Training structure EFFO Safety and good quality work Module 1: Ebola Virus Disease Module 2: Epidemic control on different levels Module 3: Standard precautions & disinfection Module 4: Screening & isolation Module 5: Personal protective equipment Module 6: Waste management & cleaning Support from the community Support from the hospital administration Support from the population The structure of the training shows the logo of the project with the content. Module 1 to Module 6 are part of the training. The parameters in the base of the structure are essential for the success of the training, but these cannot be monitored by the project. The “roof” of the structure is the objective of the training. 01.08.2017

Ebola virus disease Module 1 (Part 2) 01.08.2017

Learning objectives module 1 (part 2) General objectives To know general information on Ebola virus disease to be motivated to practice to gain more confidence and skills when dealing with suspected Ebola patients. Specific objectives To know the principle of diagnosis To know the basics of pathophysiology To recognise the bases on the treatment of Ebola virus disease To know the special challenges when working in an isolation unit 01.08.2017 3

Presentation outline Module 1 Part 1 - already dealt with- Epidemiology Information about the Ebola virus Modes of transmission and incubation period Symptomatology Differential diagnosis Part 2 - now - Laboratory diagnosis: PCR, rapid tests Pathophysiology Care of cases Work in the isolation area and the stress caused 01.08.2017

In the hospitals, a suspected case must be detected: by the symptoms by the case definition 01.08.2017

Diagnosis The definitive laboratory diagnosis is carried out in a specialized laboratory Source: RKI blood oral urine swabs Source: RKI Avoid accidents when taking samples or during packaging and transportation! 01.08.2017

Ebola virus disease - Laboratory diagnosis (I) There are different specialised laboratories, e.g. the BSL-4 lab or the stationary lab with a glovebox © RKI Martin Richter b) a) Source a), b): RKI 01.08.2017 7

Ebola virus disease-Laboratory diagnosis (II) c) the mobile lab with a small glovebox c) c) Additional information The European Mobile Lab was used for laboratory diagnosis of Ebola virus disease for example in Guinea, Liberia and Sierra Leone. Literature http://www.emlab.eu/ In an outbreak the diagnosis is mostly made in a mobile lab. Source c): RKI c) 01.08.2017

Ebola virus disease-Laboratory diagnosis (III) In the specialized laboratory, RNA of the Ebola virus is detected in a thermocycler by real-time RT-PCR. The laboratory takes about 3-4 hours to screen for Ebola virus. Long transport distances can sometimes markedly delay the diagnosis! © RKI Martin Richter Additional information Detection of Ebola virus nucleic acid (RNA) by real-time RT-PCR (real-time reverse transcriptase polymerase chain reaction) Repeated testing with a new blood sample is needed for patients with symptoms for fewer than 3 days duration, if the first test was negative. A negative RT-PCR test that is collected > 72 hours after the onset of symptoms rules out Ebola virus disease. Literature: e.g.: Bray M et al. Clinical manifestations and diagnosis of Ebola virus disease. (2016) http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of Ebola-virus-disease PCR – Thermocycler Source: RKI 01.08.2017 9

Laboratory diagnosis using rapid tests WHO has assessed different rapid diagnostic tests based on the detection of Ebola virus proteins. Rapid tests are not as reliable as PCR, they can be false negative or false positive. Recommendation by WHO: Where possible, results from rapid test should be confirmed by testing a new blood sample using an approved nucleic acid test. a) Additional information - Rapid tests = immunochromatographic tests, e.g.: ReEBOV Antigen Rapid Test SD Q Line Rapid Test Kit OraQuick Ebola Test DPP Ebola Antigen Assay If the rapid test is positive  Immediate isolation of the patient! There have to be developed rapid tests, based on emerging technologies, such as a sandwich assay based on monoclonal antibodies, biospecific monoclonal antibodies and/or IgY to detect antigen levels seen in patient body fluid samples for screening applications in hospital settings. Literature e.g.: WHO Emergency Use Assessment and Listing procedure (EUAL) for Ebola Virus Disease IVDs http://www.who.int/csr/resources/publications/ebola/ivd-assays/en/ Broadhurst MJ et al. ReEBOV antigen rapid test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study. Lancet 2015; 386: 867-874. Singh B et al. Current and Future Diagnostic Tests for Ebola Virus Disease. J Pharm Pharm Sci 2016; 19: 530-551. © RKI Martin Richter b) Source a), b): RKI 01.08.2017 10

Pathophysiology (I) Infection through damaged skin, mucous membranes or parenterally The Ebola virus enters the immune cells (monocytes, macrophages, dendritic cells) The infected cells migrate to regional lymph nodes, liver, spleen  dissemination of infection The immune response is individual. The symptoms and complications can differ. Literature e.g.: Clinical review: Beeching NJ et al. Ebola virus disease. BMJ 2014; 349:g7348 doi: 10.1136/bmj.g7348, 1-15. 01.08.2017 11

