus; intensive care; rVSV-ZEBOV vaccine; viral haemorrhagic fever; ZMAPP
Ebola virus disease (EVD) is caused by infection with Ebola virus, from the family Filoviridae. It is known to cause a severe haemorrhagic fever, with mortality rates between 25 and 90%. There are five species of Ebola virus e Zaire, Sudan, Bundibugyo, Tai Forest and Reston. Zaire, Sudan and Bundibugyo have been associated with several large outbreaks in Africa. Reston only causes symptomatic disease in animals.
Pathophysiology of EVD The Ebola virus targets a range of host tissues, including myeloid and lymphoid lineage leukocytes, endothelial, hepatic, renal and adrenal cells. Cell entry is mediated by binding to leptins and other cell surface receptors. On mast cells and Tcells, cell entry is thought to involve the TIM-1 receptor. Once endocytosed into the cell the Niemann Pick C1 receptor appears essential for viral entry into the cell cytoplasm, where replication occurs. Ebola virus uses multiple mechanisms to evade the host immune response. It sheds its glycoprotein coating to mop up circulating antibody. Efficient production of specific antibodies is inhibited by interruption of T lymphocyte signalling to B cells, as infected antigen presenting cells up-regulate T-cell inhibitory molecules and down-regulate T-cell stimulatory molecules. Early T-cell apoptosis and aberrant cytokine release depletes the cellular immune response, whilst promoting production of pro-inflammatory cytokines and inhibiting production of anti-inflammatory cytokines. The excessive proinflammatory cytokine production results in end organ damage, alongside the direct cytopathic effect of the virus which spreads widely and invades the liver, spleen, and adrenal glands, resulting in concomitant hepatic and adrenal failure. Acute kidney injury is also sustained through several potential mechanisms including, the direct cytopathic effect of the virus, acute tubular necrosis or as a direct result of hypovolaemia and deposition of microthrombi. Invasion of the endothelial lining by virus further amplifies the inflammatory cascade and leads to endothelial leakage and haemorrhagic tendencies. The latter
Epidemiology While the disease is rare, sporadic outbreaks occur in countries where the virus is present in certain mammals. The mammals identified so far include fruit bats, non-human primates and forest antelope. See Figure 1 for regions of the world known to be at risk of EVD epidemics. While Ebola virus disease is considered a zoonosis, as it must cross from its animal host into a human host for initial human disease to occur, this appears to be a sporadic event with ongoing transmission then maintained person to person (Figure 2). Healthcare workers are at particularly high risk and nosocomial transmission is common at the beginning of an outbreak when the disease may not yet be suspected in clinical settings.
Prevalence Epidemics of EVD are relatively rare, there have been approximately 23 known Ebola epidemics, occurring every few years Nathalie MacDermott BSc MBBCH is a Clinical Research Fellow in the Section of Paediatrics at Imperial College, London, UK. Conflict of interest: no competing/conflicts of interest to declare. J A Herberg MBBCH PhD is a Clinical Senior Lecturer in the Section of Paediatrics at Imperial College, London, UK. Conflict of interest: no competing/conflicts of interest to declare.
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Figure 1. Regions of the world at risk of Ebola virus disease.
Figure 2. Ebola Virus Ecology and Transmission courtesy of the Centers for Disease Control and Prevention, USA.
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is further exacerbated by thrombocytopaenia and depletion of coagulation factors through hepatic failure.
