Ebola Virus [Ebola virus disease (EVD) or Ebola hemorrhagic fever (EHF) ]

What is Ebola?

Ebola is a virus which causes rare but deadly disease Ebola virus disease (EVD) or Ebola

hemorrhagic fever (EHF) which is a disease of humans and other primates. Symptoms start two days to three weeks after contact with the virus. Symptoms area fever, sore throat, muscle pain, and headaches. Typically nausea, vomiting, and diarrhea follow, along with decreased functioning of the liver and kidneys. Around this time, affected people may begin to bleed both within the body and externally.

Ebola’s natural reservoir is unknown.Non human primates have been the source of human infections but are not thought to be the reservoirs.

Ebola Taxonomy or Scientific Classification

Order: Mononegavirales

  Family: Filoviridae

  Genus: Ebola like viruses

  Species: Ebola 

Subtypes  

Ebola-Zaire, Ebola-Sudan,Ebola-Ivory Coast-disease in humans

Ebola-Reston-disease in nonhuman primates

Filoviridae or “Filoviruses”

•          Most mysterious virus group

•          Pathogenesis poorly understood

•          Ebola

–        Natural history/reservoirs unknown

–        Exist throughout the world

–        Endemic to Africa

–        Filamentous ssRNA^- (antisense) viruses

History

Named after the Ebola River in the Democratic Republic of the Congo (formerly Zaire), near the first epidemics.

Two species were identified in 1976:

• Zaire ebolavirus (ZEBOV)
• Sudan ebolavirus (SEBOV)

Case fatality rates of 83% and 54% respectively.

A third species, Reston ebolavirus (REBOV), was discovered in November 1989 in a group of monkeys (Macaca fascicularis) imported from the Philippines.

Ivory Coast ebolavirus – Only one case. Unlucky scientist.

Outbreaks of EBOLA

Most Recent Incident

April 25 – June 16 2005 total of 12 cases including 9 deaths were reported in Etoumbi and Mbomo in the Cuvette Quest Region

Ebola Pathogenesis

•          Enters Bloodstream

–         Skin, membranes, Open wounds

•          Cell Level

–         Socks with cell membrane

•          Viral RNA

–        Released into cytoplasm

–        Production new viral proteins/ genetic material

•           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

•          Theory

–         Virus evolved to occupy special niches in the wild

Modes of Transmission

There are 3 modes of infection

1. Unsterilized needles
2. Suboptimal Hospital conditions
3. Personal contact

Symptoms and Diagnostic Tests

•          Early symptoms

–        Muscle aches, fever, vomiting

–        Red eyes, skin rash, diarrhea, stomach pain

–        Acute symptoms

–        Bleeding/hemorrhaging from skin, orifices, internal organs

–        Onset of fever.

–        Intense weakness.

–        Muscle Pain.

–        Headache.

–        Soar Throat.

–        Vommitting, Diarrhoea.

–        Impaired Kidnay and liver function

•          Early Diagnosis

•          Very difficult

•          Signs & symptoms very similar to other infections

•          Laboratory Test for the diagnosis of Ebola Virus

•          PCR detection

•          ELISA (enzyme-linked immuno-absorbant) assay

Is there a cure for Ebola?

•          There are no known curative medications for Ebola.

•          However, there have been very recent developments in preventative medications.

•          No Standard Treatment available

•          Patients receive supportive therapy

•          Treating complicating infections

•          Balancing patient’s fluids and electrolytes

•          Maintaining oxygen status and blood pressure

•          No vaccines!

•          Patients are isolated

•          Medical Staff Training

•          Western sanitation practices

•          Intake

•          Care during stay

•          After patient dies

•          Infection-control Measures

•          complete equipment and area sterilization

Vaccines

•          In June, Jones and his colleagues, Dr. Heinz Feldmann of Winnipeg and Dr. Thomas Geisbert at Fort Detrick, Maryland announced that they had successfully vaccinated monkeys against the deadly Ebola virus

•          The Ebola vaccine is based on the 1976 strain of the Zaire species and protects from the 1995, but not the other 2 species that affect humans.

Risk of Bioterrorism?

Airborne transmission of Ebola Zaire has been demonstrated in monkeys in a controlled laboratory experiment

Plum Island…?

Prevention

After Death

Virus contagious in fluids for days

•          Burial use extreme caution

–        Handling and transport

–        Cultural practices/ religious belief

–        Incinerate all waste!!!!

–        Protective clothing

–        Body sealed in body bag and coffin

–        Sanitation of all equipment before and after

–        Risk for exposure special steps need to be taken to protect the family and community from illness.

–        Family only

–        Why open casket not possible

–        Some practices cannot be done

Conclusion

•          Reservoirs in Nature

–        Largely unknown

–        Possibly infected animals (primates?)

