Pathology: ID & Micro (Viruses)

Pathology of Viral Infection .................................................................................................................................................... 2

Negative Strand Viruses .......................................................................................................................................................... 5
The Herpesviruses ................................................................................................................................................................. 10

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 Pathology of Viral Infection
Pathogenesis: how viruses cause disease in the host VIRAL STRATEGIES HOST DEFENSES
 Viruses: too small to examine with a light microscope like  Rapid replication  Barriers to viral entry
bacteria. Have to look for patterns in path.  Mutation  Innate immunity
 Virulence genes  Adaptive immunity
Viruses are obligate intracellular parasites
 Genome: RNA or DNA
 Must enter intact host cell; use host to synthesize components
 Progeny virus = virions are assembled in cell, can spread to another cell
 Each class of virus has specific host cells (species and often tissue specific)

Many similarities in viruses that have similar classification; similar symptoms Taxonomy:
even across species (good for animal models) 1. nucleic acid (DNA/RNA; +/-, ds/ss)
2. capsid (symmetry of protein shell:
Typical life cycle: entrygenome exposure  genome replicationmRNA icosahedral/helical)
synthesis  protein synthesis  assembly (viral proteins/virions) release 3. envelope (lipid membrane,
infection of new cell naked/enveloped)
4. dimensions of virion / capsid
Budding: enveloped viruses take part of the host cell membrane with ‘em.

Patterns of disease: vast majority of infections are subclinical. See chart (dark sections = viremia; can detect in blood )
 Acute (rhino, rota, influenza)
 Persistent (lymphocytic choriomeningitis v.)
 Latent/reactivating (herpes)
 Slow (HIV, measles)

Virulence: ability to cause disease (=pathogenicity)

 Polygenic control: different genes control
binding/entry/replication/effects on cells
 How does it enter/spread? Why in certain
cells/tissues? How does it cause damage?
How does immune system cause indirect
damage? How does it go to a new host?
 Can measure as: mean time to death (animal
models), viral load, T-cell counts, other
measures specific to pathogen.
Virulence classification
 Virulent: causes disease;
 Attenuated: no/reduced disease
 Avirulent: no disease

Types of viral virulence genes: studied with tissue culture & animal models + mutations
1. Viral replication: herpesviruses’ DNApol brain only; poliovirus 5’ NCR mutated so not in brain
2. Defeat host defense:
o virokines (viral equivalent of chemokines, subvert immune response),
o viroceptors (tie up host chemo/cytokines)
o not required for growth in vitro but help out in vivo
3. Promote virus spread within/among hosts: gD protein in HSV1 recognizes cell receptors; pt mutation blocks CNS spread
4. Toxic gene products: cause cell injury directly (virotoxins), cause Cl secretion (osmotic diarrhea), etc.

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Tropism: virus has to enter the cell (susceptibility) and then replicate inside it (permissivity)
 Neurotropism, Pneumotropism, Enterotropism: or all (pantropism)

Viral receptors: required for viral entry; determines tropism (host & tissue), some also need co-receptor, active process
 E.g. HIV-1: two tropic strains depending on co-receptors
o T-cell-line-tropic strain (CD4 + CXCr4 co-receptor)
o Macrophage tropic strain (CD4 + CCr5 co-receptor)
 Receptors can be integrins, Ig-like molecules, GAGs, CHOs
 target for treatment & protection (e.g. CCR5 antagonists in HIV Rx)

Spread: direction of release determines infection pattern (superficial or down deep?)

 local replication (influenza through respiratory epithelium; papilloma through skin)
 systemic spread (must cross basement membrane, etc.)