WHO EVD case definition in epidemic situations (http://www.who.int/csr/resources/publications/ebola/ebola-casedefinition-contact-en.pdf )
Clinical course
SUSPECTED CASE: Any person, alive or dead, suffering or having suffered from a sudden onset of high fever and having had contact with:
EVD initially presents in a similar fashion to many febrile infectious diseases and then progresses relatively rapidly, with death ensuing approximately 7e12 days following symptom onset. In those who survive, recovery usually follows approximately 14e21 days following onset of symptoms. While fever is a predominant feature in presentation, data from the West African epidemic reveal that up to 18% of patients did not have a fever at the time of their presentation to an Ebola treatment facility. In children under 5 years of age the data suggest this was as high as 25%. The clinical course usually commences with mild nonspecific symptoms such as fever, headache, myalgia and arthralgia and then progresses to symptoms such as abdominal pain and profuse diarrhoea. Haemorrhage follows in a proportion of patients (10e30%) a few days later, including haemorrhagic conjunctivitis, melaena/haemorrhagic diarrhoea, metrorrhagia, bleeding from venepuncture sites and bleeding from the nose and gums. Profuse and catastrophic haemorrhage as a terminal event occurs in only a small proportion of those with haemorrhagic symptoms. Clinical presentations most associated with death in the West African epidemic were those which included high fever, diarrhoea, hiccups, haemorrhagic symptoms or end organ damage. In most case series for those with overt gross haemorrhagic symptoms, the disease was invariably fatal. Children often presented with less well defined illness, making diagnosis all the more challenging, particularly in younger children. Some young infants presented in a collapsed state with a history of minimal symptoms over the preceding 24 hours. The mortality rates in children under 1 were close to 90% and for those in the neonatal period mortality was almost 100%. Teenagers on the other hand had the highest survival rates of any age group in the West African epidemic and often presented with milder symptomatology.
C C
OR: any person with sudden onset of high fever and at least three of the following symptoms: C headaches C anorexia/loss of appetite C lethargy C aching muscles or joints C breathing difficulties C vomiting C diarrhoea C stomach pain C difficulty swallowing C hiccup OR: any person with inexplicable bleeding OR: any sudden, inexplicable death. PROBABLE CASE: Any suspected case evaluated by a clinician OR: Any deceased suspected case (where it has not been possible to collect specimens for laboratory confirmation) having an epidemiological link with a confirmed case LABORATORY CONFIRMED CASE: Any suspected or probable cases with a positive laboratory result. Laboratory confirmed cases must test positive for the virus antigen, either by detection of virus RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), or by detection of IgM antibodies directed against Ebola. Box 1
Diagnosis
of EVD, the Public Health England (PHE) Imported Fever Service should be contacted. They will provide guidance as to the level of personal protective equipment required on the basis of the risk assessment. Basic observations and assessment of a patient’s hydration status are essential. Palpation of the abdomen may reveal other possible diagnoses. Caution should be applied in diagnosing an acute surgical abdomen and ruling out the diagnosis of EVD on this premise, as patients in the later stages of EVD may present with a picture consistent with an acute abdomen. There have also been reports of patients developing a gram negative sepsis during their illness. Due to the current limitations of personal protective equipment it is often not possible to auscultate the chest and heart sounds unless an electronic stethoscope with sound amplification external to the ear pieces is available.
History Patients most commonly present with a several day history of fever and symptoms common to many other infections, such as myalgia, arthralgia, headache, vomiting and diarrhoea. For this reason careful history taking is essential to elucidating suspicion of EVD amongst the many potential differential diagnoses. Suspicion of infection with Ebola virus is based on a history of contact with a confirmed or suspect case or travel to a region where there is an on-going epidemic. In regions where there is an on-going epidemic, suspicion should be heightened even in the absence of a clear history of contact. The World Health Organisation (WHO) case definition for EVD is shown below in Box 1, and Box 2 provides a list of symptoms and signs. Examination Examination of a patient meeting the case definition of a suspect case of EVD should not be undertaken other than in an isolation room with the clinician wearing full personal protective equipment. To determine risk in a potential imported case
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a suspected, probable or confirmed Ebola a dead or sick animal
Investigations The gold standard test for confirming a diagnosis of Ebola virus disease is a real-time reverse transcription polymerase chain
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In the context of a suspected case of EVD, all blood tests should be obtained with the patient in isolation and the healthcare worker wearing full PPE. Samples should be triple-contained and the laboratory notified in advance of their high-risk nature, to ensure they are handled in the appropriate manner or sent to a laboratory with appropriate containment.
