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1

Herpes Viruses
- related large enveloped DNA viruses

HSV1 - herpes Simplex Type 1 60-90% prevalence in young adults

HSV2 (15-30%)

VZV - Varicella Zoster Virus (shingles, chickenpox) (95%)

CMV - cytomegalovirus (birth defects) 30 - 80% - problem with immunocompromised and birth defects

EBV - Epstein Barr virus. (Mononucleosis) 90%

HH6 - human herpes virus 6 - roseola, cause xanthum, rash in children > 90%

HH7 not a real thing

HHV-8 - kaposi's sarcoma 5 - 10%

2

Common Feature of Herpes Virus

Enveloped/not

Proteins

Symptoms

Genome

Hallmark

- morphologically similar, enveloped

- many spike glycoproteins
- make about 100 proteins
- ubiquitous (except HHV-8)
- infection is often asymptomatic
- linear DNA genome; replicate in nucleus
- HALLMARK: all establish latent infections
- life long persistence in cells, reactivation can produce disease, frequently reactivates in immunocompromised host

3

Common features of herpes viruses: Replication

Productive (lyric) infection
- host cell supports virus growth
- viral genome replicated and viral proteins made
- complete progeny visions produced and released

Latent infection
- virus is 'hidden' inside a cell
- expression of viral genes restricted
- no virus particles produced
- reservoir for re-activation and recurrent infection
- reactivation triggered by fever, stress, menses, UV light, trauma immune suppression

4

Common Features: Cell types

During lyric infection, herpes viruses can infect many different cell types, usually > 2

But herpes virus establishes latent infection in a specific cell type (eg neurons or specific immune cells)
- EBV in B cells, HSV1 in neurons

5

Common Features: Spread

Close person to person contact: mixing and matching of skin and mucous membranes
- mouth and respiratory tract
- genital tract
- across placenta; during birth
- blood cells (Eg transfusions)
- transplants (eg solid organ and stem cell)

No seasonality or epidemic patterns

No animal reservoir

6

General Concepts in Herpes virus pathogenesis and disease

Primary infections more severe than recurrent infections that may occur months to years later becuase you have antibodies and immune response against them

Populations with severe infections
- immunodeficiency eg HIV
- immunosuppressed eg transplant recipients, cancer patients
- fetus/newborns
- malnourished
- burn victims

7

Treatment of Herpes Virus Infections

Two classes of drugs to treat HSV1, 2, VZV, and CMV

Acyclovir (Aciclovir) and its derivatives:
- valacyclovir
- famciclovir
- ganciclovir
- all basically the same- they are prodrugs - must be phosphorylated byviral thymidine kinase, incorporated into growing viral DNA chain, act as chain terminators
- mutations in viral thymidine kinase confers resistance because the drug doesnt get phosphorylated: if it doesnt get phosphorylated it wont resemble nucleotide and get incorporated into the DNA

Foscarnet - inhibits viral DNA pol
- used for acyclovir-resistant HSV and CMV
- used for CMV retinitis

No specific drugs for EBV, HHV6, HHV7, HHV8

8

Herpes Simples Virus 1

HSV1: respiratory spread in childhood; infect mucosal epithlium; latent focus in trigeminal ganglia; recurrences < HSV2

Encephalitis, conjunctivitis, gingivostomatis, tonsillitis, labialis, pharyngitis, esophagitis, herpes gladiatorum, tracheobronchitis, genital herpes, herpes whitlow

9

HSV2

Spread by intimate sexual contact

Infects genital mucosa

Latent in lumbosacral dorsal root ganglia

Recurrences > HSV-1

Meningitis, gingivostomatitis; tonsillitis; labialis; pharyngitis; perianal herpes; genital herpes, herpes whitlow

10

Common vs actual perception HSV1 vs HSV2

Common:
- HSV1 above waist, HSV2 below

Actual
- 20-50% of genital infections are HSV1
- 5 - 20% of oral herpes infections are HSV2

11

Gingivostomatitis:

HSV-1 > HSV2

- most common primary symptomatic infection HSV1 infection

- generally seen in children and young adults; 13- 30% of affected children

Prodrome of fever, malaise irritability, headache, vomiting, lymphadenopathy 1 - 2 days. Prior to lesions

Small vesicles on the inside of cheeks, gums, tongue, and mucous membranes of mouth that rapidly ulcerate with time 'dewdrop on a rose petal'

Ulcers are PAINFUL

Perioral vesicular lesions also observed

Strikingly swollen and tender gums

Latency in trigeminal ganglia (bc HSV1)