Viremia: viruses can be carried to blood & disseminated

 often within cells: monocytes (measles, HIV, CMV); lymphocytes (HIV, EBV, HHV), neutrophils (influenza) or free in
plasma (poliovirus, HBV). In cells is a good way to circumvent BBB
 Can disseminate through lymphatics too

TRANSMISSION HOST DEFENSES EXAMPLES

Hand-shaking Mucociliary apparatus URT: Rhinovirus, coronavirus,
RESPIRATORY parainfluenza virus, RSV, influenza
Coughing Alveolar Mφ LRT: adenovirus, parainfluenza, RSV,
SYSTEM
Sneezing Adaptive immune response influenza virus
Eating Stomach pH, Digestive enzymes
Rotavirus, reovirus, measles,
GI TRACT Drinking Flow of ingesta poliovirus, adenovirus
Poor hygiene Adaptive immune response
Urine flow
Sexual activity Thick epithelial layer HIV, HSV (lifelong persistent/latent)
UROGENITAL TRACT HPV: cervical cancer
Fecal contamination Acid pH
Adaptive immune response
Conjunctiva Tears
EYES Abrasions Thick epithelial layer HSV: lifelong persistent/latent
Direct inoculation Adaptive immune response
Cuts, abrasions Poxviruses, papillomaviruses, rabies,
Epidermis Insects: togaviruses/alphavirues
SKIN Insect bites Emerge from below: systemic
Skin oils
Needles infection: measles, chicken pox
Cuts, animal bites; Inhalation
Rabies, herpes simplex, HIV,
NERVOUS SYSTEM Cell trafficking (retrograde transport Blood-brain barrier measles, alphaviruses
up axons to DRG/CNS)

Types of Viral Damage to Tissues

Cytopathic effects (cyto=cell, pathic = abnormal): can be in vivo or in vitro; NOTE: not all viruses produce CPE
1. Cell swelling: bloating of cells
2. Necrosis:
a. ballooning degeneration from membrane injury Cytopathic effects
b. host protein/nucleic acid synthesis shuts down 1. Cell swelling
c. Cell death (pyknosis, hypereosinophilia) 2. Necrosis
i. Single cell necrosis 3. Apoptosis
ii. more widespread (depending on virulence of pathogen) 4. Inclusion bodies
d. Lysis / detachment allows virion release 5. Syncitia/multinucleated
e. Tissue architecture disrupted (caseous or coagulation) giant cells
f. Vesicles can form (necrotic cells, fluid-filled space under epithelium) 6. Cellular hyperplasia /
proliferation 3
 g. Can cause malformations during fetal development
3. Apoptosis:
a. Some viral genes promote apoptosis (aid in virus dissemination)
b. Some inhibit apoptosis (longer replication, establish latency)
c. Some do both (HIV’s “Tat”) depending on context.
4. Inclusion bodies: arrays/aggregates of viral/cellular products
a. Often present only very early in infection
b. Intranuclear and/or intracytoplasmic
c. Can be eosinophilic, basophilic, or amphophilic
d. Usually > ½ diameter of cell
e. Can see peripheralization of chromatin in big inclusions; some look like owl’s eyes
f. Not pathognomonic but a signature microscopic finding, good for aiding in Dx
i. Not all viral: e.g. bismuth inclusions in liver
5. Syncitia/multinucleated giant cells
a. Viral fusion proteins expressed on cell surface  cells fuse together (in vivo/vitro)
b. Allows virus transmission without exposure to host defenses
c. Differentiate from: foreign body giant cells, osteoclasts, megakaryocytes
6. Cellular hyperplasia/proliferation
a. Self-limited & transient usually but may be PRE-NEOPLASTIC
b. May be due to atypical differentiation or accumulation of viral products
c. E.g. molluscum contagiosum, pox virus, EBV burkitt’s lymphoma, HPV cervical carcinoma

Alteration of host cell functions leads to the visible cytopathic effects – can also alter other functions (cytoskeletal
depolymerization, for instance)

Host Responses

Classic: MONONUCLEAR CELL INFILTRATES (LYMPHOCYTES, lymphocytes, lymphocytes… and macrophages)

 Exception: arbovirus can produce PMN response

HIV encephalitis (somewhat general features of viral incephalitis)

 Microglial nodules (collection of macrophages)
 Perivascular cuff of lymphocytes & macrophages
 Multinucleated giant cells (macrophages fuse; full of virions)

Virus-induced immunopathology: can be CD8 or CD4 (Th1 or TH2) T-cell mediated, antibody mediated, etc.
 Can result in immune deposits in glomeruli & cause pathology there

Host susceptibility can vary:

1. Genetic:
o MHC class I diversity: different ability to present peptides;
o Chemokine receptor tropism (HIV elite suppressors); other genetic polymorphisms for different viruses
2. Non-genetic:
o Age (infants/elderly usually)
o Gender (males, pregnant women more susceptible)
o Malnutrition (measles: protein deficiency)
o Other: corticosteroids, cig smoking, stress, etc.