Symptoms and signs of EVD Systemic Fever Weakness/fatigue/lethargy/ prostration Features of shock Lymphadenopathy (rare) Skin/Ocular Rash e maculopapular or petechial Injected conjunctivae/haemorrhagic conjunctivitis Respiratory Sore throat Cough Respiratory distress Neurological Headache Acute confusion/unresponsive Neurological signs/seizures (rare)
Musculoskeletal Myalgia Arthralgia
Differential diagnosis A list of potential differential diagnoses is available in Box 3.
Gastrointestinal Anorexia Abdominal pain Nausea/vomiting Diarrhoea Hiccups Features of acute abdomen Hepatomegaly (rare)
Management Management of patients with confirmed EVD in the UK should occur only in the context of a high level isolation unit, or if overseas, in a designated Ebola treatment facility. This is to ensure the safety of healthcare workers and other patients. Design of such treatment facilities is key to the optimum management of patients and the protection of staff. Management of EVD can be complicated both by the need for full personal protective equipment or isolation tents and by the multi-organ dysfunction that can evolve. Some patients with EVD present with only mild symptoms, with little deterioration, and go on to make a full recovery. Other patients may require full intensive care support with mechanical ventilation and renal dialysis, which entails a balance of benefit between public health and individual patient benefit, which has been widely debated. Where facilities are available and the risk to healthcare workers can be minimised, intensive care support has led to good recovery in infected international healthcare workers and should be given due consideration. The essential principles of managing EVD at present are largely supportive. They involve maintenance of fluid balance, in the face of at times extremely high gastro-intestinal losses, electrolyte replacement where necessary, stabilisation of coagulation abnormalities and minimisation of end organ damage. Where multi-organ failure ensues and facilities permit, intensive care support may be required.
Laboratory parameters: Deranged electrolytes Thrombocytopaenia Coagulation abnormalities
Haematological Bleeding from: Nose/gums Venepuncture sites Gastrointestinal (e.g. melena) Womb (e.g. metrorrhagia)
Box 2
reaction (RT-PCR). Outside of the acute disease, serological tests are available. In West Africa the application of further investigations was greatly limited, but in a high-income setting this is not the case. Certain investigations are precluded given the infection risk, for example imaging techniques such as MRI or CT, however investigations for other potential causes of symptoms should be considered depending on the patient’s presentation, such as a malaria or sepsis screen. If a viral haemorrhagic fever is suspected then PCR for Lassa fever, CrimeaneCongo haemorrhagic fever and other VHF’s should be considered. These should be discussed with PHE’s Rare and Imported Pathogens Lab. Monitoring of patients’ blood biochemistry, renal and liver function, haematology and coagulation parameters should be performed, where available. Electrolyte derangement is common in patients with profuse diarrhoea, although it appeared to be less frequent in one study of children with EVD. Renal, adrenal and hepatic dysfunction is seen, reflecting the pattern of tissue infectivity, although cytopathy is only one of several mechanisms for tissue damage. Thrombocytopenia may also develop together with coagulation abnormalities, resembling disseminated intravascular coagulation. Early identification and correction of these abnormalities may prevent development of fulminant haemorrhagic disease in those predisposed to this disease phenotype.
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Experimental therapies The West African Ebola epidemic provided an opportunity to study potentially beneficial therapies for EVD. Many of these arrived late to the epidemic due to either delays in
Potential differential diagnosis of EVD Malaria Other VHF (Lassa, CrimeaneCongo haemorrhagic fever, Marburg, arenaviruses) Gastroenteritis (bacterial/viral) Sepsis Typhoid Influenza Measles Dengue/Dengue haemorrhagic fever Yellow fever Leptospirosis Rickettsial diseases Hantavirus (pulmonary or renal syndromes) Box 3
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epidemic knowledge of post-Ebola sequelae, recrudescent disease and virus persistence in survivor’s bodily fluids was limited.
