Management of hemorrhagic fevers - focus on

How de body? De body fine!

Bjørn Blomberg Assoc. Prof., infectious diseases-, Bergen, Norway ESCMIDAdvisor, Norwegian Ebola Relief 2014-15 eLibrary © by author - numbers + Kyasanur, Omsk, Colorado TF, Group Virus Reservoir Vector Cases/y Lethality Filovirus Ebola, Bat Bat 28 000 (?) 50-90% Arena- Lassa Rodent Rodent 300 000 1-70% Flavi- Monkey Aedes 200 000 20-50% Human mosquito Flavi- Dengue Human Aedes 500 000 DHF 4-5%

Bunya- Rift Valley Cattle, sheep, Aedes, - 10-50% goat culex >100 000 BunyaESCMID- Congo Crim Hares, others eLibraryTicks Hundreds 10-50% © by author EBOLA Previously, minor outbreaks in remote areas, case-fatality rates 80%

ESCMID eLibrarySource: Denis Malvy, Lancet 2019 © by author West African 2013-16 Total >28000 cases, >11000 deaths

ESCMIDFreetown, eLibrary © by author 2018-19 Ebola outbreak in Ituri & North

Beni

Since 1 august 2018: 1186 cases - 751 dead (CFR 63%) 87 healthworkers – 31 dead (CFR 36%) ESCMID eLibraryWHO 9th April 2019 © by author Management

Prevent transmission Reduce suffering and death • Prevent transmission • Supportive care – Infection control – Fluids – Safe burials – Vital organ support – Nutrition – Vaccination – • Specific treatment – Antiretrovirals – Antibody ESCMID eLibrary– Immune modulation © by author How does it spread?

• Contact with bat or sick/dead apes • High risk: Blood, vomit, diarrhea – on mucous membranes, ”broken” skin • Also present in – Saliva, breast-milk, semen (3 months) • Virus survives – for hours on dry surfaces ESCMID– for days in body fluids, incl. eLibrary dead bodies © by author Probable Suspect Morgue Confirmed

Ambulance

Happy Triage shower

“Office”

Changing room

Gate ESCMID eLibraryEntrance © by author Ambulance reception

ESCMID eLibrary © by author Triage

ESCMID eLibrary © by author Dressing Goggles - 7 € Hood “Donning”

Face mask - 1 €

2 sets of gloves - 3 €

Protective suit - 20 €

Plastic apron - 4 €

RubberESCMID boots - 12 € eLibrary © by author Foggy glasses approx. 45 minutes

ESCMID eLibrary © by author Entry to patient area

ESCMID eLibrary © by author Undressing “Doffing”

ESCMID eLibrary © by author PCR-Lab

ESCMID eLibrary © by author ESCMID eLibraryRed Cross, Freetown, Sierra Leone, 2014 © by author High-level Isolation Unit, Oslo

ESCMID eLibrary 17 © by author Gas-tight door

Karina Holten Torpp Arne Brantsæter Head nurse Head of Isolation Facility ESCMID eLibrary © by author Guinea rVSV ZEBOV trial Henao-Restrapo, Røttingen et al, Lancet 8 Aug. 2015

• Recombinant virus with ZEBOV glycoprotein • Basse-Guinée – 90 clusters 7651 volunteers – 1. April – 20. July 2015 • Ring-vaccination – randomized open-label – Immediate: 48 clusters (n=4123) – 0 ebola cases* – After 21 days: 42 clusters (n=3528) – 16 cases – *Ebola >10days after randomization – Vaccine efficacy 100% (74,7%-100%) p=0.004 •ESCMIDTo be licensed by Merck eLibrary © by author Vaccination DRC 2018-19

> 73,000 vaccinations – 18,000 contacts – 22,000 contacts of contacts – 23,000 Front-line health-workers DRC – 2,600 in Augustin Ndimu – Planned in South-, ,Burundi Nord-Kivu ESCMID• Source: WHO, 20.2.2019 eLibrary © by author Convalescent blood transfusion to Ebola patients in Kikwit, 1995 Mupapa, JID 1999; 179(suppl 1):S18-23

# Age No of days with symptoms before Blood vol (mL) Donor ID Outcome Tx 1 27 7 400 1 Survived 2 12 11 150 2 Survived 3 15 13 150 3 Survived 4 54 9 250 2 Survived 5 44 15 250 4 Survived 6 25 13 250 4 Survived 7 40 11 450 5 Survived 8 48 4 400 2 Died 84 Guineans given convalescent plasma (2 x ¼ L) vs 418 controls Survival 69% vs 62%, not significantly different ESCMIDVan Griensven, NEJM eLibrary2016;374:33-42 © by author Reversion of advanced Ebola virus disease in nonhuman primates with Zmapp - Rhesus macaque experiment