Why study this stuff? Viruses are constantly emerging and re-emerging; classes tend to cause similar diseases, so if we
study something we’ve seen before, we might be better prepared when something new emerges.

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 Negative Strand Viruses
Positive vs Negative strand viruses
 Negative strand: antisense genome, polymerase included with
incoming virion; first step is to make a + strand (full length
antigenome)
 Postive strand: sense genome, no polymerase included with
incoming virion; polymerase synthesized as first step via
genomic RNA translation
Influenza Viruses
Key features of Negative Strand Viruses
 RNA is not infectious
 Virion contains RNA-dep-RNApol
 Encapsidation: Genomic RNA
packaged in protein (“nucleocapsid”)
 Nucleocapsids have helical structure
 Enveloped virions
 Entry: virion fusion or cell-cell fusion

3 types: A, B, C
 A/B antigentically distinct, structurally similar
 Both cause dz in adults and children
 A more prevalent than B
 Influenza A: ducks, chickens, horses, swine
o Birds = largest reservoir

Transmission:
 Birds  pigs, other non-humans (rarely humans
with some exceptions)
 Pigs  Humans is most common

Virion: structural features

 Major genes: HA, NA, M2
 Segmented genomes (1-3 genes/segment; HA & transcription complex on separate segments)
 Lipid envelope with viral glycoproteins (HA/NA)
o Envelope fuses with host lysosome membrane to allow genome to enter cell

Reassortment: Antigenic shift: possible mechanism

1. 2 strains infect same cell (e.g. two swine strains in a pig cell) 1. chicken strain / human strain
2. All genome segments replicate infect a pig,
3. When virus assembles, mixing of segments happens  reassortant 2. reassortant virus results with:
progeny viruses a. chicken strain antigens
(evades human defense) and
b.human strain machinery
(replicates in humans)
Hemagglutinin
3. pandemic strain can result
 16 antigenic types (flu A, H1-14); trimer with globular head on stalk
 Functions:
o binds sialic acid
o binds and agglutinates RBCs (have sialic acid)
o mediates fusion of viral envelope with cell membrane
 Targeted by neutralizing antibodies: keep virus from binding to host cells
 Minor mutations result in antigenic drift: year/year variation, causes seasonal epidemics
 Replacement with gene from alternate hosts results in antigenic shift (causes pandemics)

Mechanism of entry:
1. virus binding (HA/sialic acid)  endocytosed 
2. low pH induces conformational change in HA in endosome  hydrophobic AAs in HA exposed 
3. fusion of envelope with endosome membrane  release genomes into cytoplasm
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HA – needs cleavage for activity:
 synthesized in pro-form; needs cleavage for conformational change/activation of fusion function
 cleaved by tryptase Clara, serine protease secreted by nonciliated Clara cells in bronchial/bronchiolar
epithelium (lumen of respiratory tract; may account for restricted location of virus replication)
 happens at defined site (R/K); both HA fragments remain bound together (dipeptide linkage)

Neuraminidase
 Tetramer; 9 recognized subtypes in influenza A (N1-9)
 Cleaves sialic acid residues on cell surface during virus exit; if mutated, can’t exit cell surface

Nomenclature: Type / # of isolate / year of first isolation / HA&NA subtypes

 Example: A/Hong Kong/156/97
 H1N1, H3N2 currently circulating (usually 1-2 for seasonal epidemics)

M2 protein
 Tetramer, spans viral envelope, activated via acidity of endosome
 Pumps protons into virion: loosens protein-protein contacts, facilitates virus uncoating
 Target of amantadine