implementation of study procedures or non-availability of the study drug. Consequently, most studies were unable to demonstrate a clinically significant impact of the medication concerned. A study in Guinea which looked at favipiravir (oral, 6000 mg D0, 2400 mg D1-9), a drug developed for influenza, was able to determine that it was safe to use and straightforward to administer, but was not able to determine its efficacy. A post hoc analysis of the data suggested it was beneficial and potentially improved survival in those patients who received it when they had low viral loads. However it appeared to have no benefit in patients who had high viral loads. A trial of brincidofovir was terminated by the manufacturers early due to a scarcity of cases, and the TKM-Ebola trial was terminated mid-way by an interim review panel due to lack of efficacy. A trial of convalescent/immune plasma demonstrated no significant benefit. The most promising medication was the monoclonal antibody mixture known as ZMAPP (3 doses e D0, D3, D6). Although the ZMAPP study failed to recruit optimum numbers to demonstrate statistical significance, it showed good promise with mortality rates 40% lower in the treatment arm than the standard care arm (22% vs 37% respectively). Another medication, currently referred to as GS-5734, did not make it to clinical trials but has been shown to be highly effective in Rhesus macaque models. It was used in a few acute patients on compassionate care grounds, and is currently being trialled in Ebola survivors with virus persistence.
Sequelae and recrudescent disease Three studies from epidemics in Uganda and Democratic Republic of Congo highlighted that some survivors developed eye disease, arthralgia and headaches for months if not years following surviving the disease. The West African epidemic has now confirmed these findings and further investigation is ongoing, the largest study of which is PREVAIL III in Liberia. The most common sequelae are an acute uveitis, which left untreated goes on to cause long term visual deficit and sometimes cataract formation, chronic joint pain (from intermittent joint aches to crippling sacroiliitis), hearing impairment, headache, disordered sleep patterns and psychological problems such as depression and post-traumatic stress disorder. The list of all sequelae described (with varying incidence and in some cases just single case reports) can be found in Box 4. Not all symptoms have been demonstrated to be related to either ongoing active virus in immune privileged sites or recurrence of the virus resulting in recrudescent disease, but uveitis is thought to be related to active virus present within the eye chambers. A recent study indicates that patients who survived but had higher initial viral loads were more likely to develop uveitis and visual complications. The most dramatic recrudescent disease was documented in a healthcare worker managed in the UK who, 9 months following the onset of their symptoms, developed meningoencephalitis with evidence of virus in the cerebrospinal fluid. This may have
Prognosis The prognosis of EVD is varied. Studies from the West African epidemic demonstrate that viral load at presentation correlates with mortality risk. Death is more likely in patients with significant end organ damage/failure and those with haemorrhagic symptoms. It remains unclear why some individuals progress to end organ damage and others do not. There was no clear correlation with level of care, even for treatment facilities providing optimal intravenous replacement, or for intensive care in patients evacuated to high income-countries. It is possible that there are genetic determinants of disease susceptibility but these have not yet been identified. Different species of Ebola virus carry different reported mortality rates, Ebola Zaire has mortality rates of 40e90%, whereas Ebola Sudan is approximately 50% and Ebola Bundibugyo is approximately 25%. The most recent epidemic demonstrated that extremes of age had the highest mortality rates. Teenagers in the 10e15 year age group had the lowest overall mortality rates at approximately 40e50%. Early treatment is also key to survival and patients should be encouraged to present as soon as possible for treatment. Factors deterring prompt presentation to treatment centres in the West African epidemic included stigma, and incorrect beliefs surrounding Ebola and activities occurring at treatment centres. Initially this resulted in patients presenting in the terminal stages of the disease and subsequently significantly higher mortality rates.
