risultati preliminari di una esperienza di farmaco ... · organ system clinical manifestation...

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Ebola (3)DR. GIULIANO RIZZARDINI AND DR. MARIA V IT TORIA COSSU

ASST FATEBENEFRATELL I L .SACCO HOSPITAL

GIULIANO.RIZZARDINI@ASST -FBF -SACCO. IT & MARIA .COSSU@ASST -FBF-SAC CO. IT

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INTRODUCTION

VIRUS

RESERVOIRS

TRANSMISSION

PREVIOUS OUTBREAKS

EBOLA 2013-2016 IN WEST AFRICA

SIGNS AND SYMPTOMS

DIAGNOSIS

TREATMENT

ITALIAN EXPERIENCE

PREVENTION

TtT: BACK UP SLIDES

Outline

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Pathogenesis of Ebolavirus

Destroys cells – focal necrosis in many organs

Suppresses inflammation

Causes cytokine storm

Induces clotting

Multi-organ focal necrosis and disseminated intravascular coagulation with focal haemorrhage and minimal inflammation

Liver with Ebolavirus (red)Martines et al J Pathol 2014

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EBOV Effects on Immune SystemHigh mortality rate believed to be the result of EBOV proteins capability of defeating the immune system

◦ Elimination of Innate IS with VP24 and VP35 proteins

◦ Prevention of enhancement of Adaptive response

◦ Infected macrophages induces apoptosis in lymphocytes

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Ebola virus: unravelling pathogenesis to combat a deadly disease.

Hoenen et al. Trends in Molecular Medicine. May 2006, 12(5).

EBOV Effect on Tissue

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Figure 3

The Lancet Infectious Diseases 2004 4, 487-498DOI: (10.1016/S1473-3099(04)01103-X)

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Ebola PathogenesisEnters Bloodstream

◦ skin, membranes, open wounds

Cell Level

◦ docks with cell membrane

Viral RNA

◦ released into cytoplasm

◦ production new viral proteins

New viral genomes

◦ rapidly coated in protein

◦ create cores

• Viral cores–stack up in cell–migrate to the cell surface–Produce trans-membrane proteins–Push through cell surface–Become enveloped by cell membrane

• ssRNA- Genome Mutations –Capable of rapid mutation –very adaptable to evade host defenses and environmental change

ebolaAttach to

walls

Leakage of blood and serum into surroundin

g tissue

Wbcs’ attack

Wbcs’ dissolv

e

Chemical released

Pro-inflammatory

cytokinesPro

coagulantsAlso released

Blood vessels more

damaged

Permanent bleeding

Entire body

leaks and dissolves

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Signs and symptomsPRODROME:

sudden onset of fever, intense weakness, muscle pain, headache and sore throat.

VIRAEMIA:

vomiting, diarrhoea, rash, impaired kidney and liver function, and in some cases, both internal and external bleeding (DIC)

Patients are infectious as long as their blood and secretions contain the virus.

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Fauci AS.N Engl J Med 2014

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Organ System Clinical Manifestation

General Fever (87%), fatigue (76%), arthralgia (39%), myalgia (39%)

Neurological Headache (53%), confusion (13%), eye pain (8%), coma (6%)

Cardiovascular Chest pain (37%),

Pulmonary Cough (30%), dyspnea (23%), sore throat (22%), hiccups (11%)

Gastrointestinal Vomiting (68%), diarrhea (66%), anorexia (65%), abdominal pain (44%), dysphagia (33%), jaundice (10%)

Hematological Any unexplained bleeding (18%), melena/hematochezia (6%), hematemesis (4%), vaginal bleeding (3%), gingival bleeding (2%), hemoptysis (2%), epistaxis (2%), bleeding at injection site (2%), hematuria (1%), petechiae/ecchymoses (1%)

Integumentary Conjunctivitis (21%), rash (6%)

WHO Ebola Response team. NEJM. 2014

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Characteristics, Symptoms, Vital Signs,

and Time Course of Clinical Progression of

37 Patients with Confirmed Ebola Virus

Disease (EVD).

Bah EI et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1411249

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Therapies Received by 37 Patients Hospitalized for EVD.

In a multivariable analysis, older had a death RR of 3.49 (1.4-8.6), as compared with younger (p = 0.007). No differences between survivors and nonsurvivors in the number of days between symptom onset and admission and viral load on admission (0.98; 0.91- 1.07; P = 0.72).

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Bleeding

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WHO Ebola responsegroup. N Engl J Med2014;371:1481-95

Bleeding

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Schieffelin JS et al, N Engl J Med 2014

Mortality associated factors

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Virus in blood

CDC. 2014 http://www.cdc.gov/vhf/ebola/transmission/human-transmission.html

>100 million viruses per ml

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The Ebola virus disease (EVD) epidemic of 2013–16 resulted in 28616 cases and left more than 17000 survivors.

Much of what was encountered about EVD was new, mainly complexity of post-EVD sequelae:

mild or asymptomatic disease, persistent viraemia, sexual transmission, and recrudescence.