3 doses, 3 days apart Intervention n Deaths Placebo 3 3 Zmapp Day 3 6 0 Zmapp Day 4 6 0 Xiangguo Qiu et al. Nature.ESCMID 2014 Oct 2; 514(7520): 47–53. Zmapp eLibraryDay 5 6 0 © by author A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection (PREVAIL II, NEJM 2016;375(15):1448-56)

• Liberia, Sierra Leone, Guinea, US • Standard care +/- Zmapp • Dose: 50mg/kg BWT every 3rd day • Std care included in Guinea • Case fatality rates – Std care: 37% (13/35) – Zmapp: 22% (8/36) ESCMID• P=0.2, posterior probability 91.2% eLibrary (prespecified 97.5%) © by author Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody Davide Corti, Science 18 Mar 2016: Vol. 351, Issue 6279, pp. 1339-1342

• Antibodies from human survivor - Kikwit 1995 • 5 macaques received lethal dose Ebola virus – 4 treated with mAb114 after 1 day survived – 1 control without treatment died

• Conclusions: – Protective antibodies ESCMID– Antibodies persist for decades eLibrary © by author (GS-5734) - Complete Therapeutic Protection Against the Development of Ebola Virus Disease (EVD) in Infected Non-human Primates TK Warren, Open Forum Infectious Diseases, 2015 & Nature 2016

3 mg/kg im/iv – 50% survival 10 mg/kg im/iv – 100% survival

ESCMID eLibraryFoto: Science © by author Investigational Therapeutics for the Treatment of People With Ebola Virus Disease (clinicaltrials.gov ID NCT03719586)

• Zmapp – cocktail (x3, over 9 days) • Remdesivir – antiviral (x1 daily, 10 days) • REGN3470-3471-3479 – antibody cocktail (once) • Mab 114 – iv (once)

MEURI Monitored Emergency Use of Unregistered and Investigational ESCMID eLibraryIntervention © by author Alternative treatments – none proven • TKM/Tekmira • interfering RNA (sand in machine), No benefit Dunning Plos Med 2016 • (CMX100, Chimerix) • inhibits DNA polymerase, In vitro effect against EBOV • No effect in vivo, Monrovia Trial stopped after few days • BCX4430 (Biocryst) – only phase 1 trial • Nucletid analogue, sand in the machine… • Amiodarone (SL), Atorvastatin (SL) • Immune modulation: , steroids, NSAIDS, statins • ModifyingESCMID coagulation: Drotrecogin eLibrary-recombinant human protein C © by author Supportive therapy – different phases Stage Time since Features Management symptoms (days) Early febrile 0-3 Fever, weak, Oral hydration , lethargy Able to care for self

Gastrointestinal 3-10 + diarrhea, vomiting, Needs intravenous abdominal pain fluids

Complicated 7-12 + bleeding, , Fluid therapy organ failure, Vital organ support neruological Seizure control complications Pain management

ESCMID eLibraryModified from Malvy, Lancet 2019 © by author Supportive therapy - I Problem Intervention Remarks

Other infections Malaria Tx Malaria – similar symptoms Broadspectrum antibiotic Translocation of bacteria from gut Doxycyclin Doxycyclin – rickettsia etc Shock Fluid, crystalloids Liberal fluid therapy, but... * Vasopressor Avoid «third-spacing» Bleeding Blood-Tx Malnutrition -> vitamin K Platelets, plasma, vit-K Low fibrinogen* -> plasma Electrolytes Add potassium? * Availability of lab testing Hypoxemia O2 therapy * Respirator Renal failure Fluid, furosemid Renal failure >50% * Dialysis Associated with fatal outcome ESCMID* Not available in low-resource areas eLibraryModified from Malvy, Lancet 2019 © by author Supportive therapy - II Problem Intervention Remarks Nausea, Metoclopramide, vomiting ondesartron Pain Paracetamol, Avoid NSAIDS, ASA – bleeding Tramadol Transdermal opiates – avoid Opiates punctures Ulcer Ulcer prophylaxis Extremely stressful – stress ulcer Seizures Benzodiazepines Malnutrition Oral > enteral Oral if possible Nasogastric tube – bleeding?

ESCMID eLibraryModified from Malvy, Lancet 2019 © by author Treatment in Moyamba • ORS+/- intravenous fluids • Malaria treatment: ACT (AL) • Antibiotics (ceftriaxone) • Pain-killers • Vitamin K • Zinc Case Fatality: 58%

Hastings protocol Patients in the West • Lethality: 23% (71/304) case-fatality rate 18.5% (5/27) • 5.Nov-7.Dec 2014 • Ansumana, NEJM Christmas Eve, 2014 Karen Marie Lundeby, ESCMID eLibraryMoyamba © by author Positive developments: Thanks • Supportive therapy works • Vaccination rolled out • Promising specific treatment in clinical trials now

Challenges: • Violence & unrest • Weak health systems • LackESCMIDof education eLibrary © by author