October 21, 2015

Ebola virus persistence Q&A

The following Q&A was prepared by experts on Ebola and infectious diseases in response to the readmission to hospital of Pauline Cafferkey, the nurse who was infected with Ebola in 2014.

The SMC produced a Factsheet with background information to the Ebola virus.

Q. When someone is said to have recovered from Ebola, does that mean no Ebola virus was detectable in their body?

We believe usually yes.  But in some patients, we do not know how commonly, the virus, or fragments of the virus, may persist in some parts of the body.

When a patient survives infection with Ebola virus there is usually complete resolution of all acute symptoms and two tests show there is no Ebola virus in the blood.  This is recommended in all patients in all countries, though may not always occur especially in resource poor areas such as parts of the affected West African countries. When two tests show no virus the patient can be discharged from hospital.  At this stage the chance of them being infectious is extremely low and there have been very few cases reported over the last forty years of survivors being infectious to others.  But of course in the past there have been very few survivors as the epidemics have been relatively small.  In this epidemic there are over 17,000 survivors.

We are learning that many survivors may go on to have chronic symptoms such as fatigue, rash, depression, joint pain or eye inflammation and/or persistence of virus in certain bodily fluids other than blood such as semen, breast milk and the fluid that surrounds the brain.  The recovery from the acute infection is the first hurdle, there then may be a prolonged recovery from the side effects of Ebola virus infection. As we have seen in the UK this week very rarely there can be a recurrence of the illness.

Q. What is viral persistence?

Viral persistence is the continued presence of Ebola virus, or fragments of the virus, in certain bodily fluids after a person has been determined to have survived Ebola and tested negative for the virus on at least two blood tests. Individuals with the presence of persistent Ebola virus may experience some signs of the disease, or there may be no indication that the virus remains in their body.

The issue of persistence has been known for a long time in virology, but the precise reasons why a virus may become persistent in some individuals is not understood. It may be that the virus “hides” in parts of the body which our immune system cannot clear the virus, in so called “immune protected sites” such as in the testes, in breast milk, in the fluid that surrounds the brain.

The result is that the virus persists as the body’s immune system cannot efficiently clear it completely.  In some situations the long lasting persistent infection may ultimately be resolved with total clearance of the virus from the body.  We do not know how long this persistence may last or how infectious the individual is during this time.  We suspect from epidemiological information over the last forty years that such individuals are not very infectious during this time but the risk of passing the infection on is not zero.  All patients are counselled on these risks prior to discharge from hospital.

Q.What is known about the persistence of the Ebola virus in survivors?

There is limited data on the persistence of Ebola virus in the bodily fluids of survivors. So far Ebola virus has been found in semen, vaginal secretions, breast milk, intra-ocular fluid (fluid inside the eyeball) and cerebrospinal fluid (fluid surrounding the brain and spinal cord) of survivors. In many of these cases there are only anecdotal reports of the presence of virus and the length it can remain in these locations for is unclear. The most consistent evidence available is for the presence of virus in semen which now has been demonstrated to be present for up to nine months following the onset of symptoms.

The test to identify the virus looks at viral genetic material. These tests can identify viral material even if the virus is dead or fragmented. This means that even though the virus may be identified in these fluids it does not necessarily mean it is infectious to other people who come into contact with it.

The bodily fluids involved tend to be those that are harder for the immune system to reach and as such the immune system has not been able to effectively fully clear the virus from this region of the body.

Q. What does it mean for someone to still have Ebola virus in their system? Does that mean they ‘have’ Ebola and are infectious?

Having Ebola virus ‘in their system’ can be taken to mean that the virus is still known to be present in one or more of the person’s bodily fluids.  This does not necessarily mean they have symptoms associated with the ongoing presence of virus, although they might. This also does not necessarily mean that the person is infectious to others; although they may be to people they have intimate contact with They are not infectious to people who do not have close contact with them, i.e. direct contact with their bodily fluid – the mode of transmission does not change. In the case of persistence in the testes, the virus may be fully functional, and therefore does have the potential through sexual intercourse be passed onto others. It is for this reason that Ebola virus survivors receive advice about the risks of sexual transmission and are encouraged to take precautions to reduce this risk, including using condoms and careful hygiene.

The case of Dr Ian Crozier who was found to have infectious Ebola virus in the eye also demonstrates that the virus can persist in other parts of the body in an infectious state.  The location of the persistent virus will determine whether there is a possibility of transmission – virus in the eye is unlikely to be transmitted.

Q. What risk does this pose to contacts of the person or the general public?

The risk to close contacts is small while the virus is in the persistent state, although this depends on which fluid contains the virus and the nature of the contact and exposure to the bodily fluid involved. The risk to the general public is negligible.

Q. What might cause a relapse?

This remains unclear. It is possible the virus has been kept at bay but not fully cleared by the immune system, when the immune system is weakened or distracted by another illness it may be that the Ebola virus can start to spread more quickly again without being kept in check by the immune system, allowing it to cause further damage to organs and causing new or prolonged symptoms.

