Holland: Skin and Soft Tissue Infections II Flashcards
HERPESVIRUSES:
General:
Fall into 3 subfamilies based on genetic and biological properties:
Over 100 herpesviruses known; 8 are considered human herpesviruses
Alphaherpesviruses
Betaherpesviruses
Gammaherpesviruses
HERPESVIRUSES
Subfamilies:
Alphaherpesviruses (3 or 4)
Betaherpesviruses (4)
Gammaherpesviruses (2)
Alphaherpesviruses: o HSV 1 o HSV 2 o VZV o Note: B virus, a monkey alphaherpes virus, can infect humans (ie. via a bite); usually results in fatal encephalitis
Betaherpesviruses: o CMV o HHV-6A o HHV-6B o HHV-7
Gammaherpesviruses:
o Epstein Barr Virus (EBV)
o HHV-8/Karposi’s sarcoma associated herpesvirus
Herpes Simplex Infections (HSV)
Incubation Period:
Primary Infection:
Recurrent Infections:
Incubation Period: 4-5 days on average (can be longer or shorter)
Primary Infection: takes ~2 weeks to run its course
Recurrent Infections: are typically shorter and involve fewer lesions
Gingivostomatitis OR
Orofacial Herpes OR
Herpes Labialis (recurrent form) OR
“Cold sores”
Typical age:
Frequency:
Usual severity:
Type:
Typical age:
Primary Infection: child/adolescent
Recurrent: any age
Frequency:
Very common
Usual severity:
Mild (asymptomatic) to moderate (infection with painful lesions)
Type:
1>2
Genital Herpes
Typical age:
Frequency:
Usual severity:
Type:
Typical age: Once sexually active
Frequency: Common
Usual severity: Moderate to severe
Type: 2>1
Keratoconjunctivitis (ocular infection)
Typical age:
Frequency:
Usual severity:
Type:
Typical age: Any
Frequency: Fairly common
Usual severity: Moderate to severe (can penetrate stroma and cause blindness)
Type: 1
Dermatitis (other than face or genitals)
Typical age:
Frequency:
Usual severity:
Type:
Typical age: Any
Frequency: Uncommon
Usual severity: Mild
Type: 1 or 2
Encephalitis
Typical age:
Frequency:
Usual severity:
Type:
Typical age: Any Frequency: Rare Usual severity: Severe (over 50% death rate; those that don’t die have severe SEs) Type: 1 or 2 (in neonates) 1 (everyone else)
Disseminated HSV
Typical age:
Frequency:
Usual severity:
Type:
Typical age: Any (associated with immunosuppression)
Frequency: Rare
Usual severity: Severe
Type: 1>2
Neonatal Herpes (from infected mother during/after birth)
Typical age:
Frequency:
Usual severity:
Type:
Typical age: Newborn
Frequency: Uncommon
Usual severity: Severe (disseminates because immune system not developed yet)
Type: 2>1
Herpevirus Latency (General): Definition: Mechanism:
Definition:
- Continued presence of viral genome
- Absence of viral replication and viral particles
Mechanism:
- Lytic cycle genes not expressed during latency
- Latent virus can reactivate, causing recurrent disease or subclinical virus shedding (most common reactivation); latent viruses last lifetime of host
Which herpesviruses establish latent infections?
Primary herpesvirus result in:
All
Primary herpesvirus infections always result in latent infections
(However, different herpesviruses establish latency in different cell types)
HSV Latency (Specifically):
Entry into nerve cells:
Transport to nerve cell body:
Virus replication:
Entry into nerve cells: at primary site of infection
Transport to nerve cell body: in ganglion; via retrograde transport
- Oral infection (trigeminal ganglion)
- Genital infection (sacral ganglion)
Virus replication in ganglion: occurs for several days, followed by latency
HSV Reactivation:
Frequency depends on:
Stimuli:
Results in:
Frequency: depends on individual; ranges from never to monthly
Reactivation stimuli: often spontaneous; others include sunlight, menstruation, infections, compromised immune system
Reactivation results in: replication in ganglion and travel back down the axon, causing infection near site of primary infection
HSV Structure:
Large, enveloped, DNA virus (linear, dsDNA; 75-80 genes)
Icosahedral capsid
HSV Replication:
Entry
Gene expression, DNA replication, and Capsid assembly
Envelopment and release
Entry:
Primary and Secondary Route:
Primary Route: attachment to host cell via glycoproteins (on virus) and fusion of viral envelope with plasma membrane
Secondary Route: endocytosis followed by fusion with endocytic vesicle
Gene expression, DNA replication, and capsid assembly occurs:
Gene expression, DNA replication, and capsid assembly occurs in the nucleus.
Envelopment and Release:
How do capsids first acquire envelope?
