(Re)Vivre après Ebola : Evaluation et accompagnement des

patients déclarés guéris d'une infection par le virus Ebola en Guinée

Eric Delaporte for the PostEbogui Study Group

Coordination Nationale de lutte contre Ebola

Background

• Guinea declared Ebola-free on May 31, 2016

• 3811 cases, 2536 deaths

• 1270 survivors (33%) – Children < 15: 16%

– Female: 55%

– Health workers: 8%

66,7%

0%

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Décès probables

Décès confirmés

Guéris

Létalité cumulée

Lé

ta

lité

cu

mu

lée

(%)In

cid

en

ce

dé

cla

ré

e

Semaine de début des signes

Source: René Migliani

Postebogui Project

- Public Health support

- Care of survivors

- Capacity building

- Training

- Research projects

- Postebogui cohort

- Contactebogui

- Reservoir

Rationale

Few data on survivors from previous outbreaks, limited cases

New questions : clinical sequels, reactivation, reservoir

• Long-term medical problems

• Psychosocial consequences

• Viral clearance in the body compartments

Which package of care to respond to the survivors’ needs?

Ebola virus epidemiology and ecology

Rationale

Few data on survivors from previous outbreaks, limited cases

New questions : clinical sequels, reactivation, reservoir

• Long-term medical problems

• Psychosocial consequences

• Viral clearance in the body compartments

Which package of care to respond to the survivors’ needs?

Objectives

Clinical, immunological, genetic and virological component

• Clinical symptoms and sequels after discharge

• Viral clearance in the different body compartments

• Immunological and genetic studies (on-going)

Psychological component

• Psychological consequences of Ebola disease (individual and family)

Social and anthropological component

• Analysis of social effects

• Subjective experience of illness and cure, impact on health workers

Design

• Ethical clearance: 16 February 2015

• Eligibility: > 12 mths old, survivor’s certificate, residency in Guinea, consent

• Recruitment sites:

– Conakry, Macenta, N’Zérékoré, Forécariah

• First inclusion: 23 March 2015,

• Expected final size: up to 800

• Follow-up schedule: D0, M1, M3, M6,…,M24

Survivors’ map, WHO. Recruitment site

Investigations

• General clinical examination and reference to specialists (ophthalmology, psychiatry, rheumatology)

• Psychological assessment using age-dependent depression scales

• Standard biological assessment

• RT-PCR in body compartments (blood, saliva, tears, maternal breast milk, urines, feces, cervicovaginal secretions, semen)

Free medical package, reimbursement of transportation:

Social emergency fund (French Embassy)

Inclusion and follow-up

0 200 400 600 800Number of visits

M12 n=201

M9 n=297

M6 n=451

M3 n=686

M1 n=752

M0 n=802

Note : 5 participants died during the follow-up

From 23 March 2016 to 2 September 2016

Number of follow-up visits - POSTEBOGUI Cohort

0

200

400

600

800

Num

ber

of in

clu

sio

ns

01apr2015 01jul2015 01oct2015 01jan2016 01apr2016 01jul2016Date

Participants were recruited from 23 March 2015 to 11 July 2016

Cumulative number of inclusions - POSTEBOGUI Cohort

Characteristics at inclusion n=802

Age : median 28.4 years [range: 1.0-79,9]

Male : 45%

Children : 20%

Median delay after discharge : 350 days (IQR: 223-491).

Median follow-up : 176 days (IQR : 92-357)

18 10 13

232

106

48

116

6

52

33 22

192

1

73

5

18

4 14

135

51 51

135

2

60

42

21

190

2

72

5

0

50

100

150

200

250

N = 802

ANSS PostEboGui

Representativeness of the Postebogui cohort

68% of the 1270 declared free post ETC

71% of the 1128 survivors identified by the National Coordination (ANNSS)

Ebola Treatment Centers of the survivors included in Postebogui

Characteristics of Postebogui patients during the acute EBOV disease phase

All patients Adults Children P-value

Inclusion in a clinical trial:

