Pac 510 Genmicro (Viral Infections)

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Virion structure

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-DNA or RNA genome is surrounded by a protein coat called the capsid
-The capsid is made of small proteins called capsomeres
-Some viruses have outer envelope composed of lipids and polysaccharides
-Bacterial viruses may also have a tail, sheath, and tail fibers
-A virus must invade a cell and take over functioning to produce a new daughter virions

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The Lytic Cycle

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-Virus binds to the cell membrane through proteins (usually glycoprotein) on the capsid and the cell membrane and uncoating takes place
-Transcription, translation, and replication of viral RNA or DNA. Host cell DNA/RNA replication is sometimes inhibited
-Host cell makes capsid proteins to get ready for release of daughter virions
-Virions are assembled and released from the host cell by cell lysis or budding

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RNA Viruses

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-Positive stranded
--RNA looks more like messenger RNA (mRNA)
--Enters the cell and can be immediately translated into proteins by the ribosomes in the host
-Negative stranded
--Enters the cell and are transcribed into a positive strand of RNA
--In order for this transcription to occur RNA-dependent polymerase needs to be in the capsid
-Retroviruses
--Transcribed in reverse (into DNA)
--Reverse transcriptase must be carried in the virus

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RNA Viruses

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-Polymerases of pathogenic RNA viruses do not proofread the strand being synthesized. Two important consequences arise from this:
--Mutation rate and therefore the plasticity of these viruses in circumvening therapies is very high
---They can mutate quickly which makes them capable of avoiding or bypassing therapies by a change in structure
--A greater percentage of daughter virions are inactive

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DNA Viruses

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-Most DNA viruses are double stranded with icosahedral symmetry and replicate in the nucleus
-Exceptions
--Parvoviridae
---Single stranded (only difference)
--Poxviridae
---Box like capsid
---Replicates in the cytoplasm

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DNA Viruses

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-DNA viruses upon entry to the cell undergo these steps to replicate genetic material:
--DNA is transcribed into mRNA
--mRNA is translated into structural proteins and enzymes
-DNA has a negative strand and a positive strand
-The positive strand is read during transcription
-DNA viruses integrate their DNA into the host cell. The integrated viral DNA is called a prophage
-This allows the DNA to be replicated from one cell to the next, a process called lysogeny
-Lysogeny takes place because the prophage uses the host cell to make host proteins. This keeps the cell multiplying and prevents cell death
* This process makes DNA viruses more problematic clinically

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DNA Viruses

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-Adenoviruses are nonenveloped DNA viruses isolated from respiratory and intestinal tract of humans and animals
--Commonly seen in acute respiratory disease and pneumonia
--Some cause chronic pulmonary disease in infants and young children

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DNA Viruses

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-Pathology: necrotizing bronchitis and bronchiolitis
--Sloughed epithelial cells and inflammatory infiltrate fill and damage the bronchioles
--Interstitial pneumonitis is characterized by areas of consolidation with extensive necrosis, hemorrhage, and a mononuclear inflammatory infiltrate
--Two distinctive types of intranuclear inclusions:
---Smudge cells
---Cowdry type A inclusions
* both of these involve bronchiolar epithelial cells and alveolar lining cells
**May cause diarrhea in immunocompetent and immunocomprised hosts
Patients with AIDs are particularly susceptible to UTI caused by adenovirus type

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The Common Cold (Coryza)

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-Most common viral disease
-Acute, self-limited upper respiratory tract disorder
-Caused by infection with a variety of RNA viruses
-Spread from person to person by contact with infected secretions
-More common in seasons that promote indoor crowding
-Children usually suffer 6-8 colds per year and adults 2-3

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The Common Cold

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-Infect the nasal respiratory epithelial cells
-Rhinoviruses and coronaviruses have a tropism (environmental stimulus) for respiratory epithelium
--Optimally reproduce at temperatures well below 37⁰C (98.6⁰F)
--Infection remains confined to cooler areas of upper airway

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The Common Cold

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-Infected cells release chemical mediators (ex: bradykinin)
--Produce most of the symptoms
-Symptoms:
--Increased mucus production and edema
--Nasal congestions
--Sore throat
--Eustachian tube obstruction
-The above symptoms may predispose to secondary bacterial infection and lead to bacterial sinusitis and otitis media.

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Common Cold Clinical Application

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-Characterized by:
--Rhinorrhea
--Pharyngitis
--Cough
--Low-grade fever
--Symptoms last about a week

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Influenza

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-Acute, usually self-limited, infection of upper and lower airways
-Caused by influenza virus.
-10-40 million cases of influenza occur annually in the US, accounting for over 35,000 deaths.
-Highly contagious.
-New strands emerge regularly, often from animal hosts.
--Infect human in parts of the world where animals and humans are in close contact, then disseminate rapidly.
-Viruses are enveloped and contain single-stranded RNA.

