Beta And Gamma Herpes Viruses 06-07

Herpesviruses Beta and Gamma

Properties of Cytomegalovirus (CMV) •

A betaherpesvirus subfamily

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Characterized by

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Nuclear inclusions (owl eye cells)

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CMV produces perinuclear cytoplasmic inclusions and enlargement of the cell (cytomegaly), a property that gives the virus its name.

Owl's-Eye Cells. The photomicrograph shows a section of kidney taken at autopsy from a three-month-old boy who died of disseminated cytomegalovirus infection contracted in utero. A single periglomerular renal tubule contains large, intranuclear viral inclusion bodies typical of those found in cells infected with cytomegalovirus..).

Epidemiology • CMB is ubiquitous • Age specific prevalence rates show 10-15% are infected with CMV during the first 5 years of life after which the rate of new infections levels off. • The rate increases by 1-2%m per year during adulthood. • CMV has been isolated from urine, saliva, semen and cervical secretions

Transmission May occur in utero, perinatally or postnatally. – Perinatal infection is acquired mainly through infected genital secretions, or breast milk. – Postnatal infection mainly occurs through saliva. Viral latency in leukocytes with latent infection as seen in • Sexual contact • Blood and blood products • Transplanted organ

Pathogenesis • Life long carrier state • Reactivation – Infectious virion appear in the urine and the saliva – Can also lead to vertical transmission • Re-infection • Can occur with another or the same strain of CMV  In developed countries 70% of adult have developed Ab  In developing countries, over 90% of people are infected.

Clinical Manifestations • Congenital infection – May result in cytomegalic inclusion disease • Perinatal infection - usually asymptomatic • Postnatal infection - usually asymptomatic. However; – Infectious mononucleosis syndrome in a minor no of cases: • Fever • Lymphadenopathy • Splenomegaly • Immunocompromised patients pneumonitis, retinitis, colitis, and encephalopathy.

Congenital Infection • Defined as the isolation of CMV from the saliva or urine within 3 weeks of birth. • May be transmitted to the foetus during all stages of pregnancy • Commonest congenital viral infection; affects 0.3 - 1% of all live births. • The second most common cause of mental handicap after Down's syndrome • Responsible for more cases of congenital damage than rubella

Cytomegalic Inclusion Disease Characterized by: • Involvement of CNS: Significant defects within 2 years of life – Severe hearing loss – Ocular abnormalities – Mental retardation • Involvement of reticuloendothelial system

Laboratory diagnosis Lab diagnosis of CMV infections depends on 3.

Detecting of CMV Cytopathology, antigens or DNA in infected tissues

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Isolating the virus from tissue or secretions

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Demonstrating seroconversion

Laboratory Diagnosis (1) • Direct detection – Histology of biopsy specimens for CMV inclusion – The detection of CMV antigenaemia is now routinely used for the rapid diagnosis of CMV infection in immunocompromised patients – PCR for CMV-DNA is diagnostic • Virus Isolation – Cell culture is regarded as gold standard but requires up to 3-4 weeks for CPE – Rapid culture methods such as shell vials can reduce the time for detection to 24-48 hours • Serology – CMV IgG antibody indicates past infection – CMV IgM is indicative of primary infection

Laboratory interpretations • Congenital infection Virus culture or viral DNA assay positive at birth or within 1-2 weeks • Perinatal infection Culture-negative specimens at birth but positive specimens at 4 weeks or more after birth suggest natal or early postnatal infections • CMV mononuclesis in non-immunocompromised patients Serconversions and presence of IgM specific for CMV are the best indicators of primary infections • Immunocompromised patients Demonstration of virus by viral antigen, DNA, or demonstration of inclusions in diseased tissue.

Treatment Congenital infections • Not usually possible to detect Perinatal and postnatal infection • Usually not necessary to treat Immunocompromised patients • Is necessary to make a diagnosis give prompt antiviral therapy: ganciclovir, forscarnet, and cidofovir

Prevention • No licensed vaccine is available • There is a candidate live attenuated vaccine • Prevention of CMV disease in transplant recipients – Screening and matching the CMV status of the donor and recipient – Use of CMV negative blood for transfusions – Administration of CMV immunoglobulin to seronegative recipients prior to transplant – Prophylaxis with acyclovir and ganciclovir

Other Human Herpes Viruses HHV-6 and 7

• Properties of HHV-6 and 7 • betaherpesviruses • HHV-6 and HHV-7 are found worldwide. • The main target cell is the CD4 † T-lymphocyte • Transmission by droplet infection (isolated from saliva and the throat)

HHV-6 • Infection is common in infancy, almost all of the population has Ab to this virus by the age of 5 Y. Clinical Manifestations • Primary HHV-6 infection is associated with Roseala Infantum (or fourth disease), which is a classical disease of childhood. • Children are protected by maternal Ag until 6 months. • A spiking fever develops over a period of 2 days followed by a faint maculopapular rash from trunk to extermities. • May be complicated by encephalitis • Reactivation is common in immuno-suppression (posttransplantation)

Diagnosis •

Primary infection can documented serologically

be

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Active virus infection can be documented by culture or DNA detection (by PCR)

Treatment Definitive therapy has not been established, but HHV-6 is more susceptible to ganciclovir Roseala Infantum

HHV-7 • HHV-7 is similar to HHV-6 • HHV-7 is distinct from all human herpesviruses and it is most closely to HHV-6 and CMV • Despite the similarities between HHV-6 and HHV-7, their antigenic diversity is such that Ab to one virus do not protect from against infection from the other • No treatment have been identified

Epstein-Barr Virus (EBV) Gammaherpesviruses

Epidemiology • Two epidemiological patterns are seen with EBV • In developed countries, • 2 peaks of infection are seen: – 1st preschool children aged 1 - 6 – 2nd adolescents and young adults aged 14 - 20 – Eventually 80-90% of adults are infected. • In developing countries • Infection occurs at a much earlier age so that by the age of two, 90% of children are seropositive. • The virus is transmitted by contact with saliva, in particularly through kissing.

