A Current Review of Ebola Virus Pathogenesis Clinical Presentation and Diagnostic Assessment

1. Education
2. Ebola virus illness
3. Ebola virus disease

Clinical Review

Ebola virus illness

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g7348 (Published 10 December 2014) Cite this every bit: BMJ 2014;349:g7348

1. Nicholas J Beeching , senior lecturer (honorary consultant)12,
2. Manuel Fenech , specialist trainee in infectious diseases2,
3. Catherine F Houlihan , clinical research young manthree

1. ¹Liverpool Schoolhouse of Tropical Medicine, Royal Liverpool University Hospital, Liverpool, UK
2. ²Royal Liverpool University Infirmary, Liverpool, UK
3. ^threeLondon School of Hygiene and Tropical Medicine, London, UK

1. Correspondence to: N J Beeching nicholas.beeching{at}rlbuht.nhs.united kingdom

The bottom line

• Ebola virus disease is a severe, often fatal, zoonotic infection caused past a virus of the Filoviridae family (genus Ebolavirus)

• Human to human transmission occurs through contact with torso fluids from infected patients. The incubation period after infection is i-21 days and patients are not considered infectious until they develop symptoms

• Initial stages of infection are non-specific, which makes the differential diagnosis broad. A history of exposure and clinical suspicion of infection should prompt isolation

• Management is currently focused on supportive care and infection control. Healthcare workers should familiarise themselves with local guidance

• Instance fatality rates range from 30% to 90%

• Because of the high likelihood of infected people travelling, all countries should accept tested and practised protocols ready for screening and managing patients

This clinical review has been developed for The BMJ in collaboration with BMJ Best Do, based on a regularly updated web/mobile topic that supports evidence-based decision making at the bespeak of care. To view the consummate and current version, delight refer to the Ebola virus infection topic on the BMJ Best Practise website.

Ebola virus illness is a severe, often fatal, zoonotic filovirus infection (fig one⇓). There are five species: Zaire ebolavirus, Sudan ebolavirus, Taï Woods ebolavirus, Bundibugyo ebolavirus, and Reston ebolavirus.i

Zaire ebolavirus is responsible for the current outbreak in westward Africa, the largest outbreak since the virus was discovered in 1976 (fig 2⇓).

Manual occurs by shut contact with torso fluids of infected patients. The incubation flow later on infection is unremarkably 5-nine days, with a range of 1-21 days in 95% or more of patients,two 3 and patients are non considered infectious until they develop symptoms. The initial presentation is non-specific, which makes early clinical diagnosis difficult. Human infection carries a high case fatality rate depending on the species of Ebola virus and quality of supportive care bachelor.4 five

Ebola virus infection (formerly Ebola haemorrhagic fever) is part of a grouping of diseases known as viral haemorrhagic fevers.6

What causes information technology?

The virus is idea to be initially acquired past exposure to trunk fluids or tissue from infected animals, such as bats and non-homo primates; notwithstanding, the natural reservoir and mode of transmission to humans has not been confirmed.7 8 Laboratory testing of reservoir competence shows that successful infection is possible in bats and rodents, simply not in plants or arthropods.9 ten 11 12 Animal to human transmission may occur during hunting and consumption of the reservoir species or infected non-man primates. The practice of butchering or eating bush meat or food contaminated with bat faeces (three species of tree roosting bats take been implicated as a reservoir) is likewise thought to contribute.

Human to human transmission occurs through contact with body fluids from infected patients.xiii In early epidemics, the re-employ of non-sterile injections was responsible for many healthcare associated transmissions.xiv Yet, although this remains a adventure, most cases outcome from close physical contact or contact with body fluids (such as sweat, blood, faeces, vomit, saliva, genital secretions, urine, and breast milk) of infected patients. In a study of viral shedding in various body fluids, Ebola virus was isolated from saliva, breast milk, stool, tears, and semen upwards to 40 days after the onset of affliction,15 16 17 confirming the possibility of delayed sexual transmission. Virus may be plant in urine during recovery, and the duration of this phenomenon needs further study.18

Infection through inhalation is possible in not-homo primates, but there is no bear witness for airborne manual in humans.xix

Exterior endemic areas, Ebola virus infection is rare and is usually imported.20 Travellers from affected areas, and laboratory scientists and others working with potentially infected materials and animals, are at loftier risk.

What is the pathophysiology of this infection

Although there have been major advances in elucidating the pathogenesis of Ebola virus infection, most of the studies were performed in non-human being primate and rodent models.viii This is considering of the difficulties in conducting human studies in poorly resourced settings where these infections naturally occur.