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Influenza

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-3 types:
--Type A: Most common and causes the most severe disease.
--Type B
--Type C
-After categorized by type, we use their serotype of hemagglutinin (H) and neuraminidase (N).
--Avian influenza that emerged in 2003 and continues to spread is designated A(H5N1).
--Swine Flu: A(H1N1)
---Epidemic
--Influenza of 1918
---Empidemic-killed 20-40 million people
-Antigenic variation: Virus antigens change so often, host immunity that develops in one type rarely protects against the next type.
--Your body cant recognize them.

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Influenza Pathogenesis

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-Spreads from person to person by virus-containing respiratory droplets and secretions.
-In respiratory epithelial cell surface, virus binds and enters the cell by fusion with the cell membrane.
--This process mediated by a viral glycoprotein (hemagglutinin) that binds to sialic acid residues on human respiratory epithelium.
-Inside the cell: the virus directs it to produce progeny viruses and causes cell death.
-Usually involves both upper and lower airways.
-Destruction of the ciliated epithelium cripples the mucociliary blanket, predisposing to bacterial pneumonia.

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Influenza Pathology

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-Causes necrosis and desquamation of the epithelium.
-In the lungs: necrosis and sloughing of alveolar lining cells and the appearance of viral pneumonitis.

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Clinical Application

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-Rapid onset of:
--Fever
--Chills
--Myalgia
--Headache
--Weakness
--Nonproductive cough
-Symptoms: upper respiratory infection, tracheitis, bronchitis, and pneumonia.
-Epidemics: death from both the disease and it’s complications
--Primarily in the elderly and those with underlying cardiopulmonary disease.
-Viral vaccines specific to epidemic strains are 75% effective in preventing influenza.

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Parainfluenza virus

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-Cause acute upper and lower respiratory tract infections.
-Enveloped, single-stranded negative-sense RNA.
-Most common cause of croup (laryngotracheobronchitis)
--Characterized by stridor on inspiration and a barking cough (d/t virus attacking vocal cords)
-Common in children younger than 3 and characterized by subglottic swelling, airway compression and respiratory distress.
-Highly contagious through infectious respiratory aerosols and secretions.

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Parainfluenza Pathogenesis & Pathology

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-Infect and kill ciliated respiratory epithelial cells and elicit an inflammatory response.
-In younger children, frequently extends into the lower respiratory tract, causing bronchiolitis and pneumonitis.
-Because of a narrow trachea and small larynx in children, when laryngotracheitis occurs, edema compresses the upper airway enough to obstruct breathing and cause croup.
-Associated with:
--Fever, hoarseness, cough
-In older children and adults symptoms are usually mild.

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Respiratory Syncytial Virus (RSV)

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-Belongs to same family (Paramyxoviridae) as parainfluenza virus.
-Spreads rapidly from child to child in respiratory aerosols and secretions.
-Common in daycare centers, hospitals, and other areas where children are confided.
-Highly contagious
--Most children have been infected by school age.

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RSV Pathogenesis and Pathology

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-Viral surface proteins interact with specific receptors on host respiratory epithelium.
--Causes viral binding and fusion.
-RSV produces necrosis and sloughing of bronchial, bronchiolar, and alveolar epithelium.
--Associated with a predominately lymphocytic inflammatory infiltrate.

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RSV Clinical Application

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-Infants and young children present with:
--Wheezing, cough, respiratory distress and sometimes fever.
-Usually resolved in 1-2 weeks.
-In older children and adults, produces much milder disease.

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Severe Acute Respiratory Syndrome (SARS)

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-Causative agent: SARS-associated cornonavirus
--Derived from a nonhuman host, most likely to be bats.
-Incubation period: 2-7 days, some cases range up to 10 days.
-Potentially fatal

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SARS Pathology

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-Diffuse alveolar damage.
-Multinucleated syncytial cells without viral inclusions.

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SARS Clinical Application

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-Begins with fever and headache, followed shortly by cough and dyspnea.
-Coryza often absent and diarrhea common.
-Lymphopenia is common.
-Aminotransferase levels modestly increased.
-Some adults develop ARDS and are at high risk of complications and death.
-Most patients recover, however mortality rate as high as 15% in the elderly and pt’s who suffer other respiratory disorders.
-No specific tx available.
--Corticosteroids may offer some benefit.
--No data from clinical trials is available.

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Measles (Rubeola)

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-Highly contagious
-May cause fetal infection

-Enveloped, single stranded RNA virus
--Acute illness
--Upper respiratory tract symptoms
--Fever
--Rash

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Measles: Epidemiology

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-Respiratory aersols and secretions
-Primarily disease of children
--Severe in the very young, the sick or the malnourished
---Mortality rate 10-25%
--Uncommon in the US
-VACCINATIONS!