0.8

No 685 (85) 545 (85) 140 (89)

Favipiravir trial 58 (7) 49 (8) 9 (6)

Plasmapheresis 44 (5) 37 (6) 7 (4)

Favipiravir and plasmapheresis

1 (0) 1 (0) 0 (0)

Plasmapheresis (other schemes)

14 (2) 12 (2) 2 (1)

Symptoms:

General symptoms 592 (74) 483 (75) 109 (69) 0.1

Haemorrhage 138 (17) 118 (18) 20 (13) 0.09

Abdominal symptoms 553 (69) 453 (70) 100 (63) 0.09

Myalgia 314 (39) 268 (42) 46 (29) 0.004

Dyspnoea 78 (10) 68 (11) 10 (6) 0.1

Ocular disorders 61 (8) 57 (9) 4 (3) 0.007

Hearing disorders 29 (4) 28 (4) 1 (1) 0.03

Neurological disorders 503 (63) 418 (65) 85 (54) 0.01

Behaviour troubles 6 (1) 6 (1) 0 (0) 0.2

Reported symptoms at inclusion

All patients Adults Children P-value

All symptoms ‡ 606 (76) 505 (78) 101 (64) 0.02

General symptoms 324 (40) 250 (39) 74 (47) <0.0001

Abdominal symptoms

198 (25) 163 (25) 35 (22) 0.4

Ocular symptoms/signs

142 (18) 124 (19) 18 (11) 0.2

Musculoskeletal symptoms

303 (38) 274 (43) 29 (18) <0.0001

Neurosensory disorders

289 (37) 231 (36) 67 (42) 0.1

Hearing disorders (deafness)

19 (2) 16 (2) 3 (2) 0.8

Association between clinical events at inclusion

General

symptoms

Neurological

disorders

Ocular symptom

s Deafness

Abdominal

symptoms

Musculo. symptom

s

General symptoms

1

Neurological disorders

<0.00001 1

Ocular symptoms

0.9 <0.00001 1

Deafness 0.3 0.06 0.05 1

Abdominal symptoms

<0.00001 <0.00001 0.8 0.2 1

Musculoskeletal symptoms

<0.00001 <0.00001 0.01 0.7 <0.0000

1 1

Acute Phase Post EVD

Phase P-value

General

symptoms 592 (74) 324 (40) 0.004

Fever 563 (70) 209 (26) 0.03

Fatigue 497 (62) 190 (24) <0.0001

Anorexia 314 (39) 89 (11) 0.5

Abdominal

symptoms 553 (69) 198 (25) 0.9

Abdominal

pain 360 (45) 178 (22) 0.02

Myalgia 314 (39) 111 (14) <0.0001

Ocular troubles 61 (8) 142 (18) <0.0001

Hearing

troubles 29 (4) 19 (2) <0.0001

Neurological

signs 503 (63) 298 (37) 0.1

Headache 502 (63) 278 (35) 0.07

Comparison of clinical events between acute and post-EVD phase

Clinical events according to participation in clinical trials

Inclusion in a clinical trial ?

No Plasmapheresis Total

p

Myalgia 91/699 (12%) 19/44 (43%) 110

<10-3

Occular symptoms /

signs 127/699 (17%) 15/44 (34%)

142

0.007

Focus on ophthalmology

• 341 patients examined: slit lamp, dilated fundoscopy

• uveitis: 46 (13,5%) 48% ant, 76% unilat

• episcleritis : 6 (1,8%) • interstitial keratitis: 3 (0,9%)

• 2 blindness due to cataract among two children surgery

Overall abnormal examination due to eye inflammation = 16.1%

Source: Esther Hereth

Focus on musculoskeletal symptoms

• 44 patients with arthalgia/myalgia examined by a rheumatologist

• No symmetric synovitis observed • Strong correlation with depression

Signs, Symptoms, and Diagnoses

n (%)

Mechanical pain 20 (45%) Inflammatory pain 4 (9%) Mechanical and inflammatory pain

20 (45%)