•          Transmission

–        Direct contact blood/secretions of infected person

–        Possible airborne (Reston primate facility)

•          Onset of illness abrupt

–        Incubation period:  2 to 21 days

–        Infections are acute and mostly deadly

Latest Morbidity and Mortality Reports

Ebola-Reston Virus Infection Among Quarantined Nonhuman Primates -- Texas, 1996

Report describes death and blood testing of cynomolgus monkey imported from the Philippines held in a private quarantine facility in Texas

•          Outbreak of Ebola Hemorrhagic Fever ---Uganda, August 2000--January 2001

–        Report describes surveillance and control activities related to the EHF outbreak

–        Presents preliminary clinical and epidemiologic findings

Ebola Information Posters

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Chronic inflammation

What is Chronic Inflammation:

Inflmmation of prolonged duration in which inflmmation, tissuue injury and attempts at repair coexist, in varying combinations.

1. Chronic Suppurative on acute: 
2. Chronic granulomatus: (Initiates without an acute phase)

Suppurative in type:

Abscesses

• Inadequate or delayed drain leads to thick fibrous wall    formation.                                         
• The residual bacteria get reactivated
• Pus formation.   
• Presence of foreign material or indigestible dead tissue.

Eg: Osteomyelitis, damaged Collagen

Chronic inflammation

Follow acute inflammation

Persistence of the stimulus

Disturbance to the healing process

ŸRepeated bouts of acute inflammation and healing in between.

Low grade persistent infection.    

Causes

• Microorganisms where body can mount limited immune reactions
• Impaired Sequelae of an acute inflammation
• Foreign bodies
• body defense
• Immune reactions

Chronic inflammation without an acute phase

Infection: TB, Leprosy, Syphilis

Immunological: Rheumatoid arthritis Ulcerative colitis Crohn’s disease

Poor blood supply (leg ulcer)

Chronic inflammatory lesions

May vary histologically according to causative agent

However there is a set of morphological features in common.  

Histologically

• Infiltration by mononuclear cells
• Macrophages
• lymphocytes
• plasma cells
• Proliferation of blood vessels/fibrosis (angiogenesis)
• Fibrosis
• Tissue destruction (induce by inflammatory cells)  

 

Mononuclear phagocytic system

Blood monocyte:

Macrophages (at extra vascular tissue) 

Tissue macrophages (Scattered in connective tissue or concentrated in organs)

Eg: Kupffer cells in Liver                                                                                                   

Sinus histiocytes in lymph nodes

Alveolar macrophages in lung

Osteoclasts in bones

Microglia (CNS)

Monocytes

Migration

Morphological transformation (macrophages and giant cells)

Activation

Secretion of biologically active products

Cells types present

• Macrophages            Ÿ 
• Eosenophils
• Mast cells                 
• ŸLymphocytes

Existence of CI, AI and repair

• Macrophages persist at the site (Due to the influence of chemical mediators)
• Destruction of invading microorganisms /normal tissues
• Secretion of chemical mediators by macrophages
• Functions of them,
• Proliferation of fibroblasts, Laying down of collagen
• Angiogenesis, Activation of lympho macrophages
• ŸDead and dieing leukocytes/necrotic tissues helps in developing acute inflammation  

Granulomas /Granulomatus infection

• Chronic inflammatory lesion in the form of mass.
• Collection of macrophages or modified macrophages (epitheliod / giant cells)
• Granulomas /Granulomatus infection
• A granuloma is a focal area of granulomatus inflammation.
• Consist of macrophage aggregation
• Epithelial cell transformation
• Collar of lymphocytes
• Appearance giant cells and of fibrosis can see with the time 

    

Eg: 

• TB
• Sarcoidosis
• Cat scratch disease
• Leprosy
• Syphilis
• Mycotic infections

Two types of granulomas: Base on pathogenesis

Foreign body type:

Form around foreign bodies

Immune type: When the foreign practical are capable of induce cell mediate immune responses

(but not always granulomas will develop)

Definition

Granulomas is a result of chronic inflammatory reaction containing a collection of cells of monocytic series arrange in a compact mass.

Cells

Macrophages

Epithelioid cells

Giant cells: Langhans giant cells

Foreign body type giant cells  

Accumulation of macrophages

Under the influence of chemotaxis

C5a, fibrinopeptides, cationic proteins

Lymphokines :

PDGF, TGF(beta)

products of collagen brake down

By mitotic division 

Immobilization and prolong survival  (if the irritants are low virulent )

Tuberculosis:

Chronic disease common worldwide.

Causes a characteristic granulomatous inflammation

Inability of the neutrophils to kill the micro organisms due to lipoprotein coating.

Mycobacterium tuberculosis.

Hominis (lungs)                                                

Bovis (Tonsils, Intestine) 

Spread

• Droplet from patients (weeks or months)
• Conjunctiva
• Punctures
• However need sustain contact than casual contact.

Tissue damage 

MT has no Endotoxins

Exotoxins 

Histiolitic enzymes

Development of immune response against outer coat of the organism.

Tuberculin test

2 to 4 weeks after infection : + Tuberculin test

PPD (purified protein derivative)

(Culture in which TB is grown)

Induration More that 5.mm within 48 hours.

Positivity indicates infection but not the disease.