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Measles: Pathogenesis

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-Initial site of infection:
--Mucous membranes of nasopharynx and bronchi
-HOW?
--Fusion with respiratory epithelium via surface glycoproteins
-Then…
--Extends to lymph nodes  bloodstream

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Measles: Pathology

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-Necrosis of infected respiratory epithelium
-Lymphoid hyperplasia:
--Cervical
--mesenteric lymph nodes
--Spleen
--Appendix
-Warthin-Finkeldey giant cells
--Characteristic of measles

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Measles: Clinical Features

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-Fever
-Rhinorrhea
-Cough
-Conjunctivitis
-Mucosal and skin lesions
--Begins on face and spreads
--Fades in 3-5 days
-Often leads to secondary bacterial infections
-CNS invasion
--Subacute sclerosing panencephalitis (SSPE)
---Slow and chronic disorder occurring years after the measles

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Rubella Infection“German Measles”

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-Enveloped, singe stranded RNA
--mild, self-limited systemic disease associated with a rash
-Destructive Fetal Pathogen
--Fetal death
--Premature delivery
--Congenital anomalies

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Rubella: Epidemiology

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-Transmission: Person to person via Respiratory Route

-Not highly contagious

-VACCINATIONS!
--Largely eliminated disease in developed countries
--10-15% of young women in unvaccinated

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Rubella: Pathogenesis

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-Initial site of infection:
--Respiratory epithelium
-Then…
--Extends to other organs via bloodstream and lymphatics
-Causing…
--Rash results from response to disseminated virus

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Rubella: Pathogenesis

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-Fetal Infection:
--Through the placenta
--Infected fetus sheds large amounts of virus in body fluids

-Infection after 20wks gestation does not cause significant fetal disease

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Rubella: Pathology

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-Mild, acute febrile illness
--Rhinorrhea
--Conjuctivitis
--Postauricular lymphadenopathy
--Rash – gone in 3 days
--(30% cases are asymptomatic)
-Fetus
--Heart
---Plumonary valvular stenosis
---Plumonary artery hypoplasia
---Ventricular septal defects
---Patent ductus arteriosus
--Eyes
---Cataracts
---Glaucoma
---Retinal defects
--Brain
---Microcephaly
---Mental retardation
--Ears
---Deafness

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Rotavirus

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-Most common cause of severe diarrhea WORLDWIDE
-Double stranded RNA virus
-Usually infects young children

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Rotavirus: Epidemiology

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-Person to person by oral-fecal route
--Common in children
---Shed huge amounts of virus in stool
---Peak age 6mos-2yrs
---Virtually all infected by 4yrs
-100 deaths in young children in US
-1 million deaths worldwide

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Rotavirus: Pathogenesis

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-Initial site of infection:
--Enterocytes of upper small intestine
-Doing what?
--Not allowing absorption
---Sugars
---Fats
---Ions
-Causing…
--Net loss of fluid into lumen
---Diarrhea
---Dehydration
--Infected cells shed from villi

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Rotavirus: Pathology

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-Confined to duodenum and jejunum
--Shortening of villi
--Mild infiltrate of neutrophils and lymphocytes

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Rotavirus: Clinical Features

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-Manifestations:
--Vomiting – lasts 2-3 days
--Fever
--Abdominal pain
--PROFUSE, watery diarrhea – 5-8 days
-HYDRATION – if not can be fatal in young children

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Other GI Viruses

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-Adenovirus

-Calicivirus

-Astrovirus

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Adenovirus

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-Transmition:
--direct contact
--fecal-oral
--occasionally waterborne transmission
-Treatment:
--Treating symptoms only

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Calicivirus: Norwalk Family

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-Non enveloped RNA virus
--Norwalk Virus
--Snow Mountain Virus
--Sapporo Virus
-Responsible for 1/3 of all outbreaks of diarrheal disease
-Infection area:
--Upper small bowel
-Manifestations:
--Gastroenteritis
--Vomiting
--Diarrhea

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Viral Hemorrhagic Fevers

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-A group of at least 20 distinct viral infections
-Cause varying degrees of hemorrhage and shock
-Sometimes cause death
--However, death is rarely caused by bleeding
-Usually named for where they were first described
-“multisystem syndromes”

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Viral Hemorrhagic Fevers (VHFs)

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-All RNA viruses
--Covered in lipid coating
-Virus survival is dependent on an animal or insect host (natural reservoir)
--Humans are not the reservoir for ANY of these viruses
-Geographically restricted to areas where host species live
-Occurrence of outbreaks is hard to predict

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Viral Hemorrhagic Fevers (VHFs)

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-Members of 4 virus families
--Bunyaviridae/bunyaviruses
--Flaviviridae/flaviviruses
--Arenaviridae/arenaviruses
--Filoviridae/filoviruses
-Separated into 4 groups based on routes of transmission, vectors, and epidemiology
--Mosquito-borne
--Tick-borne
--Zoonotic
--Filoviruses—route of transmission unknown

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General Complications

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-Uveitis:inflammation of the uvea—layer of eye just under sclera (white part); causes redness, pain, and sensitivity to light
-Blindness
-Pericarditis
-Encephalitis
-Orchitis: acute inflammation of the testes; causes swelling and pain—can lead to infertility
--Hair loss can be temporary or permanent
-Hearing problems
-Spontaneous abortion
-Hair loss