The virus genome consists of a unmarried 19 kb strand of negative sense RNA with vii viral genes that are transcribed by the viral RNA dependent RNA polymerase nowadays in the virion. The single strand of RNA is covered by helically arranged viral nucleoproteins NP and VP30, which are linked by matrix proteins VP24 and VP4 to the lipid bilayer that coats the virion.21

Tissue invasion occurs through infected fluid coming into contact with breaks in the mucosa or skin. This tin can occur with animal to homo or human to human transmission. Monocytes, macrophages, and dendritic cells are the preferred replication sites for filoviruses on initial infection. Infected cells migrate to the regional lymph nodes, liver, and spleen, thereby disseminating the infection. Ebola virus has a wide jail cell tropism and tin infect a variety of prison cell types.eight 21 It also has the remarkable ability to modulate the expression of genes involved in the host immune response, causing lymphocyte apoptosis and attenuation of the protective effects of interferon.22 23

The host immune response is crucial and dictates the issue of infection. Progression to severe disease occurs when the virus triggers expression of a host of pro-inflammatory cytokines, including interferons; interleukins (ILs) such as IL-2, IL- half dozen, IL-eight, and IL-10; interferon inducible protein; and tumour necrosis factor α (TNF-α).viii 21 24 This causes endothelial activation and reduced vascular integrity, release of tissue gene (with associated onset of coagulopathy), and increased nitric oxide levels (with associated hypotension).25 Thrombocytopenia is nearly commonly acquired past loss of platelets from damaged tissue or more generalised virus induced disseminated intravascular coagulation, where coagulation factors are depleted.26 Disseminated intravascular coagulation, forth with acute hepatic harm, predisposes the patient to bleeding complications. Other complications of severe disease include acute kidney injury, hepatitis, and pancreatitis.21 An early on antibody response, forth with reduced lymphocyte depletion, is associated with effective viral clearance and survival.sixteen

The development of shock is withal not well understood. Many factors may contribute, including bacterial sepsis, possibly through gut translocation of leaner; a direct effect of the virus; disseminated intravascular coagulation; and bleeding.23

How are people at risk identified?

Ebola virus infection is transmitted mainly through close concrete contact with infected patients. In that location is no evidence of a run a risk of infection before symptoms develop, but belatedly diagnosis delays effective patient isolation, allowing for potential transmission of the infection among contacts. Screening and active example finding are therefore essential to avoid or end an epidemic.

Early diagnosis hinges on identifying patients who are at risk. Case definitions developed by WHO and the US Centers for Affliction Command and Prevention (CDC) are based on a history of exposure and clinical evidence of illness (for case, fever, headache, and myalgia). In the current epidemic areas, history of exposure is now less useful.

Screening ensures the quick identification of potential cases that demand immediate isolation and investigation. People who are asymptomatic and have epidemiological risk factors may demand to be monitored (for case, twice daily temperature readings) for the elapsing of the incubation period, depending on their risk of exposure. This ensures rapid recognition of symptoms and immediate isolation.

Contacts

Contacts of infected patients (including healthcare workers and household contacts) are at risk of infection if they were exposed to the patient'due south body fluids without protective equipment within the past 21 days.2 iii Brief interactions, such as walking past a person or moving through a hospital, do not constitute shut contact.

Epidemiological hazard factors are divided into high risk, some risk, depression (but not zero) risk, and no identifiable risk categories.

A contact is defined by WHO equally someone who has slept in the same household as a patient; had directly physical contact with the patient during the affliction or at the funeral; touched the patient'south body fluids, clothes, or bed linens during the illness; or been breast fed by the patient (babies).27

What infection prevention and control measures are used?

Boxes 1 and two list infection prevention and control measures for healthcare workers and people living in affected areas. If infection is suspected on the basis of initial screening, immediate isolation is warranted before whatsoever further investigations. This is crucial to reduce contact with other patients and healthcare workers while the patient is being investigated. Isolation measures should be continued until the patient has tested negative.28

Box 1: Infection control measures for healthcare workers

• Wear protective wearable

• Do proper infection command and sterilisation measures

• Isolate suspected patients from each other (if possible), and patients with confirmed affliction from those with suspected disease

• Avoid direct contact with bodies of people who have died from Ebola, or suspected Ebola. During epidemics, avoid direct contact with whatsoever dead body

• Notify health officials if you accept direct contact with the body fluids of an infected patient

Box 2: Infection control measures for people in affected areas

• Practise careful hygiene (for example, launder hands with soap and water, alcohol based hand sanitiser, or diluted chlorine)

• Avoid contact with trunk fluids

• Do not handle items that have come up into contact with an infected person'southward body fluids (such as clothes, medical equipment, and needles)

• Avoid funeral or burial rituals that require handling of the trunk of someone who has died from proven or suspected Ebola

• Avoid contact with not-human primates and bats, including body fluids or raw meat prepared from these animals

• Avoid hospitals in west Africa in which infected patients are being treated

• Returning travellers, including healthcare workers, should follow national policy for surveillance and should monitor their health for 21 days and seek medical attention if symptoms develop, particularly fever

Personal protective equipment

The highest risk facing healthcare workers when looking after infected patients is inadvertently touching their own faces or neck under the face shield during patient care, and removing (doffing) personal protective equipment (PPE; shown in fig 3⇓).

