Unit 3c Flashcards
Clinical Manifestations of HSV-1
1) Most common:
-Frequently asymptomatic
-Orofacial lesions
“above the belt”
2) Less common:
- (some) genital lesions
- Encephalitis - causes childhood/adult encephalitis
- Herpes whitlow (HSV on fingers)
- Herpes keratitis (HSV in eye) - can cause blindness
3) Rare
- Neonatal herpes
Usually occurs during childhood
Clinical Manifestations of HSV-2
1) Most Common:
-Asymptomatic
-Genital lesions and
“below the belt”
2) Less common:
- (some) orofacial lesions
- Herpes whitlow
- Neonatal herpes - HSV-2 is common cause
3) Rare
- Encephalitis
- Herpes keratitis
Transmission of HSV-1 and HSV-2
HSV1 = close contact HSV2 = close contact usually sexual
Target cell type in HSV-1 and 2
mucosal epithelium
Cell that HSV-1 and 2 remains latent in
neuron (ganglia)
Trigeminal ganglion → face
Sacral ganglion –> genitals
Incubation period for HSV1 and 2
2-12 days
Reactivation of HSV-1
Usual: Asymptomatic (most common), Herpes labialis (cold sore)
Occasional: Recurrent genital herpes, Herpes Keratitis
Rare: encephalitis
Reactivation of HSV-2
Usual: Asymptomatic (most common), Recurrent genital herpes
Occasional: Gingivostomatitis
Rare: encephalitis, herpes keratitis
Diagnosis of HSV1 and 2
3
1) Viral culture of lesions (easiest)
2) Direct fluorescent antibody stain of lesions (stain adheres to HSV antigen)
3) PCR of lesions (most expensive)
Treatment of HSV-1 and 2
Nucleoside analogs (acyclovir) -
IV acyclovir used with neonatal herpes, immunocompromised hosts, pts with encephalitis
Oral acyclovir used for HSV outbreaks
clinical manifestations of chicken pox (varicella)
Symptoms: fever, malaise, headache, cough, rash - dew drop on a rose petal (vesicle on erythematosus base)
Once rash has scabbed - no longer infectious
Clinical manifestations of shingles (zoster)
reactivation of VZV
Symptoms: radicular pain in one nerve area, lesions in grouped vesicles on an erythematous base
Do not cross midline, confined to single dermatome
Transmission of VZV
contact or respiratory route - highly contagious
Target cell type of VZV
mucosal epithelium
Viral pathogenesis of VZV
Primary viremia
Secondary viremia
Gain entry via respiratory tract → lymphoid system → viral replication occurs in regional lymph nodes (2-4 days)
Primary viremia occurs 4-6 days after initial infection
Viral replication in liver, spleen, and other organs
Secondary viremia when viral particles spread to skin 14-16 days after initial exposure → rash
Latency of VZV
neuron (ganglia)
Post primary infection, virus latent in cerebral/dorsal root ganglia
Reactivation → shingles (distributed in a dermatome)
Can VZV exhibit viral shedding that is asymptomatic in normal hosts?
NOOOOOOOOO
Incubation period of VZV
10-21 days after exposure for chickenpox
Chicken pox vaccination
live or killed?
what age?
live attenuated vaccine
Initial dose 12-15 months, booster dose at 4-6 years of age
Treatment of VZV
Antiviral therapy (within first 48-72 hours)
Complications associated with chickenpox
- secondary infection/cellulitis
- pneumonia
- Necrotizing fasciitis
- Encephalitis/ Encephalomyelitis
- Hepatitis
- Congenital Varicella syndrome
Diagnosis of VZV (3)
1) Direct fluorescent antibody
2) VZV PCR
3) Viral culture
Clinical manifestations of Cytamegalovirus (CMV)
Infections mononucleosis-like syndrome (fever, swollen nodes, mild hepatitis)
- In immunocompromised → retinitis, pneumonia, colitis
- In Newborns → congenital CMV
Primary infection usually asymptomatic
Transmission of CMV
contact with infected body fluids, blood transfusions, transplantation, congenital
Incubation period of CMV
2 weeks to 2 months
Target cell type for CMV
epithelia, monocytes, lymphocytes, others
Latency of CMV
-latent in monocytes, lymphocytes, others
Latent for life and may be reactivated from time to time
Can you have asymptomatic viral shedding in CMV and HSV?
YESSSSSSSS
Complications associated with CMV
1) Pregnancy → child can have congenital CMV infection
- Low birth weight, microcephaly, hearing loss, jaundice, skin rash
2) Immunocompromised individuals → severe disease
Diagnosis of CMV (5)
1) Viral culture
2) PCR
3) Fluorescent antibody staining
4) Serology (can distinguish primary vs. recurrent infection)
5) Histology
Serology in CMV:
+ IgM, - IgG → ?