Pathophysiology (II) Complications: Intestinal damage leading to diarrhoea and dehydration Secondary infections (lymphocytopenia) Haemorrhages Encephalopathy Renal failure Hepatic failure Pancreatitis (severe abdominal pain) Shock / DIC Literature e.g.: Clinical review: Beeching NJ et al. Ebola virus disease. BMJ 2014; 349:g7348 doi: 10.1136/bmj.g7348, 1-15. 01.08.2017 12

Pathophysiology (III) Ebola virus disease is associated with a high prevalence of haematological and biochemical abnormalities! (even in mild disease and in the absence of gastrointestinal symptoms) These include: Acute kidney injury Abnormal serum potassium Severe hepatitis Raised C-reactive protein Raised haematocrit Thrombocytopenia Granulocytosis Literature e.g.: Hunt L et al. Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. Lancet Infect Dis 2015; 15:1292-1299. Severe acute kidney injury, high viral load, and severe hepatitis were independently associated with mortality! 01.08.2017 13

Care of Ebola virus disease at MSF - overview Doctors without borders (MSF) has a lot of experience with Ebola virus disease Treatment has changed over the years: until 1995: symptomatic treatment from 1995: antibiotic treatment, anti-malarial treatment, palliative care from 2007: invasive treatment, biochemical diagnosis from 2014: Experimental therapy (e.g. convalescent plasma, ZMapp, Favipiravir, vaccine rVSV-ZEBOV) Additional information The target group during the EFFO-training must be capable of implementing basic treatment (point 1 and 2) to Ebola virus disease patients. Invasive treatment is an additional risk to the health care worker, it should only be carried out by specialists! Literature MSF-Congress on Ebola in Germany (21.04.2015) 01.08.2017 14

Care of suspected cases Treatment primarily consists of supportive and symptomatic treatment. At the medical level At the psychosocial level Always protect yourself! By using PPE In physical and psychosocial terms (note: working in PPE is difficult) Any invasive procedure represents a risk to the health care worker who performs it!  Only perform invasive procedures when absolutely necessary! 01.08.2017

Non-invasive care of Ebola virus disease Important: fluid replacement! Fever and/or pain  paracetamol (avoid NSAR because of effect on platelets) Diarrhoea, vomiting  food on demand Hypoglycaemia  sugary drinks Treatment of other problems/secondary infections  broad spectrum antibiotics, anti-malarial treatment Additional information It seems that fluid replacement may significantly reduce mortality. Literature e.g.: Editorial. Guidelines for treatment of patients with Ebola virus diseases are urgently needed. Int J Infect Dis 2015; 30:e85-e86. 01.08.2017

Invasive procedures in Ebola virus disease Diarrhoea, vomiting, signs of dehydration  intravenous rehydration Signs of hypoglycaemia: glucose solution intravenously (if it is not possible to give the patient sugary drinks) Seizures: Diazepam intravenously or intrarectally … (Transfusion of whole blood or platelets, dialysis, experimental therapies…) 01.08.2017

Experimental therapies of Ebola virus disease (I) Examples of drugs Non-specific Immunostimulants Anti-haemorrhagic (FX06) Anti-coagulant (rNAPc2) Specific Convalescent whole blood or plasma Monoclonal antibodies (ZMapp) Antiviral substances (Favipiravir) Several studies with potential drugs were carried out during the West African Ebola epidemic. But some studies were stopped without an evidence of benefit for the patients. Additional information Studies were stopped or suspended for: Whole blood, Brincidofovir, TKM-Ebola (antiviral drug based on RNA (siRNA) Literature http://www.who.int/medicines/ebola-treatment/en/ DOI: 10.1126/science.aae0164 Hayden FG et al. Experimental Therapies for Ebola Virus Disease: What Have We Learned? The Journal of infectious diseases 2017; 215:167-170. 01.08.2017 18

Experimental therapies of Ebola virus disease (II) Testing continues: Favipiravir Inhibits viral RNA-polymerase Given orally it was well tolerated Putative signal of efficacy in patients with moderate and high viral load Additional studies are required ZMapp Contains 3 monoclonal antibodies, tar- geted at 3 Ebola virus glycoprotein epitopes May prove promising Further studies are needed Source: Feldmann, N Engl J Med 2014 Literature e.g.: http://www.who.int/medicines/ebola-treatment/en/ DOI: 10.1126/science.aae0164 Sissoko D et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): A historically controlled, single-arm proof-of-concept trial in Guinea. PLOS Medicine 2016, DOI:10.1371/journal.pmed.1001967. Hayden FG et al. Experimental Therapies for Ebola Virus Disease: What Have We Learned? The Journal of infectious diseases 2017; 215:167-170. 01.08.2017 19