Previously described sequelae associated with EVD Ophthalmic Uveitis Cataract development Visual impairment Musculoskeletal Arthralgia Sacroiliitis Neurological Headaches Meningitis New onset seizure disorders Neurodisability Sensorineural hearing loss Confusion & memory problems Sleep disturbance Endocrine Thyroid disorders Amenorrhoea
Sexual health Impotence Possible infertility Orchitis Infection Persistent fevers Possible increased susceptibility to other infections e i.e. TB, chicken pox, measles Mental health Depression Post-traumatic stress disorder Other Malnutrition Hair loss Parotitis Chronic fatigue
Follow up For the approximate 50% of patients who survive infection with EVD, there remain on-going sequelae. Prior to the West African
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Box 4
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epidemic. The recombinant vesicular stomatitis vaccine (rVSVZEBOV) was part of a ring vaccination study (a study immunising contacts of cases and contacts of contacts) undertaken in Guinea, and was then rolled out to the other two affected nations to control cluster outbreaks. The data so far for the efficacy of the vaccine is promising, however it remains unclear how long immunity may last and whether it provides cover for species of Ebola virus other than Ebola Zaire. Another vaccination with promise is the chimp adenovirus vaccine (ChAd3). This vaccine has been demonstrated to provide immunogenicity but did not reach phase three trials to demonstrate protection in an epidemic setting. The best form of prevention of EVD is to prevent epidemics reaching a significant scale. This is best done early, using appropriate containment measures. The epidemic in West Africa reached the size it did for several reasons, not least the lack of health infrastructure and trained healthcare workers in the affected nations, two of which were recovering from prolonged periods of civil war. This most recent epidemic helped to emphasise the importance of community engagement measures and sound contact tracing in the containment of epidemics. In the end, it was these measures, associated with sufficient beds in treatment facilities to isolate cases, that finally helped to turn the corner on the epidemic. Had these measures been implemented more rapidly and when the first cases started to appear it is likely the epidemic would not have reached the scale that it did. This further emphasises the significant global health need of establishing robust health infrastructures in every nation. A
been an isolated case in an individual with a very high initial viral load, who survived in part due to advanced medical technologies in the UK. Anecdotal reports however, suggest there may also have been cases in West Africa. Virus persistence Previous epidemics indicated that the virus might persist in the semen of male survivors up to 3 months after the onset of symptoms. The most recent epidemic has revealed that in just over a quarter of male survivors, virus persists in semen beyond 9 months. In some cases this may extend to 18 months. While viral genetic material has been identified in semen, culture of live virus has not been consistently demonstrated, and the risk of sexual transmission remains unclear. However, there have been a small number of cases of defined sexual transmission of Ebola virus from male survivors to their partners, which have largely been responsible for the cluster outbreaks seen in the three affected West African nations following the nations being declared Ebola free. Use of condoms should be advocated for all male Ebola survivors until such time as they have had serial semen samples (a minimum of two samples at least 48 hours apart) test negative for the virus on RT-PCR. Further care considerations for EVD survivors For the reasons noted above, regular follow up of EVD survivors is essential during the first year, and thereafter if there are on-going physical complaints. All EVD survivors should be provided with psychological support during their disease and also following their survival. Close attention must be paid to the potential development of psychiatric conditions. Interim guidance from the WHO is available for the care of EVD survivors. Providing care to EVD survivors must be done in a manner which provides optimal treatment, while minimising risk to healthcare workers and preventing development of undue stigma. In the UK all Ebola survivors are assigned to a designated infectious diseases unit for routine follow up and advice. Should a survivor become acutely unwell they should first contact their designated infectious disease unit for advice and risk assessment. In the event of an emergency where this may not be possible and EVD survivors present with symptoms consistent with described post-EVD syndromes, EVD relapse should be considered and patients should be isolated, and EVD infection prevention and control precautions applied. As soon as possible following admission contact should be made with the designated infectious disease unit or Imported Fever Service at Public Health England to facilitate an appropriate risk assessment. Based on this risk assessment, healthcare workers collecting or handling biological specimens from these patients may be advised to wear full EVD personal protective equipment. Appropriate precautions would also be recommended for attending to deliveries of women who were infected with Ebola virus while pregnant and performing surgical procedures.