Recurrence = cold sore (herpes labialis) - oral recurrences more common after HSV1 than HSV2, usually a single crop, shorter lived
SEE PICTURE ON SLIDE 14

12

Genital herpes; HSV2> HSV1

Pic on slide 16

Most common primary symptomatic HSV2

Incidence > 500,000 cases/yr

Acquisition correlates with number of sexual partners

Women are more susceptible than men: 8% vs 2% annual acquisition rate

70% of cases are acquired from asymptomatic partner
- during active stage, disease contagious by direct contact, excretion of virus can persist for 3 weeks and virus shedding is frequently present in absence of symptoms (can transmit infection to sexual partners)

Antivirals and condom use reduce risk

HSV2 genital ulcers increase risk of acquiring and transmitting HIV1

10 - 21 days of vesiculoulcerative lesions, intense pain and fever, may be associated with malaise, itching and burning dysuria, inguinal lymphadenopathy

13

HSV2 ulcer disease increases risk of acquiring and transmitting HIV, how? acquiring and Transmitting of genital

Acquiring: ulcer offers an entry site for HIV and attracts CD4= T cells which support HIV replication

Transmitting: higher levels of HIV shedding occur in subjects with genital ulcers

14

Genital Herpes Recurrences

2/3

Reactivation from latently infected sacral ganglia

More likely after HSV2 than HSV2; immunocompromised vs immunocompetent

Symptoms less severe than primary disease
- shorter shedding duration, lack constitutional symptoms
- fewer lesions, heal sooner

Frequency rates of recurrences
- 90% will have > 1 recurrence per year, 40% will have > 6, 20% will have > 10

Recurrence severity: HSV2> HSV1

15

Herpes Keratoconjunctivitis

Slide 18

HSV1 infection of eye

#1 cause of infectious blindness in developed world

Severe conjunctivitis and keratitis with damage to cornea

Corneal transplants done to replace damaged cornea

Can get dendritic ulcers

16

Herpes Encaphalitis- primarily HSV-1

Most common acute caus eof sporadic encephalitis

Result of primary or severe recurrent infection

Classic presentation
- fever
- headache
- focal neurological deficits
- temporal lobe involvement
- if you see these Sxs and a temporal lobe lesion, think HSV and treat immediately

FOCAL FINDINGS ARE HALLMARK becuase the virus remains localized to one or more temporal lobes

Other findings: RBCs in CSF, CSF. Pleocytosis, behavioral changes, decreased level of consciousness

High mortality/morbidity if not treated

Treat with acyclovir class of drugs!

17

HSV Meningitis- Priimarily HSV2

Recurrent episodes of HSV meningitis

Usually caused by HSV2 from genital infections

Present with fever, headache, nausea, vomiting, photophobia, stiff nick - classic meningitis signs

Illness self limited and not life threatening unclear if acyclovir treatment is beneficial

Patients can be quite ill

In presence or absence of genital lesions

No permanent neurological sequelae

Recurrences can be separated by years

18

Other skin infections- mostly HSV1

Pics 21, 22

Traumatic herpes

Local lesions on fingers and hands (eg suck on thumb, Called hermetic whitlow - primary or recurrent infections in fingers and hands) and on bodies of wrestlers (mat herpes or herpes gladiatorum) and rugby players (scrum pox, or herpes rugbiaforum)

Virus enters through abrasions/openings in skin

HSV1 or HSV2

Seen in hospital personnel, dentists, dental hygienists
Young children form thumb sucking

HERPETIC WHITLOW

19

Infections in immunocompromised host - slide 23

Everything
- localized invasive skin infx
- extensive at usual sites (oral and genital) or unusual sites (within mouth, esopahgus, or intestinal mucosa)
- lesions progress slowly--> necrosis
- healing slow or negligible
- sever infection can also occur in persons with underlying skin disorders (eczema) or burns

20

TORCH INFECTIONS

T = toxoplasmosis
O = other (syphilis, HIV, VZV,, Parvo B10)
R = rubella
C = cytomegalovirus
H = herpes simplex

Infx cause congenital abnormalities including rash and ocular findings, if fetus exposed to them in utero

21

Neonatal herpes

HSV2

Transmitted through infected birth canal - most women asymptomatic

Occurs 1 - 2 weeks after delivery

Almost always symptomatic

Primarily (~75%) caused by HSV2

Three syndromes
- 45% skin eye mouth (SEM)
- 33% encephalitis (CNS)
-- 25% disseminated disease DIS