Healthcare workers should empathize the following bones principles of using PPE:

• Donning—PPE must be donned correctly in the proper order before inbound the patient care area. Because PPE cannot be adjusted while in the patient intendance area, care should be taken to ensure it is as comfortable equally possible before entering and that no skin is exposed. Donning activities must be straight observed by a trained observer and a final check performed before inbound the patient care area

• During patient care—PPE must remain in place and be worn correctly for the duration of exposure to potentially contaminated areas. PPE should not be adjusted during patient care. Healthcare workers should regularly disinfect gloved hands using an alcohol based hand rub or chlorinated water, particularly later on handling body fluids. If at that place is a partial or total breach in PPE (such every bit gloves separating from sleeves to leave exposed peel, a tear in an outer glove, or a needlestick) during patient intendance, the healthcare worker must move immediately to the doffing area to appraise the exposure and implement the facility exposure programme, if indicated

• Doffing—Removal of used PPE is a loftier risk process that requires a structured procedure, a trained observer, and a designated area for removal to ensure protection. PPE must exist removed slowly and deliberately in the right sequence to reduce the possibility of self contamination or other exposure. A stepwise procedure should exist adult and used during training and daily practice.29

The importance of a "buddy" when inside the patient care area, and during donning and doffing, to ensure prophylactic practise cannot be overstated, together with guidance from independent monitors if available.

What other measures are needed if Ebola virus disease is suspected?

If infection is suspected, the patient should exist isolated and all healthcare workers in contact with the patient should habiliment personal protective equipment.

Contact tracing (family, friends, and work colleagues) is essential. People who accept been exposed to Ebola virus inside the past 21 days and who are asymptomatic need to exist monitored for the duration of the incubation period with twice daily temperature readings to ensure rapid recognition of symptoms. If symptoms are detected firsthand isolation is essential.30

Healthcare workers suspected of beingness infected should be isolated and treated in the aforementioned way as any other patient until a negative diagnosis is confirmed.31 If exposure to torso fluids from a patient with suspected infection has occurred, the person should immediately wash afflicted skin surfaces with soap and water and irrigate mucous membranes with copious amounts of water.

The patient's home and any personal belongings that might have been contaminated (such as clothes, linens, eating utensils, and medical textile) should be disinfected or disposed of (usually by incineration). In epidemic areas, the patient'south dwelling is sprayed with 0.five% chorine solution.

What are the clinical features?

The instance definition for Ebola virus infection is very broad and includes a long list of possible differential diagnoses (fig 4⇓).

History

The initial assessment of a patient with suspected Ebola hinges on 2 main factors: epidemiological gamble (for case, living or working in, or inflow from, an owned area such equally due west Africa in the past 21 days) and presence or history of a fever in the past 24 hours. Apart from healthcare workers, people who work with primates or bats from endemic areas or with high risk clinical samples are also at high take chances.

A detailed history helps to clarify the level of risk for infection and to appraise the possibility of other causes of an acute febrile syndrome (fig 5⇓). Because malaria is nonetheless the well-nigh common cause of febrile illness in returning travellers, the presence of risk factors for acquiring malaria should be assessed (for case, living or working in, or arriving from, an endemic area; inadequate or absent-minded chemoprophylaxis; non using insecticides or bed nets).36 Infection control take chances should be assessed. Having determined that a patient may exist infected, the doctor needs to decide how infectious the patient currently is. For case, the absenteeism of airsickness or diarrhoea reduces the risk of transmission, whereas uncontrolled diarrhoea greatly increases the risk.

Precautionary isolation procedures and use of PPE are mandated in symptomatic patients who may be at risk of infection until the infection is confirmed or excluded. It is extremely important to minimise the risk of transmission while investigating patients (see later on).28 37

Symptoms

There are typically 3 phases of illness, starting with a few days of non-specific fever, headache, and myalgia, followed past a gastrointestinal phase in which diarrhoea and vomiting, abdominal symptoms, and dehydration are prominent. In the second week, the patient may recover or deteriorate, with a third phase of affliction including collapse, neurological manifestations, and haemorrhage, which is ofttimes fatal.38

The most mutual symptoms reported between symptom onset and instance detection in the 2014 outbreak were fever (87.one%), fatigue (76.4%), loss of appetite (64.5%), vomiting (67.six%), diarrhoea (65.6%), headache (53.4%), intestinal pain (44.3%), and unexplained bleeding (eighteen%) (box 3).3 The high frequency of vomiting and diarrhoea means that patients are often dehydrated and hypovolaemic, especially if they present late.