Ebola virus disease sequelae: a challenge that is not going away

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76% of patients presented with post-EVD symptoms a median of 1 year after discharge.

The most frequent symptoms were those classed as general (fatigue, fever, and anorexia; 40%), musculoskeletal pain (38%), headache (35%), depression (17%), abdominal pain (22%), and

ocular disorders (18%).

Positive Ebola virus RT-PCR was found in 5% of adult men at a maximum of 548 days after disease onset.

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The patient A may have been exposed to

Ebola through sex intercourse with

survivor A, with PCR positive semen 199

days (September 9, 2014 to March 27,

2015) after his likely Ebola onset.

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Look to the future

• The duration of virus persistence is surprising nonetheless, and determination of its significance warrants further investigation

• Protocols for monitoring PCR in semen for 6 months as minimum follow-up

• Long lasting sequels and infectivness

• Research on how positive PCR relates to infectivity

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INTRODUCTION

VIRUS

RESERVOIRS

TRANSMISSION

PREVIOUS OUTBREAKS

EBOLA 2013-2016 IN WEST AFRICA

SIGNS AND SYMPTOMS

DIAGNOSIS

TREATMENT

ITALIAN EXPERIENCE

PREVENTION

TtT: BACK UP SLIDES

Outline

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DIFFERENTIAL DiagnosisAlways rule out

Other Viral Haemorrhagic Fevers.MalariaYellow feverDengue LeptospirosisTyphoid FeverShigellosisRickettsiosisRelapsing FeverCholeraPlagueHepatitis

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Diagnosis of Ebola

Timeline of Infection Diagnostic tests available

Within a few days after symptoms begin

•Antigen-capture enzyme-linked immunosorbent assay (ELISA) testing•IgM ELISA•Polymerase chain reaction (PCR)•Virus isolation

Later in disease course or after recovery •IgM and IgG antibodies

Retrospectively in deceased patients•Immunohistochemistry testing•PCR•Virus isolation

• Diagnosing Ebola can be difficult at first since early symptoms, such as fever, are nonspecific to Ebola infection.

• However, if a person has the early symptoms and has had contact with Ebola they should be isolated and public health professionals notified.

• Samples from the patient can then be collected and tested to confirm infection.

Source: Centers for Disease Control and Prevention http://www.cdc.gov/vhf/ebola/diagnosis/index.html Accessed Oct. 14, 2014

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DiagnosisDefinitive diagnosis by

Antibody-capture ELISA

Antigen detection tests

Serum neutralization test- serological surveys

RT-PCR assay

Virus isolation by cell culture.

Skin biopsies in postmortem diagnosis of infection with Ebola virus

Blood samples collection and transport according to guidelines and to WHO accredited labs only

Highly sensitive and confirmatory tests

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Expected diagnostic test results over time

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Interpreting Negative Ebola RT-PCR Result

If symptoms started ≥3 days before the negative result

EVD is unlikely consider other diagnoses

Infection control precautions for EVD can be discontinued unless clinical suspicion for EVD persists

If symptoms started <3 days before the negative RT-PCR result

Interpret result with caution

Repeat the test at ≥72 hours after onset of symptoms

Keep in isolation as a suspected case until a repeat RT-PCR ≥72 hours after onset of symptoms is negative

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Laboratory findings

Thrombocytopenia, leukopenia with a pronounced lymphopenia.

Neutrophilia develops after several days

Elevations in aspartate aminotransferase and alanine aminotransferase.

Bilirubin may be normal or slightly elevated.

With onset of anuria, BUN and serum creatinine rise.

Terminally ill patients : metabolic acidosis

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Lab findings and outcome

Schieffelin JS et al, N Engl J Med 2014

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WHO situation rep 25 March 2015

Providing capacity for prompt and accurate diagnosis of cases of EVD is an integral part of the response to the EVD outbreak • 27 laboratories have the

capacity to confirm EVD

cases

• 9 operational laboratories

in Guinea

• 5 operational laboratories

in Liberia

• 13 operational

laboratories in Sierra

Leone

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Laboratories

CDC has developed interim guidance for U.S. laboratory workers and other healthcare personnel who collect or handle specimens

This guidance includes information about the appropriate steps for collecting, transporting, and testing specimens from patients who are suspected to be infected with Ebola

Specimens should NOT be shipped to CDC without consultation with CDC and local/state health departmentsInformation available at: http://www.cdc.gov/vhf/ebola/hcp/interim-guidance-specimen-collection-submission-patients-suspected-infection-ebola.html

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Packaging & Shipping Clinical Specimens to CDC for Ebola Testing

http://www.cdc.gov/vhf/ebola/hcp/packaging-diagram.html

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Thank you for your attention

DR. GIULIANO RIZZARDINI AND DR. MARIA V IT TORIA COSSU

ASST FATEBENEFRATELL I L .SACCO HOSPITAL

GIULIANO.RIZZARDINI@ASST -FBF -SACCO. IT & MARIA .COSSU@ASST -FBF-SAC CO. IT