Herpesviruses

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3 subfamilies of herpesviruses:

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-HHV 8 from AIDS-associated Kaposi’s Sarcoma

-Note pleiomorphic appearance
-Note outer envelope; tegument below it

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Life cycle of herpesvirus in a cell:

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-Herpesvirus in an AIDS patient.
-Note multinucleated giant cell with intranuclear inclusion bodies; derived from monocyte lineage --> a marker of immunocompromise.

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Big picture summary of herpesviruses:
-1˚ infection disease
-Reactivation disease
-Site of latency

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Big picture summary of Herpes Viruses Transmission:

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-Mucous membrane contact is 1˚ mode of transmission.

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Key traits of HSV 1 and 2- epidemiology:

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-60% of children and 90% of adults have antibodies to HSV-1, 25% of adults have antibodies to HSV-2.

-Spread is from person to person. Oral-oral, genital-genital, oral genital and mother to child transmission of both viruses occurs.

-Spread of HSV-1 occurs readily among children in crowded conditions. There is higher HSV-1 prevalence among children in dense living environments.

-HSV-1 has become the most common cause of initial genital herpes among American college students of both sexes.

-Presence of HSV-2 antibody is strongly correlated with sexual lifestyle.

-HSV-2 infection is an important cofactor for HIV-1 infection, as well as other STDs.

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HSV Clinical Features- Mucocutaneous: 6

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-Gingivostomatitis – ‘fever blister’ – oral herpes
-Herpetic whitlow - HSV infection of the finger, a complication of primary oral or genital herpes by inoculation of the virus through a break in the skin.
-Herpes Gladiatorum (among wrestlers) and Eczema -Herpeticum -  Lesions classically occur on the face, neck, and arms.
-erythema multiforme
-Genital lesions: HSV2>>HSV1

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HSV Clinical Features- Central Nervous System Disease: 5

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-Encephalitis – severe, life threatening temporal lobe necrosis with mental status changes (usually HSV-1)
-Aseptic Meningitis – usually HSV-2
-benign recurrent meningitis,
-Bell’s palsy – Cranial Nerve VII facial nerve palsy
-transverse myelitis,

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Other HSV clinical features:
-impact on immunocompromised
-impact on neonates

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-Respiratory tract infections
-Esophagitis – usually immunocompromised
-Keratoconjunctivitis - acute onset with pain, visual blurring, and discharge.

-Immunocompromised disease : can be disseminated, end-organ disease

-Neonatal disease (TORCHeS )
*majority (85 percent) of neonatal HSV infections are acquired perinatally when HSV infection, either symptomatic or asymptomatic, is present in the genital tract of the pregnant woman at the time of delivery.
*Skin, eye, mouth (SEM), CNS, or disseminated infection.

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-Severe Gingivostomatitis from HSV

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-What is this?

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-Left: Gentlemen with leukemia (immunocompromised) with severe herpes lesions.
-Right: giant cell w/ intranuclear inclusion bodies --> marker of immunocompromise
-Bottom left: Pt has improved after recovery of immune system and anti-viral treatment.

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-HSV encephalitis with temporal lobe necrosis.
-Pt did well after anti-viral treatment

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-HSV can cause corneal disease, keratinitis, and retinal disease.

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-Herpetic whitlow - HSV infection of the finger, a complication of primary oral or genital herpes by inoculation of the virus through a break in the skin.

-Infection is in the nerve! Amputation wouldn't fix this.

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-Herpetic whitlow
-Gets on feet from babies sticking their feet in their mouths.

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Describe HSV latency:

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1. Virus migrates from the site of primary infection to regional sensory ganglia (cervical, sacral)

2. Provocative stimuli produce reactivation (common cold, sunlight, trauma, stress)

3. Virus migrates down sensory neurons to produce recurrent ulcers or asymptomatic shedding

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Epidemiology of the Chicken Pox:

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Varicella Zoster Virus (VZV):

-In pre-vaccine era:
*90% of cases occurred by age of 3, 10% of adults susceptible.
*~100-250 deaths a year, mostly among adults.

-Very efficient intra-household transmission via aerosol. Children born after a household outbreak may remain susceptible.

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Chicken Pox Clinical Features:
-progression
-special considerations

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-Incubation period about 2 weeks, can be infectious during that time, especially in the 2 days prior to developing the rash.

-Fever for 2 days, then vesicles develop on an erythematous base (“dew drop on a rose petal”).

-Start on face and trunk and spread outward. At any one time lesions at differing stages of development. Can involve mucous membranes.

-Adolescents and adults (esp. pregnant) can develop more severe forms, including pneumonia.

-Lesions progress from vesicles to crusts, and can be 2˚ infected, especially by Group A Streptococcus.

-CNS complications are rare and include a benign cerebellar ataxia, a serious encephalitis, and a vasculitis.