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Treatment of VHFs

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-No specific treatment
-Antiviral drug: ribavirin
--Can shorten course of infection and prevent complications in some arenaviridae and bunyaviridae
-Treatment with clotting factors, platelets, and heparin is a matter of debate
-Adequate fluids
-Maintain electrolyte balance
-Ventilator if needed
-Dialysis if needed

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Prevention of VHFs

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-Vaccines for yellow fever and Argentine HF ONLY
-Protection from mosquitoes and ticks
-Avoid high-risk areas
-Rodent control
-Avoid contact with hosts

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Arenaviridae

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-Lassa fever, Argentine HF, Bolivian HF, Brazilian HF, Venezuelan HF
-Fever, pain behind chest wall and in back, sore inflamed throat with white patches on tonsils, cough, abdominal pain, vomiting, diarrhea, conjunctivitis, bleeding from gums and internal organs, facial swelling, hearing loss, pleural effusion, encephalitis

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Bunyaviridae

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-Rift Valley fever, Crimean-Congo HF, HFRS, hantavirus pulmonary syndrome
-Fever, severe muscle aches, sore throat, headache, cough, diarrhea, encephalitis
-Crimean-Congo HF: sore eyes, photophobia, mood swings, agitation, bleeding into skin and from gums, rectal bleed, kidney bleed, pulmonary failure
-Hantavirus: SOB, dyspnea, possible respiratory failure

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Filoviridae

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-Ebola virus, Marburg virus
-Among most virulent of all known diseases
-Initially: fever, intense weakness, muscle pain, vomiting, diarrhea
-Later: hemorrhagic rash, bleeding from orifices, seizures, coma, delirium
-Fatal in 50-90%
-Almost always fatal in pregnant women

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Ebola HF epidemiology

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-Mainly in Africa
-Ebola virus infects humans, gorillas, chimpanzees, and monkeys
-Believed to be zoonotic
-Transmitted via bodily secretions, blood, and used needles

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Ebola HF pathogenesis and pathology

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-Ebola virus results in the most widespread destructive tissue lesions of all VHF agents
-Massive replication in endothelial cells, mononuclear phagocytes, and hepatocytes
-Severe necrosis in liver, kidney, gonads, spleen and lymph nodes
--In liver: hepatocellular necrosis, Kupffer cell hyperplasia, Councilman bodies, microsteatosis
-Lungs are usually hemorrhagic
-Petechia
-Shock

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Ebola HF clinical features

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-Incubation period is 2-21 days
-Initial symptoms: headache, weakness, fever
--Followed by N/V/D
-Some develop overt hemorrhage
--Bleeding from injection sites, petechia, GI bleeding, gingival hemorrhage

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Ebola HF

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-No cases in humans in US
--Ebola-Reston virus caused severe illness and death in monkeys imported to research facilities
--Research workers became infected, but did not become ill
-Typically appears sporadically

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Marburg HF

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-First recognized in 1967
--Marburg and Frankfurt, Germany and Belgrade, Yugoslavia
--First people to be infected had been exposed to African green monkeys
-Unknown reservoir
-Can be spread human-to-human
-Not many reported cases

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Marburg HF

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-Incubation period of 5-10 days
-Fever, chills, headache, myalgia
-Maculopapular rash
-N/V/D, chest pain, sore throat, abdominal pain
-Jaundice, pancreatitis, severe weight loss, delirium, shock, liver failure, massive hemorrhage, multi-organ dysfunction
-23-25% fatality

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Flaviviridae

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-Yellow fever, dengue fever, dengue HF, Kyasanur Forest disease, Omsk HF, West Nile virus
-Yellow fever: jaundice, fever, headache, muscle ache, flushing, photophobia
-Dengue fever: symptoms vary with age
--Infants and young children: rash, severe flu-like symptoms
--Older children and adults: high fever, severe headache, eye pain, muscle aches, rash
--Hemorrhagic form: extremely high fever, bleeding, convulsions, circulatory failure

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Flaviviridae

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-Kyasanur Forest disease and Omsk HF
-Initial signs and symptoms are followed by brief recovery and then reappearancebiphasic
-Fever (constant or intermittent), headache, pain behind eyes, arm and leg pain, rash on soft palate, swollen glands in neck, diarrhea, vomiting, bleeding in eyes, epistaxis, GI bleeding

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Yellow fever epidemiology

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-Sometimes associated with hepatic necrosis and jaundice
-Today is restricted to certain regions of Africa and South America
--Urban and jungle settings
-Reservoir: tree-dwelling monkeys
--Yellow fever does not kill the monkeys or make them ill
-Vector: mosquitoes (Aedes aegyptii)

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Yellow fever pathogenesis

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-Virus multiplies within tissue and vascular endothelium
-Travels through bloodstream
--Usually to liver where it can cause hepatocellular destruction
--Can also lead to shock, hemorrhages, and loss of vascular integrity