Box 3: Typical symptoms of Ebola virus disease4

• Fever ≥37.5°C*

• Fatigue

• Nausea or vomiting

• Diarrhoea

• Headache

• Abdominal pain

• Myalgia

• Prostration

• Sore pharynx

• Unexplained bleeding or bruising

• Spontaneous abortion or miscarriage

• Hiccups

• Rash

• *The temperature threshold for "fever" level varies between different guidelines.39

Children present with similar symptoms to adults; even so, younger children are reported to accept more respiratory (such as cough and dyspnoea) and gastrointestinal symptoms, but less haemorrhage and neurological signs, than adults.40 41 Anecdotally, children under 4 years nowadays initially with more subtle symptoms before developing a fever and are often diagnosed late.

Concrete exam

A full physical examination should be undertaken with precautionary isolation procedures and use of PPE. The aim of examination is to exclude a focus for sepsis while looking for signs of viral haemorrhagic fever (such equally conjunctival injection, purpuric rash, or other signs of bleeding).

Vital signs should be taken:

• Fever (≥37.5°C)—Fever is the presenting symptom in about xc% of patients,3 39 42 and its presence is enough to enhance concern in the appropriate epidemiological context. Broad variations in body temperature are seen during the grade of illness, with normothermia or hypothermia occurring in the later stages of fatal infection.40 43 44 Some patients initially have a low grade fever with no other symptoms

• Blood pressure—Hypotension is a feature of preterminal disease and stupor. Information technology is underdocumented in field studies, owing to a lack of measuring equipment in endemic areas43

• Pulse rate—Bradycardia may be nowadays in the initial stages of illness, whereas tachycardia may be seen in the later stages of fatal infections43

• Respiratory rate—Tachypnoea, along with tachycardia, correlates with a more astringent or advanced infection. It is more probable to be acquired by respiratory bounty of a metabolic acidosis than respiratory interest.43

Other possible findings include a maculopapular rash, haemorrhage, hiccups, hepatomegaly, lymphadenopathy, and neurological signs (box iv).43

Box 4: Physical exam findings

Maculopapular rash

• Develops early in the grade of affliction in 25-52% of patients,43 although its occurrence has been much lower (v%) in the 2014 outbreak3

• Often described equally non-pruritic, erythematous, and maculopapular

• May brainstorm focally then become diffuse, generalised, and confluent. Some have described it as morbilliform

• May become purpuric or petechial after in the infection in patients with coagulopathy

• May exist difficult to discern in night skinned patients

Bleeding

• Bleeding manifestations (such every bit epistaxis, bleeding gums, haemoptysis, easy bruising, conjunctival haemorrhage, haematuria, and oozing from injection or venipuncture sites) were nowadays in xxx-36% of infected patients in previous outbreaks,8 43 44 45 46 but they have been reported in only 18% of patients in the 2014 outbreak3 5 38 47

Hiccups

• A sign of advanced infection, typically seen in the last 2-3 days of fatal infections

Hepatomegaly or epigastric tenderness

• Tender hepatomegaly, with the border of the liver palpable below the rib cage, has been reported but is rare

Lymphadenopathy

• Enlarged lymph nodes have been reported only are rare

Neurological signs

• Confusion, depressed consciousness, encephalopathy, and seizures are rare but their presence indicates advanced infection

Multi-organ dysfunction is mutual in avant-garde infection and includes acute kidney injury, pancreatitis, adrenal failure, and liver damage. Hepatitis is mutual, with aspartate aminotransferase (AST) higher than alanine aminotransferase (ALT), although jaundice is rare.23 Renal dysfunction is common in advanced disease only tin can exist reversed with adequate fluid resuscitation in the initial stages.23 In early affliction it may be acquired by dehydration, but in afterward stages it may be a upshot of disseminated intravascular coagulation or straight damage to the kidneys by the Ebola virus.23 43 Massive bleeding, typically in the gastrointestinal tract (for instance, bloody diarrhoea or melaena), is usually seen only in fatal cases.43 Internal haemorrhage may be missed if there are no external signs.

Signs that indicate severe or advanced infection include hiccups, hypotension, tachycardia, hepatomegaly, splenomegaly, confusion, and seizures.

How is it investigated?

All specimens should be nerveless according to strict protocols.

Initial investigations

The main confirmatory test for Ebola virus infection is a positive Ebola RT-PCR.48 This examination should exist ordered in all patients with suspected Ebola infection while the patient is isolated. The results of RT-PCR are available 24-48 hours earlier those of enzyme linked immunosorbent analysis (ELISA) testing. In Western settings, Ebola RT-PCR may exist available merely in regional or national reference laboratories that have a high level of biosafety precautions (category 4 facilities).viii In epidemic settings and some European countries, category 4 laboratories are gear up locally, and RT-PCR is available iv hours afterwards the sample has arrived. Viral RNA tin be detected in the patient's blood by RT-PCR from mean solar day iii to days 6-17 of symptoms. A positive outcome implies that the patient is potentially infectious, particularly if at that place is agile diarrhoea, airsickness, or haemorrhage. If negative, the test should exist repeated within 48 hours considering viral load tin exist low and undetectable early in the disease. Negative tests should too exist repeated to rule out the diagnosis (or confirm resolution of infection) if there is a stiff suspicion of Ebola.31 Higher viral load correlates with adverse upshot.v 24 38 47 49

The choice of whether to examination for Ebola depends on the patient's history and the risk of infection (fig 5).