Occurrence of lesions: SEM (90%) > CNS (60%) > DIS (20%)

Babies may have disseminated disease without skin lesions, making diagnosis difficult

22

Varicella Zoster Virus (VZV)

Two distinct diseases

Primary varicella (chickenpox)

Recurrence: herpes zoster (shingles)

23

VZV pathogenesis

During primary infx, virus infects respiratory mucosa through oral cavity

Replicates in oral cavity and regional nodes

Primary viremia leads to replication in liver and spleen

Secondary viremia results in infection of lymphocytes that carry virus to skin and other areas

Latency established within sensory neurons of dorsal root ganglia

24

Varicella Epidemiology in US

Prior to vaccine in 1995
- all children infected by 10, highly contagious, complicated in infants < 1

After live attenuated vaccine 90% reduction in chickenpox cases
- two doses given to children at ages of 2 and between 4 and 6

25

VZV clinical symptoms

Incubation period 10-21 d

Prodrome: fever (100-103 F), malate, pharyngitis

Followed by generalized rash in 24 hours

Rash begins on chest back and face, spreads rapidly and lasts 3 - 5 days

Rash starts out maculopapular and then small fluid filled vesicles with central dimple (umbilication) on a red base; rash is itchy

All stages of rash present at any given moment- avg 300 lesions

Highly contagious at 1-2 days befor rash onset to 4 - 5 d after rash onset

26

VZV complications

Slide 30

Chickenpox generally self-limited

Bacterial superinfection of skin (Cellulitis) - renders of skin beginning near a lesion and spreading (staph or strep caused)

Encephalitis: VZV spread to cerebellum and cause unsteady gait (ataxia)

PNEUMONIA: majority of morbidity and mortality in teens and adults

Hepatitis

Congenital and perinatal infections (if fetus infected when mother develops chickenpox--> damage to infants Brian or infants born to mother with active chickenpox and can be life threatening)

Immunocompromised: everything more severe, life threatening pneumonia, encephalitis, progressive-disseminated varicella

27

When VZV reactivates--> Zoster(shingles)

Slide 31

Unilateral vesicular rash that follows a dermatome distribution following reaction of VZV in a single dorsal root ganglion

Rarely crosses midline

Rash involves thoracic and lumbar distribution; ophthalmic distribution can lead to serious eye infection

Post herpetic neuralgia: persistence of pain > 90 days after healing of rash in 20% of patients

28

Zoster epidemiology - VZV recurrence

Age is most important risk factor although anyone with prior primary VZV can get shingles

Incidence increases with age, dramatic increase after 50

Immunocompromised and underlying disorders are other risk factors

Zoster vaccine recommended in adults > 60 yo; reduces zoster by 50% and post herpetic neuralgia by 67%

29

Cytomegalovirus

Pic 34 l

Infx common and usually asymptomatic in healthy children and adults

Most adults infected

Large owls eye inclusions, giant cells with intranuclear owls eye inclusion

Clinical link CMV to congenital infections and immunocompromised individuals

30

What is the #1 congenitally acquired viral infection

CMV

31

CMV EPi

Infects humans of all ages

Seroprevalence increases with age, 50% by 30, 60-80% by 60

Prevalence peaks 2 - 5 (day care or school) and young adults (sexual)

Crowded living is risk factor

Routes of infection
- oral 30-70% infection rates in daycare
- sexual transmission
- blood transfusions (now blood depleted of WBC)
- organ transplantation - CMV-negative recipients at greatest risk for disease

32

Epidemiology of congenital CMV

C in torch

Leading infectious cause of birth defects

Primary: maternal infection poses much greater risk to fetus than reactivation

Infection in early pregnancy (first 12 - 16 weeks) poses highest risk to developing fetus

Infx in mother almost always asymptomatic, no warning the fetus is at risk

CMV infection detected in 1% of newborns and is most common identified infectious cause of birth defects

Risk of CMV transmission to fetus and rate of symptomatic fetal infection are much Ghiberti with primary maternal infection

In primary infection 90% of babies become infected and of those, many have congenital abnormalities

33

Clinical manifestations: congenital CMV

Slide 37

Petechial rash - blueberry muffin baby

CMV retinitis

Brain malformations
- periventricular calcification
- enlarged ventricles
- microcephalic
Leads to seizures cognitive deficits

Jaundice with hepatosplenomegaly

Hearing loss - can occur at birth if symptomatic CMV, can occur over first several years if infx asymptomatic