-Can be prevented by POST-EXPOSURE vaccination or VZ-IG. *relevant to pregnant women.

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Varicella Zoster Virus (VZV)

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Varicella Zoster Virus (VZV)
"dewdrops on a rose petal"

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Describe the Varicella Vaccine:
-doses?
-when is it contraindicated? why?
-other beneficial effects?

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-Live virus

-single dose between 70-90% efficacious against ANY form of the disease, and >90% against severe cases

-2 doses 98% efficacious against ANY form, 100% against severe cases.

-Contraindicated in SEVERE immunosuppression

-Reduces cases of zoster and post-herpetic neuralgia

-MMRV now available.

-Varicella vaccine reduces disease severity, even if not 100% protective!

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Describe VZV Latency:

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-Latent virus remains in dorsal root ganglia.

-Reactivation can occur with immunosuppression, but also is seen in otherwise healthy individuals, particularly in the elderly. Unknown mechanism.

-Simple reactivation can be distinguished from disseminated infection by unilateral localization – rash does not cross midline.

*If rash crosses midline --> likely disseminated disease.

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Describe Zoster:
-when do people get it
-who gets it
-how is it transmitted

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-Zoster (shingles) reactivations are often associated with periods of immunosuppression.

-Infants infected in utero may develop zoster in the first year of life without an apparent primary infection.

-Zoster cases are not transmissible via aerosol, only direct contact, although immunocompromised patients with zoster may then have 2˚ generalization.

-This is VZV.

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Clinical features of Zoster:

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-A single or multiple dorsal root ganglia can reactivate with a unilateral band-like vesicular rash.

-Usually thoracic, but can involve any root, including facial and ophthalmic, or otic (Ramsay-Hunt). Ophthalmic involvement can be sight-threatening.

*PAIN can precede rash and can be excruciating. Pain may also be present W/O rash (zoster sine herpete). Pain can persist long after the rash has resolved (post-herpetic neuralgia, tic douloureux).

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-RAMSAY HUNT SYNDROME.

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-TYPICAL ZOSTER RASH.
-~T7, unilateral, dermatomal distribution.

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Describe the Zoster vaccine:
-benefits?
-who gets it?

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-Zoster vaccine given to older adults leads to a 50% reduction in zoster cases and a 67% reduction in PHN (pain).

-Give to people 60 and older to boost VZV-specific T cells.

-It's a more potent vaccine, which is currently why we don't give it to children.

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Epidemiology of CMV:

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-50-80% of adults have antibody to CMV

-Up to ½ of all new infections occur in the first year of life

-Transmission can occur in utero, at delivery, from breast milk, between children in crowded conditions, through sexual contact, blood transfusions, or donated tissues

-Infected infants shed virus for months

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Clinical Features of CMV:
-how is it detected?
-effects on neonates?
-what important disease can it result in?

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-The majority of primary infections are asymptomatic

-If infection suspected, diagnosed by direct detection of CMV in urine or other relevant body fluid/tissue

-Following primary infection CMV may be excreted for many months so the timing of infection may be difficult to pinpoint

-5% of congenitally infected infants have profound illness with IUGR, jaundice, purpura, organomegaly, microcephaly, intracerebral calcifications, and retinitis. Some infants appear normal at birth, later showing signs of deafness, mental retardation or more subtle deficits (TORCHeS)

-20% of clinical “mono” cases are caused by CMV with fever, lymphadenopathy, and lymphocytosis

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Describe CMV in vulnerable patients:
Who should you be concerned about?

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-CMV in the immunocompromised can produce severe disease with 1˚ infection or reactivation

-1˚ or reactivated CMV in transplant patients can lead to inflammation and rejection of transplanted tissue

-Transplant and advanced AIDS patients can suffer end organ disease including retinitis, esophagitis, colitis, hepatitis, encephalitis, pneumonitis

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-CMV Retinitis
-Note retinal hemorrhages
-Note white, chalky appearance to retina --> also indicative of CMV

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-Diffuse infiltrate on chest X-ray can be indicative of CMV.
-This pt had a known blood disease and signs/symptoms of pneumonia.