Malaria is still the most common cause of fever in people who alive or piece of work in, or travellers who accept returned from, an endemic area and should be ruled out.36 If a malaria rapid diagnostic exam is positive, malaria should be treated while keeping in mind the possibility of a dual infection. Ebola virus infection should be considered in a patient who does non respond to antimalarial therapy.

It is recommended that confirmatory tests for Ebola virus infection are performed before, or in tandem with, differentiating tests for other suspected conditions if Ebola virus infection is suspected.

Other investigations

In the by, only a malaria screen and RT-PCR were recommended because of the risk to laboratory workers. However, it is now recognised that other investigations can be done safely according to recommended guidelines, equally long as the laboratory is informed of the sample in advance, and the samples are correctly packaged and retained at the end in case the results are positive.28 42 Local protocols should be clear well-nigh safety transport of samples to the local and referral laboratories and safe handling on receipt in the local laboratory.

Box 5 outlines boosted investigations that may add valuable information to help guide further management, and that should exist ordered if possible.

Box 5: Other useful investigations when diagnosing Ebola virus affliction

Antigen capture enzyme linked immunosorbent assay (ELISA) testing

• A useful diagnostic test with high specificity, although it is non universally bachelor

• Virtually likely to give a positive effect on days iii-half-dozen of symptoms and tin can give widely variable results from days seven-1617

• Can exist used to confirm the diagnosis along with a positive reverse transcriptase-polymerase concatenation reaction effect

Full blood count

• Decreasing platelet count with marked lymphopenia tin can be seen in the initial stages of infection merely is non diagnostic. This is often followed by neutrophil leucocytosis in the later stages in patients who somewhen recover, forth with normalisation of thrombocytopenia. Leucocytosis may persist and prove immature forms

• Patients with severe disease may evidence a progressive pass up in platelet count every bit a manifestation of disseminated intravascular coagulation (DIC)

• Haemoglobin may be low in patients with bleeding manifestations43

Coagulation studies

• Prolonged prothrombin fourth dimension or activated partial thromboplastin time is associated with more severe infection and haemorrhage manifestations such as DIC

• D-dimer values are 4 times higher on days 6-viii of infection in patients who die than in those who survive50

Renal role and serum electrolytes

• Raised serum creatinine or urea and abnormal electrolytes may indicate astute kidney injury; this may be seen at the end of the first week of infection51

• Some studies found hypokalaemia (associated with airsickness and diarrhoea) in about half of cases

• Hypocalcaemia has been associated with fatal infection

• Haematuria and proteinuria may likewise be seen in severe disease

• Oliguria that does not reply to fluid resuscitation is a poor prognostic sign43

Arterial blood gases

• Arterial or venous blood lactate, pH, and bicarbonate can help identify the caste of systemic hypoperfusion and guide fluid resuscitation in acutely ill patients with signs of sepsis52

• Raised lactate is a marker of tissue hypoperfusion and is an indicator of shock.

Liver function tests

• Both ALT and AST are usually raised; about studies show that AST rises more than ALT—this is more than suggestive of systemic tissue impairment rather than hepatocellular injury

• The AST:ALT ratio peaked at 15:1 on days 6-eight of infection in fatal cases compared with days 5:1 in non-fatal cases43 45 l

• Bilirubin, γ-glutamyl transferase, and alkaline phosphatase are often slightly raised. Profoundly raised ALT and severe jaundice suggests an alternative diagnosis (such as viral hepatitis)

Serum amylase

• High concentrations have been reported in several studies and indicate the presence of pancreatitis, an indicator of severe infection43

Blood cultures

• Negative blood cultures are helpful because they rule out other non-viral infectious causes (such every bit sepsis or enteric fever)

Ebola specific IgM and IgG antibodies

• Useful in later stages of infection

• IgM antibodies can appear in serum every bit early equally day ii after infection simply results are variable up to day 9. They become negative between 30 and 168 days after symptom onset

• An IgG response develops between days 6 and 18 and tin can persist for several years

• A positive IgM or a ascension IgG titre is potent show of recent Ebola virus infection17

Chest radiography

• Useful in patients with respiratory symptoms

• Pulmonary infiltrates are not typical of infection and advise an culling (or comorbid) diagnosis

• May be hard to arrange in an isolation unit and should be ordered judiciously to avoid contamination53

How is it managed?

The mainstay of treatment is early recognition of infection, coupled with effective isolation and best available supportive care in a hospital setting.

