Human Herpes Viruses

1. 2. 3. 4. 5. 6. 7. 8. HSV1: HSV2: VZV: CMV: EBV: HHV6: HHV7: HHV8: Gingivostomatitis, whitlow, Keratoconjunctivitis Genital herpes,Neonatal Infection, Meningitis Fever, Vesicular rash, Encephalitis, Zoster Congenital and postnatal infection IM, BL, NPC Exanthema subitum, Mononucleosis with cervical lymphadnopathy Exanthema Subitum Kaposis sarcoma, Burkitts Lymphoma

Herpes Viruses:
Family: Herpetoviridae Members:

1. 2. 3. 4. 5. 6. 7. 8.
Properties:

Herpes simplex virus type 1 (HSV-1) Herpes simplex virus type 2 (HSV-2) Varicella-zoster virus (VZV) Cytomegalovirus (CMV) Epstein-Barr virus (EBV) Human herpes virus 6 (HHV-6) Human herpes virus 7 (HHV-7) Human herpes virus 8 (HHV-8)

1. 2. 3. 4. 5.

Icosahedral symmetry, enveloped, ds DNA Diameter: 120-200 nm Nuclear replication Oncogenicity Latency and Reactivation

HSV Latency and Reactivation

Primary Infection Gingivostomatitis Whitlow Keratoconjunctivitis Encephalitis
Latency Factors:

Fever Sun light Cold Ultraviolet Menstrual cycles Hormonal changes Emotional upset Immune deficiency Other infections

Reactivation
Clinical Illness Cold Sore (Fever Blister)

Herpes Simplex Virus Type I (HSVI)

Family: Herpetoviridae Icosahedral symmetry, env. ds DNA, 120 200 nm Oncogenicity Latency and reactivation Cause wide variety of clinical syndromes Two types: HSVI and HSV2 Stay latent in human nervous system 1979: Scientist discovered link between HSVI and Alzheimers disease
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Clinical Symptoms (HSV-1)

A. Primary Infection:
1.

Most infections are symptomless

Gingivostomatitis: Most comon (1-4 yrs. Old) Vesicles in mouth, Gums, Form ulcers Incub.: 3-5 dayus Disease: Self- Limited

2. 3. 4. 5. 6.

Keratoconjunctivitis: Corneal ulcer Meningoencephalitis: Brain lesions Ulcerative pharyngitis: Young adults Herpetic whitlow: Dentists, Doctors, Nurses In 1979: Link between HSV-1 and Alzheimers disease by damaging the nervous system by the virus

B. C.

Latent Infection: Virus present in latent state in nerve cells Recurrent Infection: Herpes Labialis (cold sore or fever blister)
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Cold Sore = Fever Blister = Herpes Labialis (HSV) It is a recurrent infection of HSV1 Small painful blisters around lips, nose, inside mouth Virus stay dormant permanently in nerve cell ganglia On reactivation, virus travel via nerve to lips and cause cold sore Not every one who get HSV develop cold sore It is contagious, spread by direct contact with oral secretion or by contaminated hand Wash hand frequently if you have cold sore or you are around infected person Disappear within 7-10 days.
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Epidemiology (HSV-1)
Spread:
Direct contact with Saliva, Food, Water Close contact with infected persons Mainly in children Family spread Poor socioeconomic: Early life Upper socioeconomic: Adolescence Age Ab: 60%- 100% have Abs. From mother to child during delivery in birth canal
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Primary Infection:

Lab. Diagnosis (HSV):

Culture: Specimen: Vesicle Fluid, Saliva, CSF, Conjunctiva, Corneal Scrape T/Culture: HEL, Vero Observe: CPE 24 48 hrs, rounded cells EM: Fast for Morphology (from skin lesion) Direct IF: for Ag in Vesicles, Tissue

Serology: CFT: 4 Fold Rise- Recent Infection IFT, EIA, RIA: IgM and IgG

PCR: for DNA in CSF or other tissue

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 Control: (HSVI)
Vaccine: under trial. Ideal vaccine should induce immune response to prevent or reduce primary infection, that will reduce the source of virus for recurrent or transmission.
1.

Antiviral:

Acyclovir: Inhibit viral DNA polymerization, may stop the progression of Alzheimer disease Reduce severity and duration of symptoms Does not prevent latency Resistant strain exist Inhibit viral DNA synthesis
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Herpes Simplex Virus-2 (HSV-2)

1. Virology: Herpes virus, ds DNA, env., Icosahedral. 2. Latency and Recurrent Infection 3. Oncogenicity 4. HSV1 and HSV2: under EM are identical 5. Both types infect mucosal surface (mouth or genitals)

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Infection And Disease (Herpes Virus)

Persistent Infection

Disease

Latent Infection

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HSV-2
Clinically:
Incubation: 5-7 days Vesicular eruption on genital area ulceration Lesion Vesicle Pustules Ulcer Crust Healing Fever,Malaise,Myalgia, Dysuria, Meningitis, Lymphadenopathy. Severity, Lesions: More in women. Urethra, Cervix: high infection Neonatal herpes: Infants have jaundice, hepatosplenomegaly, Vescicle on skin (60% die or neurological sequelae).