Replication
 Genome replication happens in nucleus
o No mRNA capping/methylating enzymes, so steals caps (+10-13nts) to prime mRNA synthesis
 Viral mRNAs translated on sER & rER
 HA/NA transported through Golgi to cell membrane,
 Glycoproteins (HA/NA) aggregate on surface of cell membrane, viral proteins & genomes aggregate underneath,
and the virus buds off, coated in an envelope

Location: ciliated columnar epithelial cells in respiratory tract; causes tracheobronchitis

 Lots of virions  shed into respiratory tract (better transmission)
 Virus-induced apoptosis of infected cells, damages respiratory tract
o Protective mucus layer disrupted
o Respiratory epithelium denuded
o Transudates / exudates (inflammatory cells, dead epithelial cells)

Clinical features: Respiratory, seasonal (winter) transmission

 1-4d post-infection: H/A, fever, myalgias, non-productive cough, sore throat, no rinorrhea (3-7d)
o Sx: local production of IFN & IL-1 (localized cell destruction b/c of immune response)

Immunity
 Innate resistance: mucus barrier, clearance by cilia, alveolar Mφ
o Impairment in any of these: ↑ risk infection (elderly, smokers, COPD, immunocomp, pregnant)
 Adaptive immunity:
o Protection: IgA (mucosal), IgG (serum)
o Clearance: IgG + complement, CTL

Complications:
 Primary virus infection: Interstitial pneumonitis
o Cardiovascular dz; pregnancy predispose
o Progression from classical 3d sx  bilateral findings, no consolidation

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 o CXR: bilateral infiltrates
o Non-bacterial: normal flora in sputum, no Abx response (high mortality)
 Secondary bacterial pneumonia:
o from damage to innate immune system, destruction of ciliated epithelial cells, abnormal Mφ function
o Age > 65yo, pulmonary dz predispose
o Improve, then worsen; consolidation
o CXR: consolidation
o Bacterial: sputum shows S. pneumo, S. aureus, H. flu, Abx response (low mortality)

Immunization
1. Killed/inactivated vaccine (mostly HA/NA)
a. Reformulated annually (WHO isolate/IDs viruses, reports strains to reference lab, panel makes rec)
b. Health care workers, populations at high risk of morbidity & mortality
c. Partial protection: incidence ↓ 30-70%, morbidity/mortality ↓ 60-90%
2. Live attenuated intranasal (FluMist)
a. Replication restricted to nasopharynx: cold-adapted (grows best @ intranasal temp); restricted
replication at 37C)
b. Reformulated annually; approved for use in healthy people 5-49yo

Diagnosis
 Direct detection (stain NP aspirates with flu-specific mAb), culture

Paramyxoviruses
General characteristics:
 No epidemiologically important antigenic change Paramyxoviruses: medically important
 No natural reservoir: constant person-person spread 1. Parainfluenza 1-4
2. Respiratory Syncitial Virus
 Spread: respiratory route
3. Human metapneumovirus
 Various proteins: H (receptor binding), F (fusion), M (assembly),
4. Measles
others too.
5. Mumps
 Genome nonsegmented, mRNA generated by polymerase
reinitiation at different promoter regions.

Surface glycoproteins: CHO attached during ER/Golgi transit; usually 2 proteins

1. Cell attachment: binds cellular receptor, elicits neutralizing Ab
2. Fusion protein (F): must be cleaved to F1/F2 by intracellular proteases to be active; required for virion
infectivity (happens only at neutral pH)

Replication cycle:
1. fuse @ neutral pH  intracellular replication (all RNA in cytoplasm, H/F  ER/Golgi  PM)
2. exit: nucleocapsids assemble underneath H/F; virion assembly mediated by matrix protein
a. Virion budding from cell membrane
b. Fusion with adjacent cell (surface proteins fusogenic @ neutral pH)
i. Leads to GIANT CELLS & syncitia formation

Respiratory Syncytial Virus (RSV)

 Outbreaks of respiratory disease in winter
 Transmission: direct contact with respiratory secretions (not aerosolized)
Clinical presentation:
 Otitis media, bronchitis, bronchiolitis, croup (inspiratory stridor), pneumonia
o Most severe in young infants; partial immunity after primary infection (less severe disease)
 Can progress: cough, wheezing, dyspnea, ↑ RR, hypoxemia
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  1% infants require hosp, 1% of those die
Diagnosis:direct staining of NPAs with fluoro mAB, culture
Vaccine: under development