High case fatality rates may be related to the supportive care available in resources poor rural settings where outbreaks take occurred They reflect the difficulties that patients in these settings have in accessing basic medical care in a healthcare structure that is overwhelmed.3 five

During the 2014 outbreak, comprehensive supportive care—including organ support in intensive care units—was available to cases imported to developed countries such every bit Spain, Italy, Switzerland, Frg, France, Kingdom of norway, the UK, and the U.s..18 54 55 Despite this, deaths still occurred because of the lack of specific effective treatments.

There is agile debate nearly the suitability of moving patients with advanced disease and a poor prognosis to intensive care, where the gamble for nosocomial infection may be high.52 56 57 Yet, failure to provide full supportive care to those with suspected (not confirmed) infection may result in substandard care for these patients, who may later be shown to have a treatable disease such as malaria. Local hospital protocols should consider how this situation should be handled for patients with suspected infection before possible transfer to the intensive care unit, and for those who take already been transferred at that place.52 56 57

Isolation and infection command

Patients identified equally beingness at adventure of infection should immediately be isolated in a room with individual bathroom facilities.

All attending healthcare personnel must article of clothing PPE that conforms with published protocols (fig 3).29 58 All contaminated materials (such as dress and bed linens) should be treated as potentially infectious.

Specimens for laboratory investigations (such every bit Ebola RT-PCR, full blood count, serum creatinine and urea, liver part tests, arterial blood gases, coagulation studies, blood cultures, and investigations for other atmospheric condition such every bit malaria) should be collected and sent off according to local and national protocols. Judicious selection of investigations is needed to reduce the risk of transmission to laboratory workers and other healthcare personnel. Early placement of a central line (if possible) allows blood to be taken and fluids to be given while minimising the hazard of needlestick injuries.

Fluid and electrolyte replacement

Vomiting and diarrhoea are common, so patients are ofttimes dehydrated and hypovolaemic, particularly if they present late. This is probably the cause of the high instance fatality rates because essential clinical monitoring (temperature, respiratory charge per unit, pulse rate, claret force per unit area, and fluid input and output) is oftentimes hard in resource poor settings.

Oral rehydration solutions can exist used for patients who can tolerate oral administration and who are not severely dehydrated.

The book of intravenous fluids needed should be assessed on the basis of the clinical examination (level of dehydration, signs of shock) and fluid losses (volume of diarrhoea or vomitus, or both). Big volumes of fluid replacement (>ten L/day) may be needed in febrile patients with diarrhoea.eighteen

Access to point of intendance tests in the isolation facility ways that the patient'southward biochemical status can exist monitored more efficiently and reduces the risks associated with specimen transport.5 52 Electrolyte monitoring should be performed daily. More frequent monitoring can exist considered if large volumes of intravenous fluids are being given or if severe biochemical abnormalities are nowadays. Loftier blood lactate values are a reliable measure of hypoperfusion and tin assist guide fluid resuscitation.52 In patients with anuria who do not respond to fluid resuscitation, renal replacement therapy has been used,18 55 59 although there are no trial data to support its effectiveness.

Major haemorrhage is uncommon, but is seen in advanced infection that is usually fatal. When available, platelet and plasma transfusions should be given according to local protocols.60

Symptomatic management

The following direction strategies are recommended:

• Fever and pain—Fever and pain should be treated with paracetamol first. Opioid analgesics (such as morphine) are preferable for more severe pain. Non-steroidal anti-inflammatory drugs (including aspirin) should be avoided because of the associated increased risk of bleeding and potential for nephrotoxicity31

• Nausea and vomiting—Oral or intravenous antiemetics (such as ondansetron and metoclopramide) are recommended31

• Heartburn, dysphagia, and upper abdominal pain—An antacid or proton pump inhibitor (such equally omeprazole) may be beneficial31

• Seizures—Although uncommon, seizures tin be seen in advanced disease and pose a risk to healthcare workers because they increase the take chances of contact with the patient'southward body fluids. Contributing factors (such as high temperature, hypoperfusion, and electrolyte disturbances) must be recognised and corrected. A benzodiazepine can be used to abort the seizure and can exist given intramuscularly or rectally if intravenous access is unavailable. An anticonvulsant (such as phenobarbital) can be given for repeated seizures31

• Agitation—Although uncommon, agitation can occur in advanced disease. It may be associated with encephalopathy or may exist a direct effect of the virus on the encephalon. Judicious apply of a sedative (such as haloperidol or a benzodiazepine) volition help to keep the patient calm and prevent needlestick injuries in healthcare workers31

• Sepsis and septic shock—Direction follows the same principles equally for bacterial sepsis.61 It should include broad spectrum antibiotics (such equally ceftriaxone, piperacillin-tazobactam, or meropenem) in the first hr after sending blood cultures, rapid intravenous fluid resuscitation with cess of response, appropriate airway management and oxygen administration, and monitoring of urine output preferably by urethral catheterisation. Broad spectrum antibiotics in these patients are used to target the presumed translocation of gut organisms. This is not backed by whatever evidence. Claret cultures are hard to perform safely in infected patients.