Prophylaxis of Ebola virus disease ? Several candidate vaccines are under evaluation, most advanced in clinical trials are:  rVSV-ZEBOV  promising! In clinical trials it proved to be safe and highly efficacious (100% protection) Approval by the American administration FDA is expected in 2017  ChAd3-EBO-Z Safe and well tolerated Phase 1/2a completed Proceed with phase 3 efficacy trials in Africa  Ad5-EBOV Safe and highly immunogenic Phase 2 completed Additional information Vaccine rVSV-ZEBOVVaccine rVSV-ZEBOV: attenuated, recombinant vesicular stomatitis virus (VSV)-based vaccine expressing an Ebola virus glycoprotein rVSV-ZEBOV: Phase I study completed in 4 locations in Africa, Europe: save vaccine, which induces a long-lasting antibody response The vaccine was already used in phase 3 studies in Guinea and Sierra Leone called „ring vaccination trial“, in which a „ring“ of people (contacts and contact of contacts) around a newly discovered Ebola patient is vaccinated: highly efficacious and safe rVSV-ZEBOV: Final results of the „ring vaccination“ (ring vaccination trial) in Guinea: 100% efficacy, low adverse effects, no safety risks in adults and chidren Approval by the Food and Drug Administration (FDA) is expected in 2017 Vaccine ChAd3-EBO-Z Chimpanzee derived adenovirus vector (ChAd3-EBO-Z) with Ebola virus genes inserted Safe and immunogenic, requires boost vaccination, Phase 1/2 abgeschlossen, phase 3 is ungoing Vaccine Ad5-EBOV Ebola vaccine based on human adenovirus 5 vector (Ad5-EBOV) proved to be highly immunogenic and safe in phase 1 trial in China, requires boost vaccination for longer protection Ebola vaccine based on human adenovirus 5 vector (Ad5-EBOV) proved to be also highly immunogenic and safe in a phase 2 trial in Sierra Leone. Literature e.g.: Agnandji ST et al. Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe. N Engl J Med 2016; 374:1647-1660. Henao-Restrepo AM et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 2015; 386: 857-866. Henao-Restrepo AM et al. On a path to accelerate access to Ebola vaccines: The WHO‘s research and development efforts during the 2014-2016 Ebola epidemic in West Africa. Current Opinion in Virology 2016; 17:138- 144. De Santis O et al. Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study. Lancet Infect Dis 2016; 16:311-320. Good overview: Review: Martins KA et al. Ebola virus disease candidate vaccines under evaluation in clinical trials. Expert Review of Vaccines 2016; 15: 1101-1112. Li JX et al. Immunity duration of a recombinant adenovirus type-5 vector-based Ebola vaccine and a homologous prime-boost immunisation in healthy adults in China: final report of a randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet Global health 2017, 5: e324-e334. Zhu FC et al. Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2017, 389: 621-628. Henao-Restrepo AM et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ca Suffit!). Lancet 2017; 389: 505-518. 01.08.2017 20

The patient’s diet Assess patients‘ nutritional status (dehydration, appetite) according to the guideline of WHO/UNICEF/WFP („decision tree“). Meals are served in appropriate and individualized dishes. Plates are washed and decontaminated. Ensure a sufficient supply of vitamins. Families can also deliver food to their relatives but the food needs to be handed over to the patient by a health care worker in PPE. Additional information Respect individual food intolerance (lactose, gluten)! Literature Interim guideline: Nutritional care of children and adults wth Ebola virus disease: http://www.who.int/nutrition/publications/guidelines/nutritionalcare with ebolavirus/en/ 01.08.2017 21

Important in treating Ebola virus disease patients Best-practice-protocols for the treatment can change! Medication Diet Experimental treatments (studies are still ongoing) Vaccines (studies are still ongoing) Discuss the case with colleagues and the responsible authorities to create an individual treatment plan! Supportive and symptomatic treatment are the base for the care of Ebola virus disease patients! 01.08.2017 22

Stress caused by Ebola Physical fatigue Physical isolation (not allowed to touch others) Constant awareness and vigilance Risk to become contaminated or to contaminate others Fear of dying Tension between protection of public health and the needs of the patient Stigmatization Consequences in communities and families  Challenges for health care workers and patients  Good communication with the patient, explain every procedure and gesture 01.08.2017

Approach of a suspected case A patient with typical symptoms of Ebola virus disease and with a risk of infection (contact) comes to your health facility… The patient doesn´t scare me! Triage  suspected case identified Patient is isolated immediately (distance of > 2 meters!) The suspected case is communicated to the responsible persons Contacts are documented (epidemiology) The isolation unit is enabled The team in PPE can take care of the patient 01.08.2017

Working in the isolation unit Always in pairs (1 “clean” and 1 “dirty” person) Know/discuss what to do before putting on PPE (communication is more difficult and you should not stay in the PPE for more than 1 hour)) Prepare medicines, food, waste bag, and further materials If you forget something, you can’t turn around easily (one way flow in the isolation unit!) Don’t forget documentation (attention, the document stays in the red zone) In the green zone doffing instructors need to be ready for advising decontamination and doffing of PPE 01.08.2017

Thank you for your attention! Copyright Images ©Adam – Fotolia.com © macrovector - Fotolia.com © andròmina – Fotolia.com © leremy – Fotolia.com © vladis_studio - Fotolia.com 01.08.2017 26