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Yellow fever pathology and clinical features

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-Causes coagulative necrosis of hepatocytes
--Spreads toward central veins and portal tracts
-Abrupt onset of fever, chills, headache, myalgias, nausea, vomiting
--After 3-5 days: some develop jaundice, deficiencies of clotting factors, diffuse hemorrhages
-“Black vomit”: vomiting of clotted blood
-Can lapse into a coma and die within 10 days

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Yellow fever

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-Overall mortality: 5%
-If jaundice develops, mortality jumps to 30%
-Philadelphia epidemic of 1793

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West Nile virus epidemiology

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-Spread by infected migratory birds and arthropods (mosquitoes)
-First discovered in Uganda in 1937
-First identified in Western Hemisphere in 1999
--Caused outbreak of meningoencephalitis (West Nile fever) in NYC
-By 2003: 4000 people from 40 states
263 fatalities

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WNV Clinical Features

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-Most cases in humans are subclinical
--Severe in about 1 out of 100
-Incubation: 3-15 days
-Fever, rash, lymphadenopathy, polyarthropathy
-Acute aseptic meningitis or encephalitis, convulsions, coma, anterior myelitis, hepatosplenomegaly, hepatitis, pancreatitis, myocarditis
-Probability of more severe illness increases with age
-CNS infection is associated with a 4-13% mortality rate
--Highest among elderly

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Herpes
Varicella-zoster Virus

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-First exposure to VZV: chickenpox (an acute systemic illness with vesicular skin eruption)
-The virus then becomes latent and can reactivate causing herpes zoster (“shingles”)

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Herpes
Varicella-zoster Virus

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Epidemiology:
Highly contagious
VZV is restricted to human hosts and spreads by respiratory droplets or contact with skin lesion secretions
Effective vaccine has reduced incidence of cases in US

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Herpes
Varicella-zoster Virus

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-Chickenpox:
--VZV initially infects cells of the respiratory tract or conjunctival epithelium where it reproduces and spreads through the blood and lymphatic systems.
--The virus spreads from the capillary endothelium to the epidermis, where its replication destroys the basal cells.
--Vesicles are formed from the upper layers of the epidermis separating from the basal layer
---Vesicles are filled with neutrophils and can erode to form ulcers
---Over several days, vesicles become pustules, then rupture and heal

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Herpes
Varicella-zoster Virus

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-Chickenpox features:
--Fever, malaise, distinctive pruritic rash
---Fever resolves in 3-5 days and skin lesions heal in several weeks
--Skin lesions begin as maculopapules that rapidly evolve into vesicles, then become pustules that soon ulcerate and crust
---Vesicles may even appear on mucous membranes!

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Herpes
Varicella-zoster Virus

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-During primary infection, VZV establishes latent infection in perineuronal satellite cells of the dorsal nerve root ganglia.
-Transcription of viral genes continues during latency.

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Shingles

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-Occurs when full virus replication occurs in ganglion cells and the agent travels down the sensory nerve for a single dermatome
-A localized painful vesicular eruption of the epidermis results
-Pain can persist for months after resolution of the skin lesions
-Risk increases with age and in those who are immunocompromised

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Herpes
HSV Infections

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-Usual sites = skin and mucous membranes
--Sometimes involves the brain, eye, liver, lungs, and other organs
-HSV-1 and HSV-2 cause necrosis of infected cells
--Accompanied by inflammatory response
--Painful ulcerating vesicular lesions on the skin
-Clinical:
--A tingling sensation at the site often precedes the appearance of skin lesions
--Recurrent lesions appear weeks, months, or years later at the initial site or at a site served by the same nerve ganglion
--Patients with AIDS and other immunocompromised persons are prone to develop herpes esophagitis

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Herpes
HSV-1

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-Transmitted in oral secretions
-Causes disease “above the waist”
--Includes oral, facial, and ocular lesions
-Infection frequently occurs in childhood and most people are infected by adulthood (50-90%)

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Herpes
HSV-1

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-Herpes encephalitis
--Rare, but devastating (1 in 100,000 HSV infections)
--Can occur in persons who have no history of cold sores
--Can occur when the virus, latent in the trigeminal ganglion, is reactivated and travels to the brain
-Herpes hepatitis
--Can occur in immunocompromised patients
--Has been found in young, previously healthy pregnant women.