Morning stiffness 33 (75%) Myalgia 27 (61%) Muscle weakness 18 (42%) Joint pain 43 (98%)

Biological parameters at inclusion

Item All patients Adults Children

Hb (g/dL) 12.1 (10.9-

13.8) 12.5 (11.0-

14.0) 11.4 (10.3-

12.5) Anemia (< 11)

186 (23) 132 (21) 54 (34)

Creat. (µmol/L)

> 100 60 (10) 60 (13) 0 (0)

> 150 2 (0) 2 (0) 0 (0)

ASAT > 40 UI/L

52 (12) 33 (10) 19 (22)

CRP (mg/L)

> 10 43 (8) 35 (8) 8 (8)

> 40 9 (2) 7 (2) 2 (2)

RT-PCR in semen

Last positive sample 548 days after onset

Probability for EVD survivors’ semen to test positive with RT-PCR according to time from symptom onset

Psychological disorders

20 40 87 504 0%

5%

10%

15%

20%

25%

30%

3-6 years (PSYCa ) 7-12 years (CES-DC) 13-20 years (ADRS) Adultes>20 years (CES-D)

Age

Score above threshold

Sociological survey

• 81% with other EBV in their household – median number n=4

– median number of death n=1 (max 12!)

– median number of death in depressed survivors n=2

• Patients evaluated their own health status as bad/very bad:28%

• Stigmatization was felt in 204 (26%) patients

Limitations of our study

• No control group

-caution to formaly relate some symptoms to post-EBV

• Non inclusion of all the survivors

- but 74% of the identified survivors from various regions

• Robustess of the data

- difficulty to colllect data in a (post-)emergency context

• Recent reports on survivors and Postebogui contibute to the characterisation of the Postebola syndrome

– Frequent and persistent clinical symptoms long after discharge

– differences between adults and children

– rare serious complications (deaffness 2%, blindness , renal failure)

– Frequent ocular complications , which treatment??

– Frequent psychological disorders

– Long-term RNA positivity in semen (up to 18 months) w/ marked decreasing trend

• Provide care to survivors is necessary on the long term – Organize systematic follow-up visit : ophthalmology, psychological evaluation, etc

• Maintain surveillance

• Support Guinea to response to new epidemics

Discussion

Creation of a clinical center for Care, Research and Training

Capacity building: Molecular biology laboratory in the Guinean Public Health Institute, INSP Conakry

This work is supported and funded by the « Research unit » of the

French Ebola Task Force

Sponsor: INSERM

Coordination nationale de lutte

contre la maladie à virus Ebola

French Ebola Task Force: Jean-François Delfraissy, Yazdan Yazdanpanah, Yves Lévy

Institut de Recherche pour le Développement UMI 233-INSERM U1175, Montpellier Eric Delaporte, Abdoulaye Touré, Jean-François Etard, Philippe Msellati, Sandrine Leroy, Esther Hereth, Yves-Marie Pers, Bernard Taverne, Alice Desclaux, Martine Peeters, Alpha Keita, Ahidjo Ayouba, Suzanne Izard, Bruno Granouillac, Laura March Pasteur Institute/Unit of Biology of Emerging Viral Infections, Lyon Sylvain Baize INSERM/P4, Lyon Hervé Raoul ALIMA Vincent Mendiboure, Augustin Augier INSERM U955/VRI, Paris Yves Lévy, Christine Lacabaratz

INSERM/Lab génétique humaine des maladies infectieuses, Paris Laurent Abel

INSERM/Clinical Research Dep Claire Lévy-Marchal, Cécile Etienne, Christelle Delmas

Acknowledgments

CHU Donka, Conakry Moumié Barry, Mamadou Saliou Sow, Djenaba Kassé, Saliou Bella Diallo N’Fally Magassouba, Mohamed Cissé INSP lab, Conakry Lamine Koivogui Prefectoral Hospital of Macenta Ibrahima Savané Ebola National coordination response Sakoba Keita Survivors and survivors’ associations APEGUAEG, APGEM