- IgM, -IgG → ?
- IgM, +IgG → ?
+ IgM, + IgG → ?
+ IgM, - IgG → acute CMV disease
- IgM, -IgG → never infected with CMV
- IgM, +IgG → previous infection with CMV
+ IgM, + IgG → recent CMV reactivation
Histology of CMV
CMV infected cells have “owl’s eye appearance”
Treatment of CMV
no treatment for normal immune patients
Antivirals, CMV-IG for immunocompromised
Prophylaxis of CMV
no available vaccine, can give CMV-IG monthly for high risk, immunocompromised patients
Herpes virus structure
All Herpesviruses are dsDNA viruses
Icosahedral capsid
Glycoprotein-rich envelope
Herpes virus entry into cell
Bind surface receptors on host cells → fusion of viral/host membranes
Release nucleocapsid into host cytoplasm → transported to nucleus on microtubules through nuclear pores
Herpes virus replication
Organized, temporal
Immediate Early
Early
Late Genes
Immediate Early genes (IE)
expressed prior to protein synthesis
Required for E and L gene expression
Encode transcriptional activators
Brought in with the virus
Early Genes (E)
de novo synthesized
Proteins involved in DNA replication
e.g. viral DNA polymerase, helicase, etc.
Many drugs target these virally encoded proteins
Late Genes (L)
de novo synthesized
Encode structural proteins (capsid, glycoproteins)
Assembly of herpes virus is in…
the nucleus
Capsid self-assembles with new DNA packaged in it
Herpes virus egress
Bud through nuclear membrane and pass through golgi → acquire glycoprotein envelope
Exit cell via exocytosis or cell lysis
Primary infection
first infection ever - no serum Ab present when symptoms appear
Primary infections may not be symptomatic, or may be more severe
Symptoms of influenza
acute, febrile respiratory disease, NOT GI upset
Acute onset of fever, chills, myalgia, headache, cough
Presentation varies with age
Infants/toddlers can have apnea, GI symptoms
Structure of influenza
RNA virus with segmented genome - 8 different pieces of ssRNA
Lipid envelope lined with matrix protein on inner side
Surface proteins (H and N)
Surface proteins in influenza
hemagglutinin (H), neuraminidase (N) glycoproteins
Can have variety of types H1, H2, etc. and N1, N2, etc.
Subtypes identified by combo of H and N proteins on viral coat
Type A influenza strain
infects other animals also
Circulate in population
Type B influenza strain
circulates in population, can only infect humans
Tye C influenza strain
cause mild illness
RSV structure
ssRNA, non-segmented
Surface proteins
Surface proteins on RSV
F protein: fusion of viral envelope to host cell → Syncytia
G protein: initial binding of virus to host cell
Which subtype of RSV (A or B) has more severe disease
A
Can RSV get “drift” over time like influenza?
cheeeya brah
_________ inhibitors are sued to treat influenza subtype A and B
Neuraminidase
Tamiflu, Relenza, Rapivab (IV)
How is influenza transmitted?
What is its incubation period?
Respiratory
Virus lives on human hands for 5 min, steel or plastic for 24-48 hours, cloth or paper for 8-12 hours
Incubation period: 1-3 days
How is RSV transmitted?
What is its incubation period?
Invades conjunctiva/nasopharynx
Incubation period: 3-5 days
Symptoms of RSV
Constriction of smooth muscles in bronchioles
→ edema/inflammation of airway
→ Ventilation/perfusion mismatch (hypoxia)
→ Hyperexpansion by mucous plugging (seen on CXR)
Respiratory distress, wheezing/rhonchi, hypoxia, copious secretions
Clinical features of RSV
People get recurrent infections because Ab/immune protection is incomplete
Can predispose children to wheezing as adults
Creates syncytia on cellular level
Influenza vaccinations (2 kinds)
Inactivated influenza vaccine
Live attenuated influenza vaccine
Inactivated influenza vaccine (IIV)
administration
age
quadrivalent or trivalent?
injectable (IM), killed, vaccine
All individuals 6 months and older
Quadrivalent or trivalent (2 A and 1 or 2 B strains)
Live attenuated influenza vaccine (LAIV)
administration
age
quadrivalent or trivalent?
contraindications?