Even if no symptoms at birth can develop sensorineural hearing loss, visual impairment, psychomotor and or intellectual disabilities later in life

34

CMV in immunocompromised patients pic slide 38

HIV: reactivation with CD4 < 50 less common with HAART

Tranpslants

Any other immunosuppressed

Can get bad viral pneumonia, retinitis
Esophagitis with round solitary ulcer

35

CMV mononucleosis

Slide 39

Mononucleosis like syndrome

79% EBV, 21% CMV

Frequent manifestation of priamry CMV infx in young adult

Syndrome: fever 2 - 4 weeks, fatigue, mild h epatitis, lymphocytosis and small % of atypical lymphocytes in blood
- exudative pharyngitis frequently absent
- lymphadenopathy less common

Heterophile antibody negative
- IgM class antibody that agglutinate RBC from certain species like sheep

36

Epstein Barr Virus

Infects and transforms B lymphocytes
- binds to cd21 on B cells, some become latently infected
- also infects epithelial cells in oral cavity

37

EBV diseases

Mono

Cancer: burkitts lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma (B cells affected)

Lymphoproliferative disorders (psottransplant lymphoproliferative disease, oral hairy leukoplakia)

Seroprevalence 50% by age 5, 90 by age 20

Spread by oral secretions - the kissing disease

Often asymptomatic can be shed for years

38

EBV clinical symptoms: IM

Slide 42

Classic triad
- lymphadenopathy
- splenomegaly - avoid contact sports
- exudative pharyngitis

Fever malaise and rash can appear if mistakenly treated with ampicillin

War b/w infected B cells and the T cell response
- pharyngitis due to respond to infected epithelial cells
- fatigue due to energy needed to power robust T cell response so you are tired al the time

39

EBV lab finding and diagnosis

Slide 43

Symptoms

Peripheral blood smear: see atypical lymphocytes (Activated T cells, called Downey cells)

CBC; activated T cells, can comprise up to 80% of total WBC

Serology: heterophile AB positive (monospot test) - Ab that cause sheep red cells to clumb

EBV: heterophile + mono
CMV: heterophile - mono

40

EBV associated malignancies and lymphoproliferative disorders

slide 44

Burkett lymphoma
- jaw tumor of African children, EBV--> chromosomal translocation leading to activation of cmyc oncogene

Other lymphomas- Hodgkin, T cell head and neck, CNS (in HIV infected)

Nasopharyngeal carcinoma - cancer of epithelial cells common in males of Chinese origin

Post-transplant lymphoproliferative disorder (PTLD) - occurs in setting of immunosuppression associated with transplantation, can range from B cell expansion to lymphomas

Oral hairy leukoplakia**: excessive wart like growth of papillae on tongue, in advanced HIVi and othe rimmunosuppressed
- one of most common virally induced oral diseases in HIV patients
- cant be scrapped off like oral thrush

41

HHV - 6 - Roseola

Most common cause of roseola infantry
- rose red rash of children (sudden rash - exanthum subitum), virtually all children infected by 4 yo
- HHV causes ~10% roseola

Undifferentiated febrile illness without rash
- HHV6 accounts for 5 - 25% of ED visits for fever in infants

HIGH FEVER febrile seizures common with roseola
- responsible or 1/3 febrile seizures in children up to 2 years old

Lymphotropic virus (infects CD4+ T cells in particular); causes transient immunosuppresion and can exacerbate disease with other viruses

42

HHV6 exanthum subitum


Slide 47

Abrupt onset of high fever (104) that persists 2 to 5 d

Child is normally fussy and irritable

Rash develops coincidental with abatement of fever
- rash first appears on neck, behind ears and on back
- it blossoms
- spread to trunk and abdomen
- some rash on face and arms and legs
- maculopapular in appearance, not itchy or uncomfortable
- no treatment no vaccine

43

HHV 8 (KSHV)

Slide 49

Cell tropism for CD19+ B cells, macrophages, endothelial cells

Painless purplish macules, nodules or plaques

Tumors mostly on skin, but can involve any organ

Pathology shows spindle shaped tumors with red cells

44

LAb diagnosis of Herpes Viruses

No point of care ot true rapid tests

For HSV1/2 and VZV molecular is recommended

Serology still primary method for otherwise healthy populations for EBV

For CMV and HSV1/2 serology is limited to pregnant women with fetal abnormalities requiring TORCH investigation or for donor/recipient screening prior to transplant

Old fashioned: culture
Tzanck test (look for multinucleated cells in skin vessels)