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Describe latency in CMV:

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-Latently infected polymorphonuclear cells and lymphocytes produce reactivated CMV with immunosuppression or during other illnesses

-Reactivation may lead to asymptomatic shedding or disease

-Latently infected polymorphonuclear cells and lymphocytes can be transmitted with blood products. Infected organs may also serve as sites of latent virus

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Epidemiology of EBV:

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-Infection typically occurs in adolescence through oral-oral contact, but can spread in crowded conditions (day care) through close personal contact or through transfusion

-90-95% of adults have antibodies, reflecting the prolonged (months) and usually asymptomatic shedding period during which they are still infectious

-Highest incidence is in the 15-24 year age group

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Clinical Features of EBV -- most common:

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-Infection in younger ages is more likely to be asymptomatic

-Most symptomatic primary infections present as infectious mononucleosis with:
*Fever
*Exudative pharyngitis
*Lymphadenopathy
*Hepatosplenomegaly
*Atypical lymphocytosis

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Less common clinical features of EBV:

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-Other syndromes associated with primary infection include:
*Guillain-Barre syndrome
*Encephalitis
*Splenic rupture

-EBV has been linked to a number of malignancies including:
*Burkitt’s lymphoma
*Nasopharyngeal carcinoma
*Post-transplant and AIDS-related lymphoproliferative disorders

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-EBV
-top left: petichiae and periorbital edema
-top right: enlarged tonsils
-bottom left: positive ampicillin challenge
-bottom right: oral hairy leukoplakia

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Describe latency in EBV:

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-EBV remains latent in B lymphocytes.

-Virus can be shed for a year after primary infection and intermittently thereafter.

-Viral DNA has been recovered from cells of the previously mentioned malignancies.

-EBV infected nasopharyngeal epithelial cells and B lymphocytes express latent membrane protein (LMP), which transforms them and prevents apoptosis (programmed cell death).

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-Expression of Latent Membrane Protein 2 by Reed-Sternberg Cells.
-This is latent EBV in a Hodgkin's lymphoma patient.

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Epidemiology of HHV 6 and 7:

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-Up to 95% of older children and adults have evidence of past infection.

-Intrauterine infection can occur, but most transmissions seem to come from maternal saliva.

-Chromosomal integration of HHV-6 has been reported to account for 86% of congenital infections, affecting 1% of infants.

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Clinical Features of HHV 6 and 7:

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-Roseola infantum (exanthem subitum or sixth disease) in 10% of cases with:
*High fever for 3-5 days
*Upper respiratory symptoms (including otitis)
*Lymphadenopathy
*When fever resolves, a fine maculopapular rash

-Febrile seizures in young children

-Encephalitis (rare)

*Stem cell/solid organ transplant complications (especially HHV-6): delayed engraftment, fever, rash, pneumonitis
*Treatment: stop immunosuppressive therapy.

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-Exanthem occurring during chemotherapy for ALL (lymphoma).

-HHV-6 seen on immunohistochemistry of skin biopsy and DNA demonstrated by PCR.

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Describe latency in HHV 6 and 7:
-what kind of cells do they infect?
-what reactivation effects are there in both?

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-HHV 6 infects T cells, monocytes, macrophages, megakaryocytes, salivary epithelial cells and neurologic tissue. Chromosomal integration into somatic cells in 1% of infants, clinical relevance unknown.

-HHV 7 infects and persists in CD4 cells and down-regulates CD4 expression.

-With immunosuppression, HHV 6 has been reported to reactivate to produce fever, rash, hepatitis, bone marrow suppression, and pneumonia.

-HHV 7 reactivation disease not well characterized.

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Describe HHV 8 Epidemiology:
-AKA?

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-Kaposi’s Sarcoma-associated Herpes Virus - KSHV

-25% of adults have evidence of infection, 100% of those with KS have antibodies

-Transmission sexually or by injection drug use.

-Genital tract shedding has been documented

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Clinical features of HHV8:

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-Kaposi’s sarcoma: a vascular tumor of skin, mucous membranes, and viscera, especially lung and liver.

-Primarily associated with immunosuppression. Disease by MASS EFFECT and cosmetic disfigurement.

-Primary effusion lymphoma: an aggressive B cell lymphoma originating in pleural, pericardial, and peritoneal cavities.

-Castleman’s disease: can be a benign localized angiofollicular lymph node hyperplasia, or an aggressive fatal multicentric disorder associated with HIV infection.

-Evidence of KSHV in Primary Pulmonary Hypertension.

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-Kaposi’s Sarcoma (KS)
-BOTTOM shows multinucleate giant cells in KS.

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-Pulmonary KS
-Note mass lesions that are invading bronchioles and vasculature around lung

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Differing mechanisms of development of KSHV-associated diseases: 3

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Describe HHV8 latency:
-where have we isolated viral DNA?

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-Sites are unknown but HHV-8 DNA has been isolated from

*Saliva
*Semen
*Peripheral blood mononuclear cells
*Bronchoepithelial cells
*Endothelial cells

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Describe Herpes B Virus:
-how can you treat it?

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-A benign HSV-like infection in monkeys

-Nearly universally fatal infection in humans starting as ulcer at inoculation site, progressing to hemorrhagic encephalitis. No asymptomatic human infections!

-An occupational hazard for animal handlers

-Human infection can be controlled with prompt initiation of antiviral medication, continued as chronic suppression indefinitely.

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Herpes B virus in a monkey.