intranasal needle-free injection (fine mist in nose)
- For healthy persons 2yrs-49yrs of age
- Only quadrivalent (2 A and 2 B strains)
- NOT indicated in pregnancy or immunocompromised
- Slightly more expensive
RSV vaccine
Formalin-inactivated RSV vaccine: not protective, immunization caused worse disease in children (“priming” without immunity)
Still under investigation
antigenic drift
gradual change in virus through slow series of mutations, substitutions, or deletions in amino acids of H or N surface antigens
Constant and rapid change allows for repeated influenza epidemics
Adapts to antibody in host
Does NOT change the subtype of the virus (e.g. H2N2)
Antigenic shift
due to reassortment of genome segments
- Produces a new virus - swap genome segments between strains (and between strains present in other species)
- Can create novel H or N proteins
- Often can cause pandemics
- Antigenic shift is less frequent, but more severe repercussions
Type ____ influenza virus cannot undergo antigenic shift
B
can only infect humans –> can’t swap genomes with other species of influenza
Pandemic H1N1 Influenza Virus
A/California/7/2009 (H1N1)-like virus
Caused a human pandemic in 2009-2010
“Swine Flu” - most gene segments similar to influenza viruses in pigs → Antigenic shift
Mexico, US, Canada
Highest infection among children and young adults 65 yrs (preexisting immunity?)
60 million cases, 270,000 related hospitalizations, 12,000 deaths
H5N1: “Avian Flu”
Newly-emerging influenza virus
Influenza A subtype present in birds
Wild birds are asymptomatic but shed lots of virus in their stool
Currently a highly virulent strain of H5N1 circulating in bird populations
-Occasionally transmitted to humans
First noted in a goose farm in China
Infected birds found in more than 20 countries
Currently avian flu binds alpha 2,3 linkage - human viruses bind alpha 2,6 linkage → mutation in H gene may confer change in preferred binding
Qualities of influenza virus strain for pandemic (3)
1) Emergence of a new influenza subtype
2) Virus must infect humans and cause serious illness
3) Virus must have sustained human-to-human transmission and spread easily (without interruption) among humans
EX) H1N1 = pandemic (meets all 3 criteria)
H5N1 = NOT pandemic (2/3 criteria)
2 drugs used to treat influenza that inhibit neuraminidase (NA)
Zanamivir (relenza)
Oseltamivir (tamaflu)
For influenza A, B, and C
Inhibiting Neuraminidase (NA) acts to…
Block viral budding and release
Cause virus to aggregate at cell surface
→ Reduced viral infectivity
Rare development of resistance
Oseltamivir
administration
elimination
adverse reactions?
oral administration as prodrug
Eliminated via renal tubular secretion
Adverse reactions: minor nausea/vomiting
Type C for pregnancy (don’t know side effects)
Zanamivir
Administration
daily dose
elimination
adverse reactions?
inhaled
Twice daily x5 days
Renal elimination
Adverse reactions: bronchospasm (asthma or COPD patients)
DO NOT USE with COPD patients
Type C for pregnancy (don’t know side effects)
You must start antivirals for influenza when?
Must start within 48 hours of symptom onset for decrease in severity/duration of symptoms
_______ and ______ influenza drugs act by blocking viral uncoating/entry into host cell by blocking the viral M2 proton channel
Amantadine and Rimantadine
for influenza A
Mechanism of action of Amantadine and Rimantadine
Problem?
Blocks viral uncoating/entry into host cell
Block VIRALLY encoded M2 H+ channel → prevent intracellular pH change needed for uncoating → RNA not released into cytosol
HIGH RESISTANCE with mutation in proton channel - NOT USED ANYMORE
Amantadine and Rimantadine are administered _______ and accumulate in ________
orally, accumulate in the lungs
Amantadine is excreted _________
Rimantadine is excreted ___________
both can be excreted _________
in urine
hepatic elimination
in breast milk
Acyclovir and Valacyclovir are used to treat ________. They both must be activated by ___________ in order to __________ and _________
Herpes viruses (VZV, HSV)
phosphorylation by VIRAL THYMIDINE KINASE
inhibit viral DNA polymerase and act as chain terminators
Acyclovir
administration
excretion
topical and IV formulations, oral absorption poor
Renally excreted
Valacyclovir
administration
excretion
prodrug of acyclovir - given orally
renally excreted
Orally administered drugs used to treat Herpes virus are effective for…
shorten duration of pain in primary and recurrent genital herpes
Topical less effective
For VZV can decrease number of lesions and duration of chickenpox and shingles (requires HIGH dose)
IV administration of drugs used to treat Herpes virus are effective for…
used for herpes simplex encephalitis, neonatal HSV infections, or serious HSV or severe VZV infections (immunocompromised)
Adverse reactions associated with Acyclovir and Valacyclovir
headache, nausea, vomiting, reversible renal dysfunction
Docosanol (Abreva) used to treat ______ by inhibiting ___________
herpes virus
viral penetration/entry into cell - inhibits fusion between plasma membrane and HSV envelope
You must adjust the dose of Acyclovir and Valacyclovir in who?
Renal patients and neonates
RENALLY EXCRETED!