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Genital Herpes and Cervical Carcinoma

1) 2) 3) 4) 5) Histopathologic Studies: Women with HSV-2 infection developed cervical cancer 8 times as frequently as controls. Cervical Smear: Women with carcinoma contain HSV- Ag in cells. Malignant Cells:
HSV2 virus isolated HSV2 DNA in chromosome

Transformation: Culture cells infected with HSV2 Seroepidemiology:

Cervical cancer women: HSV-2 Ab: 72% USA Control women: HSV-2 Ab: 22% USA
Both groups: Same race, Age, Socioeconomic Status

6) HSV2+HPV(multistage process of oncogenic transformation)

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Herpes Simplex Virus-2 (HSV-2)

Lab.:
Isolation: In T/C (CPE in 2-3 days). EM: for morphology PCR for DNA Serology: EIA, IF, NT for antibody detection

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HSV-2
Epidemiology and transmission:
Sexual transmission Increased number of sexual partners Female more than male HIV infection: risk factor Duration of sexual relationship Genital secretion Infected birth canal fetus infection Lab. people Nurses World wide: Increase in incidence.
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HSV-2
Prevention:
Hygiene (Mother, Others) Special attention: Mother child Asymptomatic carrier shed from saliva, urethra, cervix. Observation for symptoms. Patients with lesions: Isolation Acyclovir: reduce severity and duration of symptoms, doesnt prevent latency Vaccine: inactivated, gives partial protection in women who are seronegative to HSV1 and HSV2
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Varicella Zoster Virus (VZV)

1. Family: Herpes virus 2. ds DNA, Env., Icosahedral, 150 -200 nm 3. Disease: Varicella (Chicken Pox), Zoster (Shingles)
Varicella: Primary illness, Child fever, Vesicular rash on back of head, ears, then face, neck, trunk, affect mainly children Zoster: (reactivation) from dorsal root ganglia travel down sensory nerves to produce painful vesicles on skin, common in old.

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Varicella Chicken Pox

1- Infection: Primary by Respiration 2- Disease: Childhood 5-8 yrs old 3- Epidemic: Winter, Spring 4- Highly infectious for a week after rash

Zoster Shingles
Reactivation Older Age No seasonal peaks Less infectious

5- Generalized infection
6- Spread: Via blood 7- Occur: Normal host 8- Symptoms: Rash, Fever, Mild RTI 9- Complication: Pneumonia in adult Secondary bacterial infection Encephalitis 1-2 per 1000 Congenital defects Disseminated varicella

Localized Infection
Via nerve fiber Old people, mainly immunocomp. Painful blisters on face trunk, neck

Complication: Corneal ulcer Disseminated zoster Paralysis Encephalitis Neuralgia

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Varicella Zoster Virus (VZV)

4. Epidemiology:

Varicella: Child disease, very infectious by respiration, vesicule. Nosocomial infection: big problem High rate of transmission: in group setting Active case of HZ transmit VZV to susceptible people
Direct contact: with respiratory secretions, vesicles Airborne: inhalation of nasopharyngeal secretion Varicella patients: Strict isolation Zoster patients: no strict isolation Outbreaks: in healthcare setting Via ventilation system.

5.

Transmission:

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Varicella Zoster Virus (VZV) (Contd.)

Lab.:
A. Diagnosis by: Clinical features, Ag and Ab detection

B.

Recommended when
Patient is immunosuppressed VZV in a neonate In a suspected immune person In complications or unusual clinical syndromes From vesicle, stain with Tzanek, Giemsa, HE Look for intranuclear inclusions Not specific for VZV as HSV give same result

C.

Smear:

Viral culture in HEL: difficult and slow to grow, low sensitivity EIA for
IgG: Immunity after natural infection or vaccine IgM: recent infection, may cross react with HSV-1 IgM, may occur in zoster

IFT:
For Ag Biopsy specimen Rapid and sensitive 20

PCR: from patient lesion, CSF for meningoencephalitis

Varicella Zoster Virus (VZV) (Contd.)

Treatment:
Famciclovir: reduce skin lesion in varicella. Inhibit activity of zoster in immunocomp. Help prevent complication such post herpetic neuralgia Analgesic: reduce pain ZIG: for short term protection or for patients of severe immunodeficiency.