FURTHER READING Bah EI, Lamah M-C, Fletcher T, et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N Engl J Med 2015; 372: 40e7. http://dx.doi.org/10.1056/NEJMoa1411249. Centers for Disease Control and Prevention. Communication Resources - Ebola virus ecology and transmission 2016. https://www. cdc.gov/vhf/ebola/resources/virus-ecology.html”. Deen GF, Knust B, Broutet N, et al. Ebola RNA persistence in semen of Ebola virus disease survivors e preliminary report. N Engl J Med 2015; http://dx.doi.org/10.1056/NEJMoa1511410. Henao Restrepo AM, Longini IM, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 2015; 386: 857e66. http://dx.doi. org/10.1016/S0140-6736(15)61117-5. Hunt L, Gupta-Wright A, Simms V, et al. Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. Lancet Infect Dis 2015; http://dx.doi.org/10.1016/ S1473-3099(15)00144-9. Jacobs M, Rodger A, Bell DJ, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet 2016; http://dx.doi.org/ 10.1016/S0140-6736(16)30386-5. Leligdowicz A, Fischer WA, Uyeki TM, et al. Ebola virus disease and critical illness. Crit Care 2016; 20: 217. http://dx.doi.org/10.1186/ s13054-016-1325-2. Mattia JG, Vandy MJ, Chang JC, et al. Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. Lancet Infect
Prevention Research is currently underway for potential vaccines to prevent EVD. Two candidates reached clinical trials during the recent
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Dis 2016; 16: 331e8. http://dx.doi.org/10.1016/S1473-3099(15) 00489-2. Mate SE, Kugelman JR, Nyenswah TG, et al. Molecular evidence of sexual transmission of Ebola virus. N Engl J Med 2015; 373: 2448e54. http://dx.doi.org/10.1056/NEJMoa1509773. MacDermott NE, Bausch DG. Virus persistence and recrudescence after Ebola virus disease: what are the risks to healthcare workers? J Hosp Infect 2016; http://dx.doi.org/10.1016/j.jhin. 2016.07.004. Schieffelin JS, Shaffer JG, Goba A, et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med 2014; 371: 2092e100. http://dx.doi.org/10.1056/NEJMoa1411680. Shah T, Greig J, van der Plas LM, et al. Inpatient signs and symptoms and factors associated with death in children aged 5 years and younger admitted to two Ebola management centres in Sierra Leone, 2014: a retrospective cohort study. The Lancet Glob Health 2016; 4: e495e501. http://dx.doi.org/10.1016/S2214-109X(16) 30097-3. Sissoko D, Laouenan C, Folkesson E, et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med 2016; 13: e1001967. http://dx.doi.org/10.1371/journal.pmed. 1001967. van Griensven J, Edwards T, de Lamballerie X, et al. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med 2016; 374: 33e42. http://dx.doi.org/10.1056/NEJMoa1511812. Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola virus in ocular fluid during convalescence. N Engl J Med 2015; 372: 2423e7. http://dx.doi.org/10.1056/NEJMoa1500306.
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WHO Ebola Response Team, Agua-Agum J, Ariyarajah A, Blake IM, et al. Ebola virus disease in West Africaethe first 9 months of the epidemic and forward projections. N Engl J Med 2014; 371: 1481e95. http://dx.doi.org/10.1056/NEJMc1413884#SA2. WHO Ebola Response Team, Agua-Agum J, Ariyarajah A, Blake IM, et al. Ebola virus disease among children in West Africa. N Engl J Med 2015; 372: 1274e7. http://dx.doi.org/10.1056/ NEJMc1415318.
Practice points
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There is a high risk of nosocomial transmission of Ebola virus disease if appropriate personal protective measures are not applied. Early features of EVD may resemble many other infectious diseases, a high degree of suspicion is warranted. Management of EVD should only be undertaken in a high-level isolation unit or designated Ebola treatment facility. There is no proven effective treatment for EVD other than optimal supportive care, including intensive care and organ support where available and safe to provide. Ebola survivors continue to suffer sequelae for months to years following their survival and require regular monitoring and follow up. Sexual transmission of Ebola from male survivors has been documented although remains a rare occurrence.
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Please cite this article in press as: MacDermott N, Herberg JA, Ebola: lessons learned, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.11.007