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International Journal of Infectious Diseases 43 (2016) 58–61
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International Journal of Infectious Diseases
jou rnal homepage: www.elsevier.com/locate/ijid
Perspective
Recurrence and reinfection—a new paradigm for the management of
Ebola virus disease
C. Raina MacIntyre *, Abrar Ahmad Chughtai
School of Public Health and Community Medicine, Samuels Building, Room 325, Faculty of Medicine, University of New South Wales, Sydney, 2052, NSW,
Australia
A R T I C L E I N F O S U M M A R Y
Article history: Ebola virus disease (EVD) is an understudied infection and many aspects of viral transmission and
Received 27 October 2015
clinical course remain unclear. With over 17 000 EVD survivors in West Africa, the World Health
Received in revised form 11 December 2015
Organization has focused its strategy on managing survivors and the risk of re-emergence of outbreaks
Accepted 11 December 2015
posed by persistence of the virus during convalescence. Sexual transmission from survivors has also been
Corresponding Editor: Eskild Petersen,
documented following the 2014 epidemic and there are documented cases of survivors readmitted to
Aarhus, Denmark.
hospital with ‘recurrence’ of EVD symptoms. In addition to persistence of virus in survivors, there is also
some evidence for ‘reinfection’ with Ebola virus. In this paper, the evidence for recurrence and
Keywords: reinfection of EVD and implications for epidemic control are reviewed.
Ebola
ß 2015 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
Healthcare workers
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- Recurrence nc-nd/4.0/). Reinfection
Body fluids
Infection control
1. Introduction There is much we do not yet understand about Ebola virus, and it
is timely to review the implications of recurrence and reinfection
Ebola virus disease (EVD) is an understudied infection, with for epidemic control.
1,2
uncertainty around many aspects of transmission and disease.
Acute infection is characterized by overwhelming viremia and
3 2. Recurrence of Ebola virus
immune evasion. Direct contact with blood and body fluids is the
dominant mode of transmission, but evidence is increasing that
Ebola virus may persist at immunologically protected sites in
other modes, including blood-borne, vertical, sexual, and aerosol
the body, including semen, vaginal fluids, sweat, aqueous humour,
transmission, are possible. Ebola virus can cause symptoms in
4,9–13
urine, and breast milk. A study of 93 survivors showed that
clinically recovered patients despite clearance of virus from the
4,5 100% had Ebola virus RNA in the semen at 2–3 months post onset of
blood. With over 17 000 EVD survivors in West Africa, the World
13
EVD, decreasing to 65% at 4–6 months and 26% at 7–9 months. A
Health Organization (WHO) has focused its strategy on managing
positive PCR test may or may not indicate the presence of viable
survivors and the risk of re-emergence of outbreaks posed by
6 virus. Only a positive virus culture confirms infectious potential.
chronic persistence of the virus. In addition to chronic persistence
7,8 During the outbreak in Kikwit, Democratic Republic of the Congo in
of virus in survivors, there is also some evidence for reinfection.
1995, in addition to positive PCR for urine, semen, conjunctiva,
‘Recurrence’ or recrudescence refers to the reappearance of
sweat, vaginal, and rectal samples from recovered patients, one
symptoms in survivors due to the persistence of virus at
patient had live virus isolated from seminal fluid up to 82 days
immunologically protected body sites, while ‘reinfection’ refers
9
after disease onset. In another case, PCR was positive in sweat and
to survivors being susceptible to acquiring new infections after
urine up to day 40. The last urine culture was positive for Ebola at
recovery. Both of these phenomena create a risk of emergence of
12
day 26 after onset, while sweat cultures were negative.
Ebola virus outbreaks and are a challenge to disease control efforts.
The persistence of virus poses three risks: transmission to
others while asymptomatic (e.g., sexual transmission), reactivation
of illness (risk to the affected individual), and transmission to
* Corresponding author. Tel.: +61 2 9385 3811; fax: +61 2 9313 6185.
E-mail address: [email protected] (C.R. MacIntyre). others from symptomatic individuals with recrudescent illness
http://dx.doi.org/10.1016/j.ijid.2015.12.011
1201-9712/ß 2015 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
C.R. MacIntyre, A.A. Chughtai / International Journal of Infectious Diseases 43 (2016) 58–61 59
(which may go unrecognized as recurrent/recrudescent EVD). studies also suggest that variability in host immunity can
Animal studies support the persistence of Ebola virus at some sites determine whether the host can become susceptible to reinfection.
14,15
and the subsequent re-emergence of symptoms. However in Conditions of partial immunity can lead to the reinfection of
most animal studies, especially non-human primate studies, the recovered mice, which have been shown to develop lethal infection
15
animals have tended to be sacrificed early; when this has not been after re-challenge with the virus. In the trial of ZMAb in
the case, the animals have not always been followed up for long macaques, a second challenge with Ebola virus was done to test
24
enough periods to be analogous to the time course of recrudescent reinfection. Viremia was demonstrated after re-challenge, and
illness described in humans. two of 12 monkeys that had lower immunity succumbed to a re-
During the 2014 outbreak, a 43-year-old US physician challenge. This shows that there is variability in individual host
developed uveitis 9 weeks after clinical recovery and Ebola virus immune responses and that in some cases a first infection does not
4
was isolated from the aqueous humour. Whilst uveitis and ocular protect from a second. The converse of this is that some people,
complications had been described previously, this was the first presumably with a more robust immune system, are thought to
25,26
time viable virus had been demonstrated to persist in the eye. In develop subclinical or asymptomatic infection. According to a
past outbreaks, uveitis during convalescence was thought to be a recent report, a group of women in Guinea were not infected
delayed immunological phenomenon, but recent evidence has despite repeated exposure to the virus, and only one of them had
27
shown that reactivation of the virus can cause these symptoms. Ebola virus antibodies in the blood. All of this points to great
Uveitis in survivors may be due to one or both of these factors and variability in individual host susceptibility to infection and
needs further study. reinfection based on innate immunity, as well as the viral load
More recently, neurological symptoms reappeared 9 months to which the individual is exposed during a challenge or re-
5
after recovery in a nurse who survived EVD. She developed challenge.
