dr…je$reviensde$guinée$etje$ fais$de$laﬁèvre! · objecfs $ • a$laﬁn$de$la présentaon...

Dr… Je reviens de Guinée et je fais de la fièvre!

Caroline Quach, MD MSc FRCPC FSHEA Microbiologiste-‐infec=ologue pédiatrique; Préven=on & Contrôle des infec=ons; The Montreal Children’s Hospital – MUHC

Professeur agrégé Départements de pédiatrie et d’épidémiologie; Université McGill

April 9, 2015

Divulga=on de l’enseignant/du présentateur

• Enseignant : Caroline Quach

• Rela<ons avec des intérêts commerciaux : – Subven<ons/sou<en à la recherche : GSK (2012-‐2014), Sage

(2013-‐2014), AbbVie (2013-‐2014), Pfizer (2013-‐2014).

– Aucune des ces subven=ons ne sont en lien avec la présenta=on.

Colloque Bleu 2015

Objec=fs

• A la fin de la présenta=on, les par=cipants seront en mesure de: 1. Discuter des modes de transmission et des

facteurs de risque associés à la maladie à virus Ebola (MVE)

2. Discuter de la prise en charge des voyageurs au retour de pays endémiques pour MVE

3. Discuter des diagnos=cs différen=els à envisager

Mi-‐avril 2014…

• Bébé 8 mois, transféré de Sorel pour fièvre, 12 jours après être revenu de … Guinée, Guyane, Ghana, où?

• Santé publique nous le transfère pour une possibilité d’ébola…

Le diagnos=c le plus probable est:

1. Une infec=on virale des voies respiratoires supérieures

2. Une malaria

3. Une maladie à virus Ebola

4. Une fièvre typhoide

J’accepte le transfert?

1. Oui 2. Non

L’équipement de protec=on individuelle devrait contenir:

1. Rien… ce n’est qu’un rhume, franchement! 2. Précau=ons goukelekes/contact, c’est un

rhume, franchement! 3. Rien… c’est une malaria, franchement! 4. Une combinaison imperméable, N-‐95, double

paire de gants, bokes imperméables, tablier imperméable et une chambre à pression néga=ve… c’est un ebola, franchement!

5. Une blouse imperméable, gants à poignets longs, N-‐95, couvre-‐chaussures.

A bit of virology

• Ebolavirus and Marburgvirus: RNA viruses, belonging to the family Filoviridae

• Animal reservoir: fruit bats; chimpanzees and gorillas become sick and die

• Cause hemorrhagic fevers in human and non-‐human primates (rarely)

• EBOV: > 1 million virions per ml in blood, diarrhea and vomit (acute terminal phase) – infec=ve dose: 1-‐10.

Del Rio C et al. Annals Intern. Med. 2014; In Press

Aggregated CFR = 78%

Timeline of 2014 EVD outbreak

hkp://www.healthmap.org/ebola/

WHO count (October 14): Cases: 9216 Deaths: 4555

hkp://www.healthmap.org/ebola/

WHO (Sitrep Nov 26, 2014): 15,935 cases; 5,689 deaths Current CFR = 60%

hkp://virologydownunder.blogspot.com.au/2014/07/ebola-‐virus-‐disease-‐evd-‐2014-‐west.html

Current outbreak

hkp://virologydownunder.blogspot.com.au/2014/07/ebola-‐virus-‐disease-‐evd-‐2014-‐west.html

Gomes MFC. PLoS Current Outbreaks 2014

Air traffic connec=ons

EVD: ecology and economy

• HFV outbreaks: areas where economy and public health systems have been decimated

• Civil wars in Liberia and Sierra Leone • Guinea: decades of inefficient and corrupt government

• UN Development Program Human Development Index: – Liberia (174); Sierra Leone (177); Guinea (178) of 187 countries

Adapted from Bausch DG. PLoS Neglected Tropical Diseases 2014; e3056

Serves as amplifica=on and triggers ac=on

EVD in Healthcare sexngs • 1976 EVD (Zaire): linked ot use of unsterilized syringes – hospital closure terminated the outbreak. – Akack rate (nursing pa=ent): 81% vs. 0 if no physical contact

• Total (before 2014 outbreak): – 2079 cases; 1409 deaths… 156 nosocomial transmission (range: 2-‐93 per outbreak)

– 130 HCW infected, 57 (43.8%) died (range: 1-‐72 infected per outbreak)

F=ka L et al. J Hosp Infect 2013; 185-‐92

Au 1er avril 2015: • 25 213 cas rapportés • 10 460 décès • TS: 861 infec=ons; 495 décès

hkp://apps.who.int/ebola/current-‐situa=on/ebola-‐situa=on-‐report-‐1-‐april-‐2015-‐0

Transmission of EBOV

• Infec=ous only when symptoma=c • Incuba=on period: 2-‐21 days (average 6.3 days)

• Direct contact with pa=ents’ body fluids, especially blood

• Sharing airspace: NOT a risk factor – only pigs manage to transmit EBOV via airborne route – but they have respiratory symptoms!