Envelope fuses:
Capsid buds:
What release virions from the cell? How?
Capsids first acquire envelope by budding through inner nuclear membrane
Envelope fuses with outer nuclear membrane, and naked capsid released into cytoplasm
Capsid buds into vesicles from cytoplasmic membrane (acquires envelope again)
Enveloped virions release from cell via fusion of vesicles with plasma membrane
Antivirals Against HSV DNA Replication:
HSV encodes its own DNA replication system:
Steps of Activation (Phosphorylation):
How does triphosphate form inhibit DNA synthesis? (2)
HSV encodes its own DNA replication system:
DNA polymerase is the target for most anti-herpes drugs (most are nucleoside analogs)
Steps of Activation (Phosphorylation):
- HSV-encoded TK phosphorylates acyclovir (or other) to monophosphate-acyclovir
- Cellular kinases synthesize di- and triphosphate forms
Triphosphate form inhibits DNA synthesis by:
- Inhibiting viral DNA polymerase
- Becoming incorporated into DNA, resulting in termination of strand
Varicella-Zoster Virus
Primary VZV Infection:
Reactivation of Latent Virus:
Current vaccine:
Primary VZV Infection: typically manifests as varicella (chickenpox)
- Worse in adulthood than in children
- Latent infections established in dorsal root ganglia
Reactivation of Latent Virus: causes zoster (shingles)
- Incidence increases with age
Now use a live attenuated vaccine against VZV in the United States
Varicella
Portal of Entry:
Viremia: First, second stages Lesions appear where first? Lesion stages: Healing
Incubation Period:
Portal of Entry:
- Primary: upper respiratory tract (some replication occurs here)
- Secondary: fluids from vesicles containing high concentrations of infectious particles
Viremia:
- First Stage: spread to lymphoid organs (replication)
- Second Stage: spread to epithelial tissue (lesions) and respiratory tract (more transmission)
- Lesions appear on trunk first, spread outward (centrifugal spread)
- Lesion stages: macule, papule, vesicle, crusting
- Typically heal without scarring (unless secondary bacterial infection)
Incubation Period: 14-21 days
Zoster
Reactivation of latent VZV:
Lesions:
What is possible?
Reactivation of latent VZV: causes unknown; can happen more than once
Prodromal syndrome may exist: nerve pain/tingling before outbreak
Lesions: generally limited to skin/mucous membranes innervated by the reactivated ganglion (sharply demarcated areas)
Post-Herpetic Neuralgia is possible: persistent nerve pain after lesions disappear (can last for months)
Betaherpesvirus Infections:
• General:
Types:
Slow replication cycle (many days vs. ~24hrs for alphaherpesviruses)
Restricted host range and cell type specificity
CMV
HHV-6
HHV-7
CMV:
Causes cell enlargement (cytalomegaly)
Latent infections in cells of myeloid lineage
HHV-6:
How common?
T cell tropic?
2 subtypes:
Common: by 12 months of age, nearly everyone is seropositive for HHV-6
T cell tropic
2 Subtypes:
HHV-6A: not associated with disease
HHV-6B:
- Establishes latency/replicates in monocytes and macrophages
Primary HHV-6B- Exanthem Subitum (Roseola):
Common? Age? Incubation period: Transmission: Symptoms: Complications
- Common childhood infection
- Incubation Period: 5-15 days
- Transmission: saliva?