meningitis and Ebola virus was detected in blood and cerebrospi- Reinfection is theoretically possible due to waning or partial
nal fluid (CSF). She was treated with an experimental drug that had immunity, a high viral load during a re-challenge, or a combination
16
been used successfully to treat severe infection in primates. of both of these factors. Studies have shown that Ebola virus
28
Whilst similar syndromes had been described in past outbreaks, antibodies wane after a few years in some survivors. The
this was the first time viable virus had been isolated in the CSF. In a antibody level required for optimal protection or immune memory
30-year-old woman in Sierra Leone, Ebola virus was detected is not known, but cell-mediated immunity is also thought to play a
23
through RT-PCR at day 41 in CSF and at day 44 in sweat, while role. Figure 1 shows the possible outcomes for an EVD survivor
17
blood and urine tests were negative. Studies of women who and the pathways through which a new outbreak could occur.
acquired the infection during pregnancy have indicated that while
the woman may recover and clear the virus from blood, a high viral 4. Discussion
18
load persists in amniotic fluid, placenta, and foetus. The delivery
of recovered women, therefore, should be done with full infection The 2014 West African epidemic is the largest in history,
29
control precautions. resulting in more than 28 000 cases and 11 000 deaths. With over
There is a lack of data in relation to the transmission of Ebola 17 000 survivors in West Africa, the magnitude and long-term
through the body fluids of recovered Ebola patients. Rowe et al. implications of recurrence and reinfection are unknown. If more
examined the transmission of infection from convalescent patients than one in four male EVD survivors has virus in the semen at 7–9
13
(who had recovered from the acute phase) to household members months, further cases are likely through sexual transmission. In
10 10,19
and did not find direct evidence of transmission. Five household fact, at least two cases have been documented.
members had serological evidence of Ebola infection and one was Detailed studies of persistence in the vaginal fluid of female
10
possibly due to sexual transmission after recovery. To date, only survivors have not been reported to date, but the available data
9
one confirmed case of EVD has been documented due to suggest that this is an additional risk. In terms of reinfection or
transmission through the body fluid of clinically well Ebola recrudescence, variability in host immunity and waning immunity
survivors. During the 2014 West African outbreak, a 44-year-old might be important. It is commonly said that healthcare worker
Liberian woman acquired Ebola virus from a recovered Ebola EVD survivors are immune and can safely go back into the field to
survivor who was positive for Ebola virus by RT-PCR in semen at treat EVD patients again, and may not even need personal
30
199 days after recovery; the Ebola virus strain was genetically protective equipment. Some have even claimed that survivors
19 30
matched with that of the case patient. The genetic sequencing of have ‘super powers’. This is clearly not the case, with increasing
31
virus in this couple has provided strong evidence of sexual case reports of recrudescence of disease in survivors. In addition,
20
transmission of Ebola virus. the possibility of reinfection exists and is a function of host
immunity as well as the viral load to which an individual is
3. Reinfection with Ebola virus exposed. It may be possible that individuals who clear the virus
completely may be susceptible to reinfection under conditions of
Anecdotal reports have raised questions around the possibility waning or lowered immunity and a high viral load on re-challenge.
of reinfection with Ebola virus, however a confirmed case of However, immunological conditions (e.g., arthralgia/arthritis) may
21,22
reinfection has never been reported. The first potential case of not easily be differentiated from symptoms of virus reactivation –
7
reinfection was reported by an aid worker, but was not confirmed. especially when it comes to treatment. Therefore, symptoms in
In this instance, it was thought that lowered immunity in a survivors require thorough evaluation, where possible, to identify
recovered patient may have contributed to reinfection after underlying infectious and non-infectious causes.
7
exposure to a new Ebola patient. In another report, virus was Whilst there remains uncertainty about the long-term sequelae
detected through PCR in two children aged <5 years in Monrovia of EVD, a range of precautions can be taken to minimize the risk of
who had recovered clinically and had negative PCR results at the new cases and outbreaks in the context of a large number of
8
time of discharge. Whether this was recrudescence or reinfection survivors in West Africa. Firstly, the use of condoms for sexual
is unclear. contact should be promoted for survivors for at least 12 months,
Recovery from EVD requires both humoral and cell-mediated until further research is available to determine the possible
immunity, and variability in the immune response has been duration of persistence in vaginal and seminal fluid. Past outbreaks
23 9
described between individuals and between outbreaks. Animal indicate the presence of viral RNA in vaginal fluids, and this needs
60 C.R. MacIntyre, A.A. Chughtai / International Journal of Infectious Diseases 43 (2016) 58–61
Figure 1. Possible outcomes for Ebola virus disease survivors.
nhs.uk/news-media/news/pauline-cafferkey-recovering/ (accessed November
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Professor C. Raina MacIntyre: Raina MacIntyre has held an Engl J Med 2015. http://dx.doi.org/10.1056/NEJMoa1511410
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Australian Research Council Linkage Grant with 3M as the industry
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partner, for investigator driven research. 3M have also contributed
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supplies of masks and respirators for investigator-driven clinical 15. Gupta M, Mahanty S, Greer P, Towner JS, Shieh WJ, Zaki SR, et al. Persistent
infection with Ebola virus under conditions of partial immunity. J Virol
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kind support from Pfizer, GSK and Bio-CSL for investigator-driven
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