View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

International Journal of Infectious Diseases 43 (2016) 58–61

Contents lists available at ScienceDirect

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: 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 , 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

to be studied more fully in the context of the 2014 epidemic.

30, 2015).

Although the WHO recommends testing survivors who have

6. World Health Organization (WHO). Ebola survivors clinic opens in Monrovia.

positive semen on a regular basis until the virus is cleared, Geneva: WHO; 2015 , Available at: http://www.who.int/features/2015/

32

ebola-survivors-clinic/en/ (accessed October 19, 2015).

recommendations are ambiguous for other body fluids. The

7. Baschiera D. Ebola outbreak: Darwin volunteer writes from Sierra Leone

clinical care and follow-up of survivors should focus on preventive

treatment centre, ‘I just cry in my goggles’. 2014. Available at: http://www.

health (including vaccinations for vaccine-preventable diseases), abc.net.au/news/2014-11-26/

darwin-ebola-volunteer-dan-baschiera-writes-from-sierra-leone/5919516

the management of chronic conditions and comorbidities, and

(accessed January 27, 2015).

nutrition, to ensure optimal health and well-being. Ageing is

8. Hand L. A turning point for Ebola? Possible reinfection? 2014. Available at:

associated with immunosenescence and a predictable failing of http://www.medscape.com/viewarticle/833730 (accessed October 16, 2015).

33

immunity. Therefore there may be an increased risk of 9. Rodriguez LL, De Roo A, Guimard Y, Trappier SG, Sanchez A, Bressler D, et al.

Persistence and genetic stability of Ebola virus during the outbreak in Kikwit,

recrudescence of Ebola virus in ageing survivors over the longer

Democratic Republic of the Congo, 1995. J Infect Dis 1999;179(Suppl 1):S170–6.

term, in much the same way as the risk of herpes zoster or

10. Rowe AK, Bertolli J, Khan AS, Mukunu R, Muyembe-Tamfum JJ, Bressler D, et al.

33

tuberculosis increases with age. This is correlated with an Clinical, virologic, and immunologic follow-up of convalescent Ebola hemor-

34 rhagic fever patients and their household contacts, Kikwit, Democratic Republic

exponential decline in immune function after the age of 50 years,

of the Congo. Commission de Lutte contre les Epidemies a Kikwit. J Infect Dis

and may pose a long-term risk for West Africa with its large

1999;179(Suppl 1):S28–35.

population of EVD survivors. Finally, surveillance and rapid 11. Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, Sanchez A, et al.

Assessment of the risk of Ebola virus transmission from bodily fluids and

diagnostic and response capacity should be improved in high-

fomites. J Infect Dis 2007;196(Suppl 2):S142–7.

risk countries for the rapid detection and control of new outbreaks.

12. Kreuels B, Wichmann D, Emmerich P, Schmidt-Chanasit J, de Heer G, Kluge S,

et al. A case of severe Ebola virus infection complicated by Gram-negative

septicemia. N Engl J Med 2014;371:2394–401.

Conflict of interest:

13. Deen GF, Knust B, Broutet N, Sesay FR, Formenty P, Ross C, et al. Ebola RNA

persistence in semen of Ebola virus disease survivors—preliminary report. N

Professor C. Raina MacIntyre: Raina MacIntyre has held an Engl J Med 2015. http://dx.doi.org/10.1056/NEJMoa1511410

14. Strong JE, Wong G, Jones SE, Grolla A, Theriault S, Kobinger GP, et al. Stimulation

Australian Research Council Linkage Grant with 3M as the industry

of Ebola virus production from persistent infection through activation of the

partner, for investigator driven research. 3M have also contributed

Ras/MAPK pathway. Proc Natl Acad Sci U S A 2008;105:17982–7.

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

trials. She has received research grants and laboratory testing as in-

2004;78:958–67.

kind support from Pfizer, GSK and Bio-CSL for investigator-driven

16. Fink S. New clues into Ebola as ill nurse improves. 2015. Available at: http://

research. Dr. Abrar Chughtai had testing of filtration of masks by www.nytimes.com/2015/10/22/world/europe/

new-clues-into-ebola-as-ill-nurse-improves.html?_r=2 (accessed October 23,

3M for PhD.

2015).

17. Howlett P, Brown C, Helderman T, Brooks T, Lisk D, Deen G, et al. Ebola virus

References disease complicated by late-onset encephalitis and polyarthritis. Sierra Leone

Emerg Infect Dis 2016;22:150.

1. MacIntyre CR, Chughtai AA, Seale H, Richards GA, Davidson PM. Uncertainty, 18. Baggi FM, Taybi A, Kurth A, Van Herp M, Di Caro A, Wolfel R, et al. Management

risk analysis and change for Ebola personal protective equipment guidelines. Int of pregnant women infected with Ebola virus in a treatment centre in Guinea,

J Nurs Stud 2014;5:899–903. June 2014. Euro Surveill 2014;19:1–4.