Human Metapneumovirus
ID’d Netherlands 2001 from respiratory specimens from 20+ yrs; cytopathic effect similar to RSV (syncytia),
 Most infections: childhood (<5yr)
 Causes 7-40% ped resp infections
 Parallels to RSV:
o seasonal (winter), initial exposure in childhood, severe dz in infants/elderly
o range of clinical sx: mild respiratory symptoms to severe cough, bronchiolitis, pneumonia
o repeated infections occur but less severe dz (URI only)
Dx: RT-PCR, Ab for direct-detect

Parainfluenza
 Common cause of URIs
 Most common cause of croup (laryngotracheo-bronchitis) in young children
 Most children: infected by 5 yo, can be re-infected by less severe
 Diagnosis: culture; vaccine not yet available

Measles
 Worldwide distribution; incidence varies with vaccination rates
o Epidemic if high vaccine coverage; Endemic if low
 Age: changed with countries with high vax rate
 Transmission: Respiratory & Aerosol
o Attack rate: 99.9% (only 1:1000 escapes infection if exposed!)
o Mortality rate: developing countries, 30% in infants 6-9mos

Pathogenesis: Systemic replication

1. Respiratory epithelium  local lymph nodes  dissemination via infected monocytes from resp LNs
a. Primary viremia (LOW) from this first dissemination
2. Epithelial / endothelial cells infected throughout body, release virus into blood
a. Secondary viremia (HIGH) from this second dissemination

Clinical Symptoms: happen during viremia

 Prodrome: fever, cough, coryza (sx of head cold), conjunctivitis, Koplik spots (in oral mucosa: red dot & white
clearing around it, virtually pathognomonic)
 Maculopapular rash with immune response (virtually diagnostic): cellular response
o Immune responses: CD4 help, CD8 clearance, IgM, neutralizing IgG

Measles-induced immune deficiency

 Generalized immunosuppression; increased susceptibility to secondary infections
 Multiple mechanisms:
o Early: lymphopenia (activation-induced cell death, apoptosis of infected cells)
o Middle: delayed DTH, decreased lymphoproliferation
o Late: thymus effects?
Diagnosis: clinical picture, direct mAb stain of resp secretions, culture, serology (IgM)
Prevention: live attenuated vaccine (infants 2-15mo)
 has changed age distribution (now very young infants and older children/young adults 10-22yo)

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 Mumps
Infection of glandular epithelial cells
 Parotitis & orchitis most commonly recognized (big swollen jowls or testicles; mumps gives ya bumps)
 Pancreatitis/ovarian infection occur but infrequently recognized
 Meningitis 10% all cases
Diagnosis: Culture (saliva, urine, CSF); serology, molecular methods now
Prevention: live attenuated vaccine

Rhabdoviruses
Rabies is only important human pathogen
 Incidence: depends on control of domestic animals (better in US than developing world)
 Endemic in wildlife: bats, raccoons, skunks, coyotes, foxes
 < 10 cases / yr in US; mostly imported or contact with rabid bats

Pathogenesis:
1. in saliva of bite of infected animal  limited replication in muscle, subepithelial tissue
2. uptake by sensory/motor neurons; retrograde transport to cell body & major replication there
3. trans-synaptic transmission: early avoidance of immune reponse

Prodrome: fever, malaise, parasthesias at bite site

Later (in CNS now): anxiety, aggressive behavior, seizures, hypertonia, paralysis

Diagnosis: clinical Hx of exposure, biopsy, immunohistochemical staining, PCR

Prevention: inactivated vaccine
 Long incubation period allows for post-exposure use
 Pre-exposure if in vocation with high risk of exposure: vet, wildlife managers, etc.