Vaccine:
In 1995: live attenuated (Varivax), reduce incidence, hospitalization and death of varicella Effective for >10 yrs Second dose recommend before school entry In 2006: Live attenuated (Zostavax) for shingle prevention in old people, reduce postherpetic neuralgia.
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Cytomegalovirus (CMV)
Herpesvirus, ds DNA, Env, Icosahedral, 120-200 nm Primary infection Latency Reactivation Virus excretion: Saliva, Urine for several month. Opportunistic infection: Immunocompromised patients (Pneumonia, Hepatitis) Transplants patients: Major problem (Re-activation) Immunity: IgM, IgG: and CMI important Symptoms: fever, sore throat, fatigue, swollen salivary gland.
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Cytomegalovirus (CMV) (Contd.)

Clinical Features: Fever, Swollen salivary glands, sore throat Congenital Infection: Placenta Fetus virus shed
Maternal infection Mostly symptomless Fetal damage can be in all trimesters Primary and reactivation can infect fetus Signs: Jaundice, Hep. Spl.megaly, Microcephaly, Mental Retardation, Deaf, Vision loss Postnatal Disease:Widespread, mostly symptomless In young children, adult (Hepatitis, CMV mononucleosis) In immunocomp. Patients (Pneumonia, Retinitis, Gastroenteritis)

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Infectious Mononucleosis (EBV) and post transfusion Mono. (CMV)

A.

Similarities:
Disease: Self limited Incubation: 3-6 wks Symptoms: Fever, Malaise, Hepatosplenomegaly Transmission: Blood Transfusion, Saliva Atypical Lymphocytes: Similar in both Viruses

B.

Differences:
Properties
Pharyngitis Lymphadenopathy Hetrophil Abs Specific Abs

EBV-Mono
+ve +ve (P-B Test) +ve EBV-IgM +ve

CMV-Mono
-ve -ve -ve CMV-IgM +ve

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Cytomegalovirus (CMV) (Contd.)

Transmission:

Worldwide: person to person Saliva, Sexual, Urine, Blood, Breast Milk. Close contact via body fluid 50-90% of adult get infected Widespread in developing countries and lower socioeconomic Common in immunocompromised patients.

Lab Diagnosis:
Isolation in T/C (HEL) EIA, IFT: IgM, IgG PCR: for early diagnosis and treatment.
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Cytomegalovirus (CMV) (Contd.)

Prevention:
Donors of blood / Organs: must be Seronegative Blood treated to remove WBC Hygiene: wash hands, gloves

Treatment:
a) Ganciclovir: Inhibit CMV replication, reduce severity of infection, used in life-treat. In Immunocomp. (Pneumonia, Retinitis) and for infants with severe congenital CMV Foscarnet: CMV retinitis in AIDS patients Vaccine: Still in research CMV-IG: given I.V. as prophylaxis for transplant patients.

b) c) d)

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Clinical Features (EBV)

Infectious mononucleosis (Glandular Fever): Disease: Self limited Comes as a primary infection or due to reactivation Incubation: 3-6 weeks Symptoms: Fever, Malaise, Hepatosplenomegaly, Pharyngitis, Lymphadenopathy. Transmission: Saliva, (Blood Transfusion: rare), healthy people carrying the virus Infected people: Spread the infection to other for wks. Healthy people can carry and spread the virus for life Incidence: 50% in adolescence Blood: atypical lymphocytes EBV IgM Abs: +ve P.B. test: hetrophil Abs (IgM) hemaglutinate sheep RBC
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Infectious Mononucleosis (EBV) and post transfusion Mono. (CMV)

A.

Similarities:
Disease: Self limited Incubation: 3-6 wks Symptoms: Fever, Malaise, Hepatosplenomegaly Transmission: Blood Transfusion, Saliva Atypical Lymphocytes: Similar in both Viruses

B.

Differences:
Properties
Pharyngitis Lymphadenopathy Hetrophil Abs Specific Abs

EBV-Mono
+ve +ve (P-B Test) +ve EBV-IgM +ve

CMV-Mono
-ve -ve -ve CMV-IgM +ve

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Association of EBV with Burkitts Lymphoma (BL) and Nasopharyngeal Carcinoma (NPC)
Majority of NPC and BL Patients have EBV-Abs

BL and NCP contain EBV-DNA in biopsy

Racial and geographical distribution of BL and NPC due to genetic or environmental (smoke fish diet contain nitrosamines Carcinogens) factors Rise in EBV-IgA with NPC after reactivation Patients with other malignancy have no EBV-Ab or Ag

BL: Malignant tumor of jaw, ovaries, Lymphoid tissue, common in African children, sporadic worldwide
NPC: Malignant tumor of nasopharynx epithelium, common in China and Africa 29

Human Herpes Virus-6 (HHV-6)