Other possibilities may be that the immune system starts to over-react to virus still being present and as a result of this turns on the body and can cause inflammation in parts of the body such as the joints or the eyes. Alternately the immune system will have been weakened by fighting the Ebola virus and this means the body is susceptible to other infections and so a person may develop new or further symptoms. These latter two do not mean the person is relapsing with Ebola virus disease but they are suffering from a complication of their previous infection.

The ongoing symptoms seen following Ebola virus disease are being referred to as post-Ebola syndrome or Ebola survivor syndrome.

Q. If it is reinfection of Ebola, is it likely to be as serious as first time around?

It is not a reinfection with the virus as this would imply complete clearance of the virus, re-exposure to a symptomatic patient and then contracting the virus again. Infection with one of the other strains of the virus is a possibility but this would be deemed a new infection not a re-infection.

When persistent viruses reappear they usually proceed in the way seen in an initial infection, though if the persistence arose because of an impairment in the patient’s immune system that is still present the disease may be different.

The persistence of the virus or the development of a relapse or continued ongoing symptoms is an area of ongoing and urgent medical research. What has been observed so far in West Africa and previous epidemics is that people may develop chronic debilitating symptoms but not life threatening symptoms. The symptoms seen in post-Ebola syndrome differ from the original acute infection but can take many different forms and the full extent and severity of these is still being determined. It is possible some of these could cause serious, critical illness but this has not been seen among in survivors in West African to date.

In non-human primate (monkey) studies of Ebola virus infection, there have been cases where Ebola-infected animals have appeared to recover (either naturally or following administration of experimental drugs) but then had a serious relapse where the symptoms are unlike those seen in the  initial infection (e.g. diarrhoea, bleeding etc.), but instead involving other organs, notably the brain.

Q. If a person recovered from Ebola, doesn’t that mean their immune system managed to fight it off and so should be able to do so again?

That is the hope.  Although it is thought that a survivor of Ebola establishes immunity that protects them from future infection by the same strain of virus although it is not clear how long this protection lasts.  The process by which a survivor develops chronic symptoms or relapse of infection is not fully clear and so it is possible a person can develop symptoms or a new complication of infection that is in a difficult location for the body’s immune system to fight. Alternately if the process occurring is related to the immune system fighting the body this requires a different type of clinical approach and can be complicated to manage.

Q. Could treating a patient with convalescent plasma from Ebola survivors make them more likely to suffer from later complications or relapses?

Convalescent plasma treatment involves taking the blood plasma from Ebola survivors and giving it as a transfusion to patients so that existing protective antibodies from the survivor can help fight the infection in the recipient. All blood transfusions used in this, including plasma, are rigorously screened for the Ebola virus and for viral fragments, as well as a very broad range of other infections like HIV and hepatitis. Survivors would have to have no traces of Ebola virus or Ebola RNA in their blood before their plasma could be given as a transfusion, and so even if they had persistent Ebola virus reservoirs in places like the eye or testes, the risk of transferring a fresh strain of the virus to a patient is close to zero. This makes it extremely unlikely that treating a patient with convalescent plasma would lead to complications from Ebola virus persistence or secondary infections, but further studies and trials need to be done to fully investigate the long-term impact of the virus on survivors.

Q. Is it possible that mutation of the Ebola virus might be at play here, or is it simply that we don’t know enough about the aftermath of the infection?

The latter is more likely. The Ebola virus genetic sequence has been studied extensively throughout this 22 month epidemic and has shown only slight and expected changes in the genetic sequence. There is no evidence of a significant change in the virus or how transmission occurs.

Virus persistence might arise through genetic mutation. At the moment there is no evidence that this has happened but further study, especially of viruses present in these long-lasting reservoirs will tell us if this is happening, and if it is what impact it has on persistence and disease.

Q. Does this mean the virus has mutated within the individual that has fallen ill again?

No, while it is possible the virus may mutate we have not observed significant mutations in the viral genetic sequence throughout this epidemic. We have observed small mutations that enable us to trace the origins and spread of the virus but these would not be significant enough to change the function of the virus. In an individual that has fallen ill again, it is more likely to be due to a change in the status of the patient rather than the virus.

Q. What are the known complications of having had (and recovered from) Ebola from other examples, and what is different in Pauline Cafferkey’s case?

The serious damage to organs and tissues during an Ebola virus infection can have consequences that last a long time, depending on the individual and the precise details of that damage.  Long lasting effects can include:

Chronic join pain

Uveitis (inflammation of the eye) with development of cataracts or blindness in some of those untreated.

Persistent fatigue

Hair loss

Mental health problems including depression and post-traumatic stress disorder

Thyroid problems

Seizure disorders and neurological problems

Anorexia

Susceptibility to other infections (such as chicken pox, measles, tuberculosis)

Hearing loss and deafness

Sleep disorders

Memory loss

Pauline Cafferky’s case appears to have caused her to become seriously unwell again whereas the above symptoms, although debilitating and with serious long term implications, are generally not life threatening (except for potential complications of seizures/neurological disorders). We have no information about her particular case and so cannot speculate with any accuracy.