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 The Herpesviruses
Note that these are in the same family as EBV, HHV8, etc. which cause cancer (previous lecture)

Common features: similar morphology, ubiquitous, asymptomatic infection, common modes of replication / life cycles
 ALL establish LATENT infections ≪ notorious feature of herpesviruses; Reactivation can produce disease
 Seroprevalence: extremely high in young adults (latent & lifelong)
o HHV8 is the only rare one

Physical characteristics:
 Enveloped, have nucleocapsid with genome woven into protein coat
 Gargantuan genome (>100k, 50+ genes)
1. Enzymes & structural genes
2. Non-structural genes too: modulate host cell gene expression, host immune responses

Infection: 2 “modes”
1. Productive (“lytic”) infection: release of progeny virions
2. Latent infection: no virions produced, reservoir for recurrent disease
a. Recurrent disease results from:
renewed replication or induced cell proliferation (tumor-inducing γ-herpesviruses only)
Lytic infection:
1. Viral entry (envelope fusion  nucleocapsid transported to nucleus 
2. Gene tx, genome rep, progeny nucleocapsid assembly in nucleus 
3. Nucleocapsids bud from nucleus – viral envelope is formed from nuclear membrane (unusual)! 
4. Release via exocytosis
TEMPORAL CASCADE OF LYTIC INFECTION GENE EXPRESSION
Genes Functions
Although latent infection has restricted cell tropism (see
α (immediate early) regulators of viral gene expression
comparison table), knowing where the virus “hides out”
β (early) proteins for genome replication
during latency is important (see slide on right)
γ (late) viral structural proteins
Transmission:
LYTIC INFECTION LATENT INFECTION
Natural modes: “mixing & matching of skin & mucous
membranes” Lots, temporal
 skin, genital tract: HSV-1/2 GENE EXPRESSION cascade (see Restricted
 oral secretions: HSV-1/2, CMV, HHV-6, EBV table)
INFECTED CELL TYPES
 respiratory tract: VSV (weird) Many (≥2) Few (1-2)
(TROPISM)
Iatrogenic modes
VIRION PRODUCED? Yep Nope
 transfusion (e.g. CMV, hiding in monocytes)
 transplants

Disease manifestations:
 Low severity: Recurrent infections, immune competent
 High severity: Primary infections, immune impairment
o Populations with severe infections:
immunodeficient (HIV, etc.),
immunosuppressed (transplant pts, cancer pts),
fetuses/newborns, malnourished pts, burn
victums
o Use prophylactic antibiotics when indicated; high index of suspicion to dx/treat

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 Herpes Simplex Virus Diseases
Most common presentations: herpes labialis & genital herpes

Pathogenesis
1. Transmission: skin/skin or mucous
membrane/mucous membrane contact
2. Primary infection: epithelial cells (productive)
3. Retrograde transport up axon
4. Secondary infection: sensory neuron cell body
(latent)
a. Orolabial: trigeminal ganglia
b. Genital: sacral ganglia
5. Reactivated(stress, illness, UV light)
6. Anterograde transport down axon
7. Recurrent infection: epithelial cells (productive)

Genital herpes infections: mostly HSV-2 (20-50% HSV-1)

Oral herpes infections: mostly HSV-1 (5-20% HSV-2)
(Note that it’s not “1 above the waist, 2 below” like people think)

Reactivation can be symptomatic or asymptomatic (1-5% Asx in orolabial, 3% Asx in genital)

 Still shedding during Asx reactivation! Good way to spread

Clinical presentations (non-genital herpes)

1. Primary gingivostomatitis (lesions on gums, oral cavity, lips)

2. Herpes Whitlow (from sucking thumb – lesion on end of finger)

3. HSV keratitis: #1 cause of infectious blindness in developing world; dendritic ulcers in eye
2 mechanisms of pathogenesis
o Autoinoculation (orolabial, spread to eye)
o Trigeminal nerve ophthalmic root infection (after ganglion reactivation)

4. Neonatal herpes: 1/3500-5000 deliveries, Neonatal Herpes: 3 syndromes

o transmission through infected birth canal (rarely placental) 1. Skin, eye, mouth (SEM): 40%.
o Most women asymptomatic during labor Usually not fatal but recurs;
o Presentation: first 1-2 wks life; 3 syndromes (see box) 30% w/ neuro sequelae
o Vesicles: can’t use to rule in/out (SEM>CNS>disseminated) 2. Encephalitis:35%
3. Disseminated: 25%
5. Herpes encephalitis:
o most common acute, sporadic encephalitis (10-20% cases)
o Primarily HSV-1
o Classic presentation: fever + focal neuro defects (temporal lobe: memory, mental status)