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Herpes
HSV-2

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-Transmitted in genital secretions
-Causes disease “below the waist”
--Includes genital ulcers and neonatal herpes infection
--Aseptic meningitis without genital involvement may be a manifestation of HSV-2 infection
-C-section commonly done if mom is herpetic

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Herpes
HSV-2

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-itching, burning, may be sharp pain
-grouped vesicles → blisters → ulcers

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Epstein-Barr Virus

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-The “kissing disease”
--1.5M college kids infected annually!
-Infection can be asymptomatic
-In some people, EBV causes infectious mononucleosis
--Characterized by fever, pharyngitis, lymphadenopathy, and increased circulating lymphocytes
---Symptoms usually resolve in 3-4 weeks
--Occurs in people who are not immune from childhood exposure
-EBV has also been associated with cancers
--African Burkitt lymphoma
--B-cell lymphoma (in immunosuppressed persons)
--Nasopharyngeal carcinoma

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Epstein-Barr Virus

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-Epidemiology:
--By adulthood, most people have been infected with EBV
---According to CDC, as many as 95% of adults between 35 and 40 years of age have been infected
--In crowded areas of the world, EBV usually occurs before the age of 3 and infectious mononucleosis is not encountered
---EBV transmission requires close contact with infected persons
--In developed countries, many people remain uninfected into adolescence or early adulthood
--Once EBV enters the body, it remains for life (latent as with other herpesviruses)
---About 10-20% can intermittently shed the virus

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Epstein-Barr Virus

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-Pathogenesis:
--Virus first binds to and infects nasopharyngeal cell and then B lymphocytes which carry the virus throughout the body
--infects throat epithelium → pharyngitis (with pus)
--travels to lymph nodes → lymph node swelling
---rare complication is splenic rupture
---Nodes are movable, discrete, and tender
--passes to blood → infects B cells
---kills some of them
---transforms some of them → B cells replicate
----random B cell proliferation produces “heterophile antibody”
(MonoSpot Test) – see if pt serum agglutinates on RBCs
---T cells also activated by EBV antigens on surface of B cells

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Cytomegalovirus I (CMV)

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-Congenital and opportunistic pathogen
-Most common congenital pathogen!
--Infects 0.5-2% of all fetuses and injures 10-20% of those infected
-Usually asymptomatic
--However, the fetus and immunocompromised persons are vulnerable to the destructive effects of the virus.

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CMV

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-Epidemiology:
--Spreads from person to person by contact with infected secretions and bodily fluids
---Spread to fetus across the placenta
----Causes widespread necrosis and inflammation
---Kids: mainly spread via saliva or urine
---Adults: mainly spread via sexual contact

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CMV

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-Pathogenesis:
--Infects epithelial cells, lymphocytes, and monocytes
--Establishes latency in WBCs
--The normal immune response rapidly controls CMV infection
---Infected people rarely show ill effects, but do shed the virus periodically in body secretions
--Infection often symptomatic in immunosuppressed people (ex: organ transplant recipients)

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CMV

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-Pathology:
--In a fetus with CMV, the most common sites of involvement are the brain, inner ears, eyes, liver and bone marrow.
---The most severely affected fetuses may have microcephaly, hydrocephalus, cerebral calcifications, hepatosplenomegaly, and jaundice
---Cellular necrosis and marked cellular and nuclear enlargement
----The giant nucleus may have a large central inclusion surrounded by a clear zone

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CMV

Back 85

-Congenitally acquired CMV can cause fetal death in utero, lesions of the CNS, liver disease, and bleeding problems
--Most CMV congenital infections manifest as subtle neurologic or hearing defects (may not be detected until later in life)
-Disease in immunosuppressed patients can manifest as decreased visual acuity (chorioretinitis), diarrhea or gastrointestinal hemorrhage (colonic ulcerations), change in mental status (encephalitis) or SOB (pneumonitis)

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Human Papillomavirus (HPV)

Back 86

-Nonenveloped, dsDNA viruses
->100 HPVs
-HPVs cause proliferative lesions of squamous epithelium
--HPV types 1, 2, 4 = common and plantar warts
--HPV types 6, 10, 11, 40-45 = anogenital warts
--HPV types 16, 18, 31 = squamous carcinoma of the female genital tract
-Some HPV infected cells display kilocytosis
--Features larege squamous cells with shrunken nuclei enveloped in large cytoplasmic vacuoles (kilocytes)

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HPV

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-Pathogenesis:
--Infection begins in stratified squamous epithelium, where the virus enters the nuclei of basal cells
--Infection stimulates replication of the squamous epithelium (proliferative lesions)
---Progeny viruses are replicated and shed in the degenerating superficial cells
--Depressed cell-mediated immunity is associated with the spread of HPV lesions
--Many HPV lesions resolve spontaneously

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HPV

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-Common warts (verruca vulgaris) are firm, circumscribed, raised, rough surfaced lesions
--Usually appear on surfaces subject to trauma such as the hands
-Plantar warts are squamous proliferative lesions on the soles of the feet
--Compressed inward by standing and walking
-Anogenital warts (condyloma acuminatum) are soft, raised, fleshy lesions
--Found on the penis, vulva, vaginal wall, cervix or perianal region
-Flat warts can develop into malignant squamous cell proliferations

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Viral Hepatitis

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-An infection of hepatocytes that produces necrosis and inflammation of the liver.
-Many viruses and infectious agents can produce hepatitis and jaundice, but in the industrialized world, more than 95% of cases of viral hepatitis involve a limited number of hepatotropic viruses, named from A to G.