1986: Isolated from HIV Patient in blood Herpes virus, ds DNA, ENV., Icosahedral Latency and reactivation Virologically: close relation to HHV7 Genetically distinct, Morpholog. Similar to herpes viruses. Has 2 variants: HHV6A and HHV6 B
HHV6A: affect older children or adults with CNS involvement HHV6B: cause roseola in children

Latent Infection: In T-lymphocytes, Salivary glands. CMI: control HHV6 replication. Immunosupp. Patient and drug induced hypersensitivity reactivate the virus. Infection: Most children by age 2 years, 90% of adults sero (+). Transmission: Saliva, close contact, respiratory route, persistent shedding from oropharynx. Serological test: 95% of worlds population are HHV6-Abs positive, indicating immunity. 30

Human Herpes Virus-6 (HHV-6)

Clinically:
Mostly asympotomatic Swollen salivary glands Exanthem subitum (Roseola infantum): rash on babies face with high fever Opportunistic infection in transplant recipients Fever: might confuse with other disease Most infants get infected before age 2 yrs Chronic fatigue syndrome (CFS) Complication:
Bone marrow suppression (decreased production of WBC and platelets) Encephalitis Disruption of immune system function 31

Human Herpes Virus-6 (HHV-6)

Lab.:
Abs. cross react with HHV7 IFT:
HHV6 IgM: primary infection HHV6-IgG: 4 fold rise indicate active infection

PCR : HHV6 and EBV are cell associated, so little free virus found in sera, so if DNA found in serum indicate active infection Virus isolation: difficult, time consuming, cannot tell if active or latent virus.
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Human Herpes Virus-6 (HHV-6)

Control:
Isolate the sick children Antipyritic, analgesic, bed rest Vaccine: not yet Antiviral: valacyclovir in combination with B-INF, cidofovir, Foscarnet

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Human Herpes Virus-7 (HHV-7)

1990: Isolated from T-Lympocytes of a healthy person. Herpes virus, ds DNA, env., icosahedral Virologically: close relation to HHV6 Infection: Most children by age 3 years,90% of adults sero (+ve)

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Human Herpes Virus-7 (HHV-7)

Clinically: Exanthema subitum (Roseola Infantum): rash on babies face with high fever HHV7 primary infection reactivate HHV6 infection Complication: encephalitis, Pneumonitis
Mostly asymptomatic or not associated with clear syndrome in majority of children. Interaction of HHV6 and HHV7 may play important mechanism of pathogenesis Reactivation of both viruses associated with viremia Salivary Glands: Major reservoir for HHV6, HHV7. Spread: Direct contact with Saliva, Food, Water 35

Human Herpes Virus-7 (HHV-7)

Lab
Virus isolation: difficult, time consuming PCR: for DNA from salivary glands EIA,IFT: for Abs Abs cross react with HHV6

Control:
Medicine to control fever, pain Bed rest Vaccine: not yet Antiviral: (cidofovir, Foscarnet: under trial)

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Human Herpes Virus -8 (HHV8)

1. Herpes virus, ds DNA, env., icosahedral 2. Known as Kaposis sarcoma associated herpes virus (KSHV) 3. Occurs in humans, no animal reservoirs 4. Cause primary infection latency reactivation 5. Prevalence: Italy, Greece, Africa, Mediterranean 6. Who should be tested for HHV8:
Patients suspected of HHV8 or KS lesions Transplant donors and recipients Blood transfusion donors and recipients HIV and AIDS patients
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Human Herpes Virus -8 (HHV8)

Clinical Features:
1994: Isolated from Kaposis sarcoma (KS) cells in AIDS patients
KS is rare with milder disease in HIV negative persons. KS: Cancer on skin (purple lesion), GIT, Lungs Speed the progression of KS in HIV positive patients Cause Burkitts lymphoma and Non-Hodgkins lymphoma

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Human Herpes Virus -8 (HHV8)

Transmission:

HHV8-Abs found in:

90% KS patients 1-5% B. donors.

50% of transplant recipients and HHV8 +ve will develop KS African people at high risk due to high prevalence of the virus 30-51% HIV seropositive gay men (high risk group) 15 - 20% seronegative gay men Gay men at high risk for infection with HHV8 (why ?) How the virus is transmitted? Sexual, saliva, others
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Human Herpes Virus -8 (HHV8)

Lab.:
PCR for HHV8 in KS lesion or blood IFT, EIA for IgG Abs Virus isolation difficult Samples saliva or tumor cell lines
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Human Herpes Virus -8 (HHV8)

Control:
Bed rest Pain killer Antiviral: (cidofovir, Foscarnet: under trial) Difficult because mode of transmission not well known New drugs for HIV may reduce the risk of KS Vaccine: not yet
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