Genital Herpes
TRANSMISSION IS COMMONLY UNRECOGNIZED
 Asymptomatic shedding is common Epidemiology of genital herpes
(70% acquired from asymptomatic partner)  500K cases/yr in US; 40-60M prevalence
 Primary infections are often asymptomatic  Correlated to number of sexual partners
(80-90% infections unrecognized!)  Women > Men for susceptibility
 Factors unknown (shedding rates don’t impact transmission!) (unknown why, 8% vs 2% /yr)
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Recurrence
 Recurrence w/ Sx can occur after years of “silent” infection; don’t assume infidelity!
 Symptoms less severe than primary (shorter shedding duration, fewer lesions)
 Frequency: 90% have >1 recurrence / yr, 40% >6, 20% >10
Acyclovir & Genital Herpes
 Factors that affect recurrence:
 Reduces recurrences
o time since acquisition (shedding declines 70% over 10 yrs) (w/Sx by 75%, Asx too)
o virus type (HSV-2: more, more severe recurrences than HSV-1)  Reduces transmission
o immune status (immunocompromised = more frequent (50%)
recurrence)

Varicella-zoster Virus (VSV)

Primary infection: Varicella (chicken pox) Recurrent infection: Herpes zoster (shingles)
“dew drop on rose petal” lesions Reactivation in sensory ganglion
(glistening vesicle, red base) Lesions localize to innervated dermatome

Causes severe disease in: Immunocompromised pts:

1. Teens/adults  can disseminate (bad) & spread epidermally
o At risk for varicella pneumonia  ≥ 2 dermatomes
2. Immunocompromised/newborns  Across midline
o life-threatening pneumonia
o encephalitis Disseminated zoster infection: everywhere
o progressive/disseminated varicella

Cytomegalovirus
Usually asymptomatic but can cause disease:
CMV Mononucleosis 80-20 rule (wards)
 20% of mono (EBV = 80%) If common: say 80%
 Frequent manifestation of primary CMV infection in young adults If uncommon: say 20%
 Fever, lymphadenopathy, lymphocytosis without exudative pharyngitis
o EBV = sore throat, CMV = usually not
 HETEROPHIL ANTIBODY NEGATIVE: monospot test will come up negative! (unlike EBV)

Congenital infection
 Most common congenital viral infection
 Severity depends on maternal serostatus in pregnancy
o Primary maternal infection: severe symptoms ~25% births
 Jaundice, hepatosplenomegaly, petichial rash, cerebral calcifications, chorioretinitis, motor disability
 20%: late onset hearing loss
o Reactivation during pregnancy: usually asymptomatic at birth
 but 15% with late onset hearing loss!

Special populations (solid-organ/bone marrow transplants; leukemia/lymphoma pts, AIDs pts with low CD4)
 HIV: reactivation/disease when CD4 < 50 (uncommon with HAART)
o Retinitis, encephalitis, colitis with ulcers
 Bone marrow transplant: commonly pneumonia (prophy with ganciclovir)
 SOLID ORGAN TRANSPLANT: huge problem!
o Usually manifests as disease in allograft
 liver = CMV hepatitis, lung = CMV pneumonitis (renal ≠ nephritis though)
o Highest risk: CMV seronegative recipient and seropositive donor

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 HHV-6 and -7
Roseola infantum (exanthum subitum): rash-like illness in young kids & transplant patients
 Can see febrile seizures, other sx possible, may contribute to HIV disease progression & exacerbate other viral dz
 Erythematous rash

Herpesvirus diagnostics
 Viral culture (HSV from all sites except CSF, makes it hard to culture for HSV meningitis!)
 Rapid antigen detection from lesions
 PCR for nucleic acids (including CSF)
 Antibody detection: limited utility except mono & to identify high risk pts for transplants

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