In the absence of a response to initial management, inotropic support should be considered, preferably through a central venous catheter in an intensive care unit of measurement where invasive monitoring enables more ambitious correction of fluids, electrolytes, and acrid-base of operations remainder.52 54

Malaria should exist tested for and treated with appropriate antimalarial therapy. In endemic settings all patients in Ebola treatment centres are treated for malaria routinely.five 38 47

Are there any emerging treatments?

Although experimental treatments for Ebola virus infection are under development, they have not yet been fully tested for safety or effectiveness.62 63

Convalescent whole claret or plasma

There is limited evidence from past outbreaks that transfusion of blood from convalescent patients might exist benign in the acute phase of infection and may reduce mortality.46 63Trials are planned.62 64

ZMapp

The all-time known emerging treatment so far, ZMapp, is a combination of iii humanised monoclonal antibodies targeted at three Ebola virus glycoprotein epitopes and is engineered for expression in tobacco plants.62 63 65 66 Before the electric current 2014 outbreak, ZMapp had proved protective when given to non-human being primates 24-48 hours after infection. Some other study showed that the drug could rescue non-human primates when treatment was started up to v days after infection.67 It has not yet been tested in humans for safety or efficacy; nonetheless, very limited stock (seven doses) was made available to infected patients during the current outbreak, and only one patient died. Despite its potential, numbers are too small to make any conclusions most the drug's safety and efficacy. More doses are non currently available to conduct larger trials, but development is being accelerated with back up from the U.s.a. regime.68

TKM-Ebola

TKM-Ebola consists of a combination of small interfering RNAs that target Ebola virus RNA polymerase L, formulated with lipid nanoparticle technology. Information technology has been shown to be protective in not-human primates and is effective confronting Marburg virus in republic of guinea pigs and monkeys.62 63 66 69 70 71 The U.s.a. Food and Drug Administration has granted expanded access to this drug under an Investigational New Drug application. Under emergency protocols, it has been given to a small number of patients.

Brincidofovir

Formerly known every bit CMX-001, brincidofovir is currently undergoing stage III trials for the treatment of cytomegalovirus and adenovirus. It also shows action confronting Ebola virus in vitro. The drug has been used in patients with Ebola virus infection in the US under Emergency Investigational New Drug applications approved by the FDA. Trials are planned in the near future in west Africa.62 63 64

Favipiravir

Formerly known as T-705, favipiravir selectively inhibits viral RNA dependent RNA polymerase. It is active against flu viruses, West Nile virus, yellow fever virus, foot and oral cavity illness virus, equally well every bit other flaviviruses, arenaviruses, bunyaviruses, and alphaviruses. The drug is approved in Japan for flu pandemics and is effective against Ebola virus in mouse models.62 63 72 Human trials are due to kickoff in due west Africa.64

BCX-4430

BCX-4430 is an adenosine counterpart that is agile confronting Ebola virus in rodents. It is idea to act through the inhibition of viral RNA dependent RNA polymerase. It is active against flaviviruses, bunyaviruses, arenaviruses, and paramyxoviruses. The drug has been shown to exist protective in non-human primates and rodents, fifty-fifty when given 48 hours after infection with filoviruses63 73; however, no human studies take been performed.

AVI-7537

AVI-7537 consists of antisense phosphorodiamidate morpholino oligomers (PMOs) that target the Ebola virus VP24 gene. It confers a survival benefit to Ebola virus infected non-human primates.63 74 AVI-6002 consists of 2 PMOs (AV-7537 and AV-7539, which targets the VP35 cistron). AV-6002 has undergone phase I clinical studies.

Other agents

Interferons have been used in the past, with uncertain benefit.16 63 Therapeutic agents used for other diseases, such as amiodarone, clomiphene, and chloroquine, inhibit Ebola virus interactions with human cells in models, and amiodarone volition before long be trialled in west Africa.62 75

Vaccines

Two experimental vaccines are currently undergoing trials.62 63 cAd3-ZEBOV is a chimpanzee derived adenovirus vector with an Ebola virus gene inserted.76 Trials are under way in the Great britain, United states of america, Switzerland, and some African countries. rVSV-ZEBOV is an attenuated vesicular stomatitis virus with ane of its genes replaced by an Ebola virus gene. Human trials accept started in the US.

What is the prognosis?