• Studies of household contacts: – 173 household contacts of 27 confirmed pa=ents – Transmission: 16% -‐ without any rou=ne prac=ces

• Contamina=on of care environment: – 54 clinical specimens from 26 lab-‐confirmed cases – EBOV + 16/54 specimens: saliva, stool, semen, breast milk, tears, blood and skin swabs NOT dialysate fluid

– 33 environmental samples: the ONLY that tested posi=ve: physician’s blood-‐stained glove and bloody IV inser=on site

Klompas M et al. Annals Intern Med 2014; In Press


• Effec=veness of rou=ne prac=ces for body fluid exposure (South Africa): – Anesthe=cs assistant developed EVD – traced back to a pa=ent that she had cared for 3 days earlier – inser=ng CVL

– Over 300 HCP provided care to these 2 pa=ents, including invasive procedures: NO addi=onal transmission

Richards GA et al. Crit Care Med 2000; 240-‐4.

Basic Reproduc=ve Number (R0)

• Number of secondary cases generated by an index case in the absence of control interven=ons

Outbreak Start of interven<on

CFR (%) Es<m. R0 SD R0

Congo (1995) May 9, 1995 81% 1.83 0.06

Uganda (2000) Oct 22, 2000 53% 1.34 0.03

Chowell G et al. J Theoret Biol 2004; 119-‐126

R0 – 2014 EVD outbreak

Parameter Guinea Sierra Leone Liberia R0 1.51 (1.50-‐1.52) 2.53 (2.41-‐2.67) 1.59 (1.57-‐1.60)

Transmission rate (per day)

0.27 0.45 0.28

CFR 0.74 0.48 0.71

Rate at which control measures reduce transmission (per day)

0.0023 0.0097 0

Ibid

R0 – other pathogens

Infec<ous disease R0

Measles 15-‐17

Pertussis 15-‐17

Varicella 10-‐12

Mumps 10-‐12

Rubella 7-‐8

Poliomyeli=s 5-‐6

Influenza 1.68-‐20

SARS 2-‐3 Tang JW et al. J Hosp Infect. 2006; 100-‐14

DEFINITIONS & CLINICAL PRESENTATION

Case defini=on

• Fever (380C) or more OR – Viral-‐like illness OR – Syndrome affec=ng mucous membranes; GI; CNS or bleeding disorder

AND • Travel to a country/area with EVD transmission in the past 21 days

• A high-‐risk exposure to EVD cannot be excluded

Clinical presenta=on EVD

• Symptoms of EVD: – Contagious when symptoma=c…

– Fever, headache, myalgia, abdominal pain, vomi=ng and diarrhea, bleeding.

List of countries with EVD transmission

• Guinea • Liberia • Sierra Leone

• Senegal (Oct 17) and Nigeria (Oct 20) now off the list: 2 incuba=on periods with no new case. No ac=ve EVD case in US, Spain or Mali.

Recommenda=ons for returning travelers

Situa<on Recommenda<ons (PHAC) Follow-‐up (DSP)

Symptoma=c ED – designated centre

No symptom; high-‐risk exposure

Isolate oneself x 21 days; monitor temperature BID; No=fy PHAC if need for travel; Report EVD sx

DSP will follow daily by phone. If symptoms? ED…

No symptom; low-‐risk exposure

Contact DSP x 24 h; monitor temperature BID; No=fy if need for travel; Report EVD symptoms

DSP will follow once per week

Humanitarian worker

Contact DSP x 24 h; monitor temperature BID; No=fy if need for travel; Report EVD symptoms

DSP will follow daily NO pa=ent-‐care during incuba=on period

hkp://www.msss.gouv.qc.ca/professionnels/ebola/mesures-‐aux-‐fron=eres

INFECTION CONTROL & PREVENTION

Pa=ent placement

• Single room – ideally with toilet • Nega=ve-‐pressure ** • Door closed

– Facilitates AGPs (no need to change room) – AGPs: BiPAP, CPAP, high frequency ven=la=on, bronchoscopy, sputum induc=on, intuba=on and extuba=on, open suc=oning of airways and nebuliza=on treatments

PPE – category 1 (MSSS)

INVESTIGATIONS

Quel(s) tests demandez-‐vous?

a) Aspira=on NP pour virus respiratoires b) Malaria – ELISA, goukes mince et épaisse

c) Cross-‐match et coagulogramme

d) Parasites (selles) e) Hémocultures

1. Toutes ces réponses 2. A, B et E 3. E seulement

Pa=ents with Fever from Sub Saharan Africa

• Most frequently malaria (42%) • Fever without diagnosis (19%) • Respiratory illness (10%) • Diarrheal illness (10%) • Very rarely dengue (1%)

(Yellow Book 2014 includes: Schistosomiasis, filariasis, =ck borne rickeksiae, trypanosomiasis)

What to do for labs?