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Hepatitis A Is the Most Common Cause of Acute Hepatitis

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-Hepatitis A virus (HAV) is a small RNA-containing enterovirus of the picornavirus group.
-The hepatocyte is the principal site of viral replication.
-Shedding of progeny virus into the bile accounts for its appearance in the feces.
-HAV is not directly cytopathic, and hepatic injury has been attributed to an immunologic reaction to virally infected hepatocytes.

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Epidemiology of Hepatitis A

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-The only reservoir for HAV is the acutely infected person.
-Transmission depends primarily on the fecal-oral route.
-Epidemics of HAV occur under crowded and unsanitary conditions or by fecal contamination of water or food.
-Edible shellfish can also contain the virus in contaminated waters and can cause infection if eaten after being inadequately cooked.
-In industrialized countries, most cases of HAV are seen in older children and adults.
--In less developed regions, where the disease is endemic, most of the population is infected before the age of 10 years.

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Hepatitis A

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-In the U.S. about 10% of the population younger than 20 years of age have serologic evidence of previous HAV infection.
--This indicates that most infections of HAV are without jaundice.
-HAV is common in daycare centers, international travelers, and male homosexuals (oral-anal contact).
-An effective vaccine for hepatitis A confers long-term protection against the disease.
-Hepatitis A never pursues a chronic course. There is no carrier state, and infection provides lifelong immunity.

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Symptoms of Hepatitis A

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-People with HAV infection develop nonspecific symptoms including fever, malaise, and anorexia.
-Jaundice may appear and last for an average of 10 days but may persist for more than a month.
-Virtually all patients recover without hepatic encephalopathy, and fatal hepatitis occurs only rarely.

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Hepatitis B

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-Hepatitis B is a major cause of acute and chronic liver disease.
-The DNA of HBV is predominantly double-stranded and consists of one long circular strand containing the entire genome, and a shorter complementary strand.
-The HBV genome contains four genes:
--Core C gene: the core of the virus contains the core antigen(HBcAg) and the e antigen (HBeAg).
--Surface gene: The core of HBV is enclosed in a coat that expresses and antigen termed hepatitis B surface antigen (HBsAg)
--Polymerase gene: The P gene encodes the DNA polymerase.
--X gene: The small X protein activates viral transportation and probably plays a role in the pathogenesis of hepatocellular carcinoma associated with chronic HBV infection.

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Hepatitis B

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-It is estimated that there are about 200 million chronic carriers of HBV in the world, constituting an enormous reservoir of infection.
--U.S. and western Europe have the lowest rates.
--In the U.S. it is estimated that there are between 500,000 and 1.5 million chronic HBV carriers, and 200,000 to 300,000 persons newly infected with HBV annually.
--Of the new cases, only ¼ are clinically recognized because of jaundice.
-Fulminant hepatitis B results in 250 to 300 deaths a year.
-Only 10% of adults infected with HBV become carriers.
--Neonatal hepatitis B is usually followed by persistent infection.
--Males exhibit an increased tendency to become carriers.
--In the U.S. chronic HBV carriers are particularly common among male homosexuals and drug addicts.

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Hepatitis B

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-Humans are the only significant reservoir of HBV.
-Most cases of HBV result from transmission associated with intimate contact.
--The routes by which contact-transmission occurs are not entirely defined, but it seems probable that direct transfer of the virus through breaks in the skin or mucous membranes is most common.
--In this respect anal sexual contact is an important mode of transmission.
-Synthetic vaccines for HBV are highly effective and confer lifelong immunity.

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Hepatitis B

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-Acute Hepatitis B
--Most patients have acute, self-limited hepatitis similar to that produced by HAV, in which complete recovery and lifelong immunity are the rule.
--The symptoms are similar to those of HAV and tend to be more severe.
--HBV is like HAV in that most infections are without jaundice so they are not usually clinically apparent.
-Fulminant Hepatitis B
--Rare case in which hepatitis B pursues a fulminant course characterized by massive liver cell necrosis, hepatic failure, and a high mortality.

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Chronic Hepatitis B

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-Chronic hepatitis refers to the presence of necrosis and inflammation in the liver for more than 6 months.
-Chronic hepatitis B develops in 5 to 10 percent of the cases of hepatitis B.
--For reasons unknown, 90% of patients with chronic HBV are male.
-Can lead to cirrhosis
-Is associated with a significant risk of liver cancer.

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Hepatitis D

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-Synthesis of hepatitis D (HDV) in the liver requires the synthesis of HBsAg and, therefore, infection with this agent is limited to persons infected with HBV.
-Infection with HDV may occur either simultaneously with HBV or following HBV infection.
-In some patients, coinfection between HBV and HDV can lead to severe, fulminant, and often fatal hepatitis, particularly in intravenous drug abusers.
-Superinfection of an HBV carrier with HDV typically increases the severity of existing chronic hepatitis.