The natural clinical course of Ebola virus infection varies markedly betwixt the dissimilar viral species and according to the level of supportive medical intendance available. The virtually lethal species is Zaire ebolavirus, which has a reported case fatality rate of up to xc%. The charge per unit in the current 2014 outbreak is less than this and is estimated at 60-seventy%, although accurate information are biased by poor record keeping and registration.three Near epidemics accept occurred in resource poor settings with niggling supportive care, and the case fatality charge per unit in loftier income settings could exist less than 40%.52 Mortality is higher in younger children (<5 years) and adults over 40 years than in adolescents and immature adults.3 five 38 twoscore 41 47 51 An observational study during an outbreak in 1995 showed a marked decrease in the case fatality rate from 93% to 69% between the initial and final phases of the outbreak.77 This suggests that later cases were recognised earlier and possibly received college quality intendance. Significant women have a loftier incidence of miscarriage and the infection is almost ever fatal in these women.38 78 79 80

Infection class

Patients who die tend to develop clinical signs early on in the infection, with death, normally attributed to shock and multi-organ failure, typically occurring between days vi and sixteen (median 9 days) from symptom onset.19 81 82 Patients who eventually recover exhibit isolated fever for several days with comeback typically effectually days half dozen-xi. A high viral load at presentation is correlated with bloodshed.5 24 38 47 49 Biomarkers equally prognostic indicators require further study.51 81

Recovery and convalescence

Patients who live through the second calendar week of infection have more than than a 75% risk of surviving.43 Patients are usually discharged from the isolation facility when they are ambulant, able to self care, have no serious symptoms (such as diarrhoea, vomiting, or haemorrhage), and have two negative Ebola RT-PCR results taken 48 hours apart.47

Patients who survive usually accept a protracted recovery characterised by asthenia, weight loss, and migratory arthralgia. Pare desquamation and transient hair loss are as well common. Late manifestations during convalescence are uncommon just include uveitis, orchitis, myelitis, parotitis, pancreatitis, hepatitis, psychosis, hearing loss and tinnitus.44 The cause of these manifestations is unclear merely they might exist related to immune circuitous phenomena.

Survivors of infection probably have lifetime immunity to the same strain of Ebola virus. Such patients have therefore been invaluable in caring for those with active infections.

What advice should patients be given during recovery?

Patients should exist educated about the likely course of convalescence and the possibility of long term complications. In that location are no specific requirements for monitoring after discharge; however, eligible patients may be asked to donate blood from 28 days subsequently discharge to be used in the treatment of patients with active infection.

Male person patients should be reminded near the importance of using condoms to prevent sexual manual in the three months after resolution of infection.fifteen 16 17 Women should exist advised not to breast feed during infection.15

Survivors and orphans of those who died from the disease face stigma and ostracism in many communities. This—along with substantial associated psychological disturbance—was reported after previous outbreaks,83 84 and it is an increasing problem in the 2014 outbreak.

Boosted educational resources

Notes

Cite this as: BMJ 2014;349:g7348

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Footnotes

• The authors thank Adam Mitchell, clinical editor and drug editor, BMJ All-time Practice, for his all-encompassing editorial back up on this topic.

• Competing interests: NJB is an author of several references cited in this monograph. NJB is partially supported by a National Institute of Health Inquiry grant to the Health Protection Unit in Emerging Infections and Zoonoses, a partnership between the University of Liverpool, the Liverpool Schoolhouse of Tropical Medicine, and Public Health England.

• Provenance and peer review: Not commissioned; externally peer reviewed.

• This clinical review series has been developed for The BMJ in collaboration with BMJ Best Practice (http://bestpractice.bmj.com), an independent production produced past BMJ Publishing Group Limited. BMJ All-time Do comprises web/mobile topics that support evidence-based decision making at the point of care. Peer review of the content in this clinical review was carried out exclusively co-ordinate to BMJ All-time Practice'southward own, contained process (http://bestpractice.bmj.com/all-time-do/marketing/how-is-best-exercise-produced.html). This adaptation of a BMJ Best Practice topic for a clinical review in The BMJ uses just a portion of content from the latest available web version of BMJ All-time Practice. BMJ Best Do is updated on an ongoing basis, and the content of any BMJ All-time Practice topic is expected to alter periodically including subsequent to its publication as a clinical review in The BMJ. To view the complete and electric current versions of all BMJ Best Practice topics, delight refer to the BMJ Best Practice website (http://bestpractice.bmj.com).

• Content from BMJ Best Practice is intended to support, help and supplement the expertise, discretion and judgment of licensed medical health professionals who remain solely responsible for decisions regarding diagnosis and handling of their patients. Content from BMJ Best Practice is not intended to office as a substitute for a licensed medical health professional's judgment. BMJ All-time Practice reflects evidence available to its authors and licensors prior to publication. The BMJ relies on its authors to confirm the accuracy of the data presented to reflect generally accepted practices. While The BMJ seeks to ensure BMJ Best Practice is up to date and accurate, information technology does not warrant that is the case. Content from BMJ Best Practice is supplied on an "equally is" basis and any statements made to the contrary are void. BMJ All-time Practise does not endorse drugs, diagnose patients, or recommend therapy. The full disclaimer applicable to BMJ All-time Practice can be found at http://bestpractice.bmj.com/best-practice/marketing/disclaimer.html.

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