- Symptoms: fever (3-5 days), rash developing over trunk/face and spreading to limbs as fever diminishes
- Possible Complications: very high fever, neurological symptoms (convulsions, aseptic meningitis), hepatitis, mononucleosis-like syndrome
HHV-7:
- Also T cell tropic
- Establishes latency in T cells
- May also cause exanthem subitum (roseola)
Gammherpesvirus Infections:
Epstein Barr Virus (EBV)
HHV-8/Karposi’s sarcoma associated herpesvirus
Epstein-Barr Virus:
- B cell tropic
- Latent in B cells
HHV-8 (Kaposi’s Sarcoma Associated Herpesvirus)
Prevalence:
Associated with many forms of cancer (3):
Prevalence: sub-Saharan Africa and Mediterranean regions (rare elsewhere, besides in HIV-1 patients)
Associated with many forms of cancer:
o Kaposi’s Sarcoma:
o Body cavity based lymphomas
o Multicentric Castleman’s Disease (lymphoid hyperplasia)
Kaposi’s Sarcoma: (4)
Classic KS:
- Slow progression (disease you die with, not from)
- Found in older men of Mediterranean descent
- Nodular/plaque-like dermal lesions (often on lower leg)
Endemic-African KS:
- More aggressive
- LN involvement
Iatrogenic KS:
- Caused by a medical procedure (ie. solid-organ transplant patients)
- Also more common in those of Mediterranean descent
Lymphadenopathic KS (HIV Positive Patients): - Disseminated and aggressive (involvement of internal organs, viscera, LN and skin)
HUMAN PAPILLOMA VIRUS:
General:
Structure
General:
- Virus Family: papovaviraidae
- Virus Subfamily: papilomavirinae
Structure:
- Small, DNA virus (circular, dsDNA; 8-10 genes)
- Nonenveloped icosahedral
HPV-16 Genome (Carinoma-Causing):
Composed of:
Transforming Genes:
Major Capsid Protein:
Gardasil Vaccine against types:
Composed of 8 genes (6 early, 2 late)
Transforming Genes:
o E6: destruction of p53 TSG
o E7: inactivation of Rb TSG (primary regulator of cell cycle)
Major Capsid Protein:
o L1 gene product
o Target of virus neutralizing Abs (active component of Gardasil HPV vaccine)
Gardasil Vaccine: against types 6, 11, 16, 18
Manifestations of HPV Infection
Cutaneous Warts (3):
Common Wart:
- Painless and hyperkeratotic (hypertrophy of striatum corneum)
- Round papules often occurring in groups
- Caused by HPV 2, 1, 4 and others
Plantar Wart:
- Painful, deeply set warts on weight-bearing surfaces of feet
- Caused by HPV type 1 (most commonly)
Flat Wart:
- Multiple flat, asymmetric, smooth papules
- Caused by HPV types 3, 10 and others
Manifestations of HPV Infection
Mucosal Warts (2):
Laryngeal, oral, conjunctivival papillomas: HPV 6 and 11 (most common)
Anogenital papillomas:
- External genitalia, anus and near external opening of urethra
- Types 6 and 11 most common (low risk for carcinoma)
- Types 16, 18, 31, 33, and 35 are relatively uncommon (highest risk)
- Risk for cervical, vulvar, penile and anal carcinoma
Manifestations of HPV Infection
Epidermodysplasmia Verruciformis:
Associated with a rare uncharacterized genetic disorder
Multiple flat wart-like lesions caused by unusual HPV types
Frequent progression to cancer in sunlight exposed areas
Clinical Outcomes of HPV Infection (4):
- Subclinical infection with viral clearance
- Latent infection with possible subsequent reactivation
- Development of warts/condylomas/low grade neoplasia
- Progression to high grade lesion/carcinoma/invasive carcinoma
HPV Pathogenesis:
Transmission
Infection
Process
Transmission: direct contact or transfer to/from inanimate objects
Infection: requires that virus reaches basal layer of epidermis; often requires minor injuries/breaks in skin to get access to these cells
Process:
o Hyperplastic growth of basal layer cells
o Expression of HPV late genes (capsid proteins) and virion production
o Mature virus contained in highly differentiated cells at the surface of the lesion (those in basal layer are not as differentiated)
HPV
Development to Cancer:
Normal Circumstances: virus replicates like an episome/plasmid in the nucleus, but does not integrate into host DNA
Molecular Accident Occurs: integration into host DNA, and cell undergoes excessive cell division
HPV Cervical Intraepithelial Neoplasia :
Stage 1, 2,3, Invasive Carcinoma
Stage 1: mild dysplasia in epidermis (less than 1/3); koilcocyte may be seen in higher layers
Stage 2: moderate dysplasia in epidemis (2/3s); koilcocyte may be seen in higher layers
Stage 3: severe dysplasia (entire epidermis)
Invasive Carcinoma: cells penetrate basement membrane and invade surrounding tissue
PICORNAVIRUSES:
• Structure:
- Very small
- Non-enveloped
- ssRNA (plus sense)
What type of picornaviruses cause infections of the skin/mucous membranes?
Coxsackieviruses, as well as Echoviruses and Enterovirus 71
Coxsackieviruses:
Cause infections of the skin/mucous membranes
o Herpangina: mainly oral lesions
- Associated with certain types of Coxsackie A virus, Coxsackie B viruses, and Echoviruses
- Mistaken for herpes
o Hand, Foot and Mouth Disease
Coxsackieviruses
Clinical Signs of Infection:
Prevalence:
Symptoms:
Lesions:
Resolution when compared to HSV:
Prevalence: most common in infants and children (often associated with epidemics- ie. outbreak at daycare; this is one way to differentiate from HSV)
Symptoms: fever, sore throat, headache, anorexia, lesions
Lesions:
- Arise within 2 days of symptoms
- Small, papulovesicular lesions on the tonsils, soft palate and tongue (can be confused with HSV lesions); enlarge within a day
- Lesions can also occur on hands, feet and diaper area (H,F and M Disease)
Resolution: more rapid than HSV (healing of lesions in 1-5 days)