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Hepatitis C

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-Hepatitis C virus (HCV) contains a single strand of RNA.
-The virus is genetically unstable, which leads to multiple genotypes and subtypes.
--Six different but related HCV genotypes are recognized.
--Types 1,2,and 3 are the most common in the United States.
--Genotypes 2 and 3 are more responsive to antiviral therapy than 1.
-In an individual patient, many mutant strains arise, which likely accounts for several features of infection, including:
--The inability of anti-HCV IgG antibodies to clear the infection
--Persistent and relapsing infection (chronic hepatitis)
--Lack of progress in developing a vaccine.

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Hepatitis C Epidemiology

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-It is estimated that 200 million people are infected worldwide.
-HCV is the most common indication for liver transplantation.
--Accounts for up to 50% of patients on the waiting list.
-HCV is transmitted by contact with infected blood and is particularly associated with intravenous drug use, high-risk sexual behavior, and alcoholism.
-Transmission from an infected mother to her newborn baby is infrequent.
-A minority of cases occur in the absence of known risk factors.

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Hepatitis C

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-The clinical course of acute hepatitis C is surprisingly mild and is only very rarely complicated by fulminant hepatitis.
--Only 10% of patients become jaundiced in the acute phase.
-The major consequences of infection with HCV relate to chronic disease.
-Despite complete recovery from clinical and biochemical acute liver disease, the probability of persistent HCV infection and chronic hepatitis is at least 80% and may be higher.
-Chronic hepatitis ensues in 50 to 70% of infected persons.
-Clinical morbidity in most patients remains mild for at least 10 years, and in many cases for 20 or more years.

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Hepatitis C

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-20% of patients with chronic hepatitis C eventually develop cirrhosis.
-Alcohol consumption has been shown to worsen the course of chronic hepatitis C.
--The relationship is unexplained, and the possibility that HCV actually accounts for a proportion of cases otherwise classified as alcoholic cirrhosis is intriguing.
-HCV is also an important risk factor for the development of hepatocellular carcinoma.

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Hepatitis E

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-A major cause of epidemics of hepatitis in underdeveloped countries.
-Transmitted via the fecal-oral route.
-Large outbreaks have been reported in India, Nepal, Burma, Pakistan, and the former Soviet Union.
-Most of these epidemics have followed heavy rains in areas with inadequate sewage disposal.

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Pathology of Viral Hepatitis

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-The hallmark of acute viral hepatitis is liver cell death.
-Within the hepatic lobule, scattered necrosis of single cells or of small clusters of hepatocytes is seen.
-In acute viral hepatitis , many liver cells appear normal, but others show varying degrees of hydropic swelling and differences in size, shape, and staining qualities.
-Chronic inflammatory cells, principally lymphoid, infiltrate the lobule diffusely, surround individual necrotic liver cells, and accumulate in areas of focal necrosis.
-Characteristically, lymphoid cells infiltrate between the wall of the central vein and the liver cell plates.

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Pathology of Acute Hepatitis Continued

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-Swelling and proliferation of the endothelial cells of the central vein often develop (endophlebitis)
-The Kupffer cells are enlarged, project into the lumen of the sinusoid, and contain lipofuscin pigment and phagocytosed debris.
-Cholestasis is common. In this situation, many liver cells arranged around a lumen, thereby presenting an acinar or glandular appearance. The lumen of such an acinus may contain a large bile plug.
-All of the pathologic changes are gradually reversed during recovery of acute hepatitis and the normal hepatic architecture is completely restored.

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Confluent Hepatic Necrosis

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-Refers to particularly severe variants of acute viral hepatitis, which are characterized by the death of numerous hepatocytes in a geographical distribution and, in extreme cases, by the death of almost all the liver cells (massive hepatic necrosis).
--Most common cause is acute hepatitis B. Only rarely does confluent hepatic necrosis result from infection with other hepatotropic viruses.
-In contrast to the most common forms of acute viral hepatitis, in which the necrosis of hepatocytes appears to be random and patchy, confluent hepatic necrosis typically affects whole regions of the lobule.
-There are 3 types of lesions of confluent hepatic necrosis: Bridging necrosis, submassive necrosis, and massive necrosis.

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Confluent Hepatic Necrosis

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-Bridging Necrosis: at the milder end of the spectrum of lesions.
-Submassive Confluent Necrosis: this form of acute hepatitis defines an even more severe injury involving necrosis of entire lobules or groups of adjacent lobules.
--Clinically these patients manifest severe hepatitis, which may rapidly proceed to hepatic failure.
-Massive Hepatic Necrosis: Uncommon, most feared variant of acute viral hepatitis.
--Form that is almost invariably fatal.

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Chronic Hepatitis

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-A complication of hepatitis B and C.
-Causes development of piecemeal necrosis, portal tract lesions, intralobular lesions, and periportal fibrosis.
-Over time can lead to cirrhosis.