2. Osterholm MT, Moore KA, Kelley NS, Brosseau LM, Wong G, Murphy FA, et al. 19. Christie A, Davies-Wayne GJ, Cordier-Lasalle T, Blackley DJ, Laney AS, Williams

Transmission of Ebola viruses: what we know and what we do not know. MBio DE, et al. Possible sexual transmission of Ebola virus—Liberia, 2015. MMWR

2015;6. e00137-15. Morb Mortal Wkly Rep 2015;64:479–81.

3. Wong G, Kobinger GP, Qiu X. Characterization of host immune responses in 20. Mate SE, Kugelman JR, Nyenswah TG, Ladner JT, Wiley MR, Cordier-Lassalle T,

Ebola virus infections. Expert Rev Clin Immunol 2014;10:781–90. et al. Molecular evidence of sexual transmission of Ebola virus. N Engl J Med

4. Varkey JB, Shantha JG, Crozier I, Kraft CS, Lyon GM, Mehta AK, et al. Persistence 2015;373:2448–54.

of Ebola virus in ocular fluid during convalescence. N Engl J Med 21. MacIntyre CR. Reinfection with Ebola—is it possible and should health worker

2015;372:2423–7. survivors use PPE?; 2014. Available at: https://sphcm.med.unsw.edu.au/

5. Royal Free Hospital. Pauline Cafferkey recovering. , UK: Royal Free infectious-diseases-blog/reinfection-ebola-%E2%80%93-it-possible-and-

London NHS Foundation Trust; 2015 , Available at: https://www.royalfree. should-health-worker-survivors-use-ppe (accessed January 27, 2015).

C.R. MacIntyre, A.A. Chughtai / International Journal of Infectious Diseases 43 (2016) 58–61 61

22. Ikeke N. Ebola: cured victims can be re-infected—WHO Member. 2014. Avail- 28. Wauquier N, Becquart P, Gasquet C, Leroy EM. Immunoglobulin G in Ebola

able at: http://www.naij.com/279159-cured-ebola-victims-can-re-infected. outbreak survivors. Gabon Emerg Infect Dis 2009;15:1136–7.

html (accessed January 27, 2015). 29. World Health Organization. Global Alert and Response (GAR). Ebola situation

23. Sobarzo A, Eskira Y, Herbert AS, Kuehne AI, Stonier SW, Ochayon DE, et al. reports. Geneva: WHO; 2015. Available at: http://www.who.int/csr/disease/

Immune memory to Sudan virus: comparison between two separate disease ebola/situation-reports/en/ (accessed October 5, 2015).

outbreaks. Viruses 2015;7:37–51. 30. Wieners B. In Liberia, Ebola survivors find they have superpowers. 2014. Avail-

24. Qiu X, Audet J, Wong G, Fernando L, Bello A, Pillet S, et al. Sustained protection able at: http://www.bloomberg.com/bw/articles/2014-10-31/in-liberia-

against Ebola virus infection following treatment of infected nonhuman pri- ebola-survivors-find-they-have-superpowers (accessed October 16, 2015).

mates with ZMAb. Sci Rep 2013;3:3365. 31. Boyle D. Ebola nurse Pauline Cafferkey now critically ill. 2015. Available at:

25. Heffernan RT, Pambo B, Hatchett RJ, Leman PA, Swanepoel R, Ryder RW. Low http://www.telegraph.co.uk/news/health/news/11931143/

seroprevalence of IgG antibodies to Ebola virus in an epidemic zone: Ogooue- Ebola-nurse-Pauline-Cafferkey-is-now-critically-ill.html (accessed October 18,

Ivindo region, Northeastern Gabon, 1997. J Infect Dis 2005;191:964–8. 2015).

26. Leroy EM, Baize S, Volchkov VE, Fisher-Hoch SP, Georges-Courbot MC, Lansoud- 32. World Health Organization. Interim advice on the sexual transmission of the

Soukate J, et al. Human asymptomatic Ebola infection and strong inflammatory Ebola virus disease. Geneva: WHO; 2015, Available at: http://www.who.int/

response. Lancet 2000;355:2210–5. reproductivehealth/topics/rtis/ebola-virus-semen/en/ (accessed November 30,

27. The Guardian. Ebola study finds women in Guinea who appear immune to the 2015).

virus. London, UK: Guardian News and Media Limited; 2015. Available at: 33. MacIntyre CR. Elderly vaccination—the glass is half full. Health 2013;5:80–5.

http://www.theguardian.com/world/2015/oct/15/ 34. Hope-Simpson RE. The nature of herpes zoster: a long-term study and a new

ebola-study-finds-women-guinea-appear-immune-virus (accessed October hypothesis. Proc R Soc Med 1965;58:9–20.

20, 2015).