Primary Tuberculosis

Occurs in individuals who have never previously been infected with M. tuberculosis (childhood infection if TB is common, adult life if uncommon)

Usually caused by inhalation of the organisms or rarely by ingestion of the organism.

Primary infection

Lungs             Hilum

Tonsils           neck nodes

Intestine         mesentery

Primary Tuberculosis

In respiratory system, inhalation of the organisms cause a subpleural lesion usually in the lower part of the upper lobe or upper part of the lower lobe. This is called Ghon focus.

Location is in these sites is because bacterium is a strict aerobe and prefers these well oxygenated regions

Ghon’s focus

When the tissue is invaded by the mycobacteria there is no hypersensitivity reaction. Instead there is acute, non specific inflammatory response with predominant neutrophils.

This is followed by macrophages which ingest the bacilli and present Ags to to T lymphocytes leading to proliferation of a clone of T cells .

The emergence of specific hypersensitivity lead to release of lymphokines,that attract more macrophages.

These accumulate to form the characteristic granuloma.

Ghon focus

Usually single

1 to 2 cm

Location –Beneath pleura- mid zone of the lung 

Microscopic appearance

Primary complex

Tubercle bacilli, either free or contained in macrophages, may drain to the  regional lymph nodes and set up granulomatous inflammation, causing massive lymph node enlargement.

The combination of the Ghon focus, draining lymphatics and the regional lymph nodes is called the primary complex.

Calcification of the lymph nodes

Sequelae of primary complex

Healing  with small fibrous scar replacing caseous necrosis. Lesion will be walled off.

Calcification

Reactivation of infection later when host defences become lowered.

plural effusion

Enlarged caseous nodes can obstruct bronchi, leading to collapse, retention of secretion and inflammatory consolidation

Caseous node erodes into a bronchi  with satellite lesions in lungs (TB bronchopneumonia).

Eroding into a pulmonary vein causing generalised milliary TB.

Erosion into pulmonary artery leads to miliary TB of lungs

TB bronchopneumonia

Opening of the caseous node to a bronchus.

Air bone infection

TB bronchopneumonia

(Multiple pneumonic patches arrangeed in and around terminal bronchi)

The lesions spread rapidly and accumulate macrophages and lymphocytes followed by necrosis 

Necrotic patches get enlarged and discharged which will lead to dissemination and cavitations. (no fibrous walls)

Pneumothorax

TB bronchopneumonia can happen after both 1ry and 2ry TB.  

Rapidly spreading tuberculous bronchopneumonia: debilitated by intercurrent disease, diabetes, malnutrition etc.

Acute miliary tuberculosis of the lungs due to blood stream spread to lungs. Grey tubercles visible to naked eye 3mm in diameter. More numerous and larger in upper lobes than lower lobes. Microscopically these are ill formed and often giant cells are absent. Usually these lesions do not cavitate

Effects on the other organs of the body

Miliary tuberculosis due to systemic spread to kineys, spleen, brain, liver etc.

Tuberculous ulcers in the intestine  due swallowed sputum.

Tuberculosis of larynx due to direct spread from sputum.

Secondary amyloidosis.

Miliary TB

Common with 1ry TB

Due to involvement of veins

Multiple scatted tubercles

Not well developed/uniform in size

1-2 mm

Some times without giant cells (necrosis)

Secondary  Tuberculosis (Post primary)

Infection may me exogenous or endogenous

After active primary infection

Reactivation asymptomatic primary lesions:

Malnutrition,

Severe illness,

Intercurrent lung infection,

Systemic immunosuppression

Exogenous: caused by inhaled organisms

Immunity

During primary tuberculosis or during BCG immunisation, the patient develops cell mediated immunity to antigens of tubercle bacillus.

This is demonstrated by skin test (Mantoux) test

Immunity is associated with increased resistance to subsequent infection.

Re infected lesions:

Apex of the lungs

Endogenous infections (swallowing sputum) 

Metastatic lesions are similar to re-infected

Lesions

Large in size (spread locally) no lymph node involvement

Cavity formation

Caseous material discharge gradually leaving a small cavity.

Cavities can become very large with overgrowth of fibrous tissue.

Cavity walls are irregular with raised bands representing obliterated blood vessels.

The surface is lined by caseous material or by pus and debris mixed with blood.

If the disease is inactive the wall becomes very smooth

In early cases the lesions are often in the apices of the lungs

In advanced cases there may be more than one cavitatory lesion.

All the lesions are distributed in the upper part of the lungs

Caseation may involve the wall of a bronchus leading to obstruction of the lumen.

Sequelae of tuberculous cavities
Local effects

Due to fibrosis lung tissue shrinks causing bronchiectasis (upper lobe bronchiectasis)

Blood vessels  can become weaken and rupture leading to haemoptysis

Aneurysm formation- called Rasmoussen’s aneurism leading to fatal haemorhage.

Fungal infections can be localized in these cavities.

Tuberculosis                 
Primary

Seen in non immune people.

Usually childhood cases

Subpleural mid zone

Lymph nodes are always involved

Seen in immune people

Secondary

Often adults

Lung apices

Lymph nodes are not always involvecd