Pathogenesis • A lifelong carrier state • Low grade virus replication and shedding can be demonstrated in the epithelial cells of the pharynx of all seropositive individuals. • EBV is able to immortalize B-lymphocytes in vitro and in vivo: a few EBV-immortalized B-cells can be demonstrated in the circulation which are continually cleared by immune surveillance mechanisms. • EBV is associated with several very different diseases

Disease Association 1. Infectious Mononucleosis 2. Chronic infectious mononucleosis 3. Burkitt's lymphoma 4. Nasopharyngeal carcinoma 5. Lymphoproliferative disease and lymphoma in the immunosuppressed. 6. X-linked lymphoproliferative syndrome 7. Oral leukoplakia in AIDS patients 8. Chronic interstitial pneumonitis in AIDS patients.

Infectious Mononuclosis (IM) • Primary infection is usually subclinical in childhood • In adolescents and adults, there is a 50% chance of IM • Features include: – Fever – Lymphadenopathy – Splenomegaly – Usually a self-limiting disease • Jaundice (in some patients)

Infectious Mononuclosis (IM) • Complications are rare: – Splenic rupture – Meningoencephalitis – Pharyngeal obstruction • Chronic IM may occur in some patients who have lymphoproliferative disease or lymphoma

Burkitt’s Lymphoma (BL) • Endemic in parts of Africa (where it is the commonest childhood tumour) and Papua New Guinea • Usually in age 3-14 years • Responds well to chemotherapy • It is restricted to areas with malaria: may be a cofactor. • In theory BL can be controlled by the eradication of malaria (as has happened in Papua New Guinea) or vaccination against EBV

Nasopharyngeal Carcinoma (NPC) • NPC is a malignant tumour of the squamous epithelium of the nasopharynx. • It is very prevalent in S. China, where it is the commonest tumour in men and the second commonest in women. • NPC usually presents late and thus the prognosis is poor.

Immunocompromised Patients • Transplant recipients e.g. renal – Associated with lymphoproliferative disease and lymphoma • AIDS patients – Associated with oral leukoplakia and with various Non-Hodgekin’s lymphoma • Ducan X-linked lymphoproliferative syndrome – This condition occurs exclusively in males who had inherited a defective gene in the X-chromosome

Diagnosis •

Laboratory analysis of EBV is usually usually documented by the demonstration of b) c) d)

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Demonstration of atypical lymphocytes (Downey cell) The heterophil antibody test Anti-EBV IgM

Burkitt’s lymphoma: Histology NPC Histology – The determination of the titre of anti-EBV viral – caspid antigen (VCA) IgA in screening for early lesions of NPC

This so-called "Downy cell" is typical of lymphocytes infected by EBV (Epstein Barr Virus) or CMV (Cytomegalovirus) in infectious mononucleosis.

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Vaccination • A vaccine against EBV which prevents primary EBV infection should be able to control both BL and NPC • Must be given early in life to: – Seronegative organ transplant recipients – Those developing severe IM • This vaccine is being tried in Africa.

Human Herpes Virus 8 • Gammaherpesviruses • Associated with Kaposi’s Sarcoma (KS) • HHV-8 DNA is found in almost 100% of cases of Kaposi’s sarcoma • Most patients with KS have antibodies against HHV-8

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Kaposi's Sarcoma - Close-Up

Close-up

Human Herpesviruses Designation

Common name

Disease

HHV-1

Herps simplex virus-1

Oral (fever blister), ocular lesions, encephalitis

HHV-2

Herps simplex virus-2

Genital, anal lesions, severe neonatal infections, meningitis

HHV-3

Varicella-Zoster virus

Chicken box (primary infection),. Shingles (reactivation)

HHV-4

Epstein-Barr virus

IM (primary infection). Tumors including B-cell tumors (Burkitt’s lymphoma, immunoblastic lymphomas of immunosuppressed), NPC

HHV-5

Cytomegalovirus

Mononucleosis, severe congential infections. Infections in immunocompromised (GIT, retinitis, pneumonia)

HHV-6

Human herpesvirus-6

Roseola in infants (Primary Infection) Infections in allograft recipients (pneumonia, marrow failure)

HHV-7

Human herpesvirus-7

Some cases of roseola (primary infection)

HHV-8

Kaposi’s sarcoma associated herpesvirus (KSHV), human herpesvirus-8

Tumors, including Kaposi’s sarcoma, Some B-cell lymphomas

HHV-1,2,3 are alpha group HHV-5,6,7 are beta group HHV-4 and 8 are gamma group

Learning assessment 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Which opportunistic infections or conditions are used as indicators for AIDS? Which immunologic markers are used to diagnose a HIV infections? Which viral agent is suspected to cause meningitis in patients who have AIDS or have had transplants? Which infection do EBV produce? Which complications may result from EBV infections? How is an acute viral hepatitis B infection differentiated from a chronic infection? Which marker indicate the resolution of the infection? What is the method used to identify the rabies virus? Which viruses comprise the enteroviruses? What is the fifth disease ? What is the causes of this disease? What are arenaviruses? Which types of infections do papillomaviruses produce? Which virus has the potential for latency? Why vaccine for influenza not always effective? Which antiviral agents has been developed, and which specific viral agents are they used?