• Need to rule out more common diagnoses – but limit blood work to a minimum

• For suspected cases (fixng defini=on): all samples are hand-‐delivered to microbiology and core-‐lab

• EVD diagnosis: – 2 x 1.5-‐ml EDTA tube for virus detec=on – PCR for EVD may be nega=ve if done in first 3 days of symptoms

– ***PCR done at LSPQ: TAT 4h once they have it.

Labs to order

• Basic blood word: – CBC, LFT, Basic biochemestry, – Blood culture, – Malaria ELISA and thin blood smear – EVD PCR – (NPA for virology)

• Op=onal: Stool O+P, stool culture, urine culture • Not un=l EVD PCR nega=ve: Coagulogram, cross-‐match and typing, thick malaria smear

Malaria diagnosis and EVD

• Using inac=va=on (CDC): heat + Triton X… • Binax Now (Before/a�er inac=va=on) – Sensi<vity: • T1 band P. falciparum: 100% vs. 97% • T2 band (pan-‐plasmodium) at very low parasitemia (0.1%): 44 vs. 19%

• qPCR: 100% – Specificity: 100%

Lau R. J Clin Microbiol 2015; 53: 1387-‐90

THERAPIES

Experimental therapies

• Convalescent sera: – Donors clinically asymptoma=c with 2 nega=ve PCR for EBOV

– For pa=ents in early stage of confirmed EVD

– Need to monitor efficacy

hkp://www.who.int/mediacentre/news/ebola/26-‐september-‐2014/en/

Experimental therapies • Monoclonal an=bodies (ZMapp): – 3 different mAb that bind virus

– In NHP: ZMapp rescued 100% of macaques when treatment ini=ated up to 5 days post-‐challenge

Clinical scores Fever

Viremia

Qui X. Nature 2014

Prevalence of EBOV immunity (Gabon)

Becquart P et al. PLoS One 2010; e9126

Vaccines in development

• cAd3-‐ZEBOV: GSK and US NIAID -‐ chimpanzee-‐derived adenovirus vector with an Ebola virus gene inserted

• rVSV-‐ZEBOV: PHAC -‐ weakened vesicular stoma==s virus, a pathogen found in livestock; one of its genes has been replaced by an Ebola virus gene

WHO: hkp://www.who.int/mediacentre/news/ebola/01-‐october-‐2014/en/index4.html

Milestones • October 2014: Remainder of phase 1 trials must be

started • Oct.–Nov. 2014: Agreed common protocols (including for

phase 2 studies) across different sites must be developed • Oct.–Nov. 2014: Prepara=on of sites in affected countries

for phase 2 b • Nov.–Dec. 2014: Ini=al safety data -‐ phase 1 trials

available • Jan. 2015: GMP grade vaccine doses available -‐phase 2 • Jan.–Feb. 2015: Phase 2 studies ini=ated in affected and

non-‐affected countries • ASAP aber data on efficacy become available:

Planning for large-‐scale vaccina=on, including systems for vaccine financing, alloca=on, and use

WHO website

cAd3-‐EBO vaccine (phase I)

• N = 20 pa=ents (healthy volunteer) aged 18-‐50 years enrolled in September 2014 – 10: 2x1010 – 10: 2x1011

Ledgerwood JE. NEJM 2014; DOI: 10.1056/NEJMoa1410863 -‐ published online Nov 26, 2014

Results

• No fever in par=cipants in lower dose group • 2/10 – fever in higher dose group

rVSV-‐Ebola vaccine

• N=158 (138 reported on) – 8 placebo • Doses: – 300 000 PFU (n=20) – 3 x 106 PFU (n=49) – 10 x 106 PFU (n=35) – 20 x 106 PFU (n=30) – 50 x 106 PFU (n=16)

Agnandji ST et al. New Engl J Med 2015; published online April 1, 2015

Adverse events

Adverse events (2)

Immunogenicity

To control the epidemic

• Basic epidemiology: – 1 -‐ (1/Re) = 1 – (1/1.4) = 0.28

• Based on the current effec=ve reproduc=ve number: approximately 30% of the popula=on would need to be immune to control the outbreak

In summary

• Transmission: contact body and body fluid • In Quebec, likelihood is that a traveler with fever is unlikely to have EVD

• At-‐risk countries as of April 1, 2015: Guinea, Liberia and Sierra Leone

• Ebola is not airborne • Too much PPE is risky… if one doesn’t know HOW to remove

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