Herpes Viruses Lecture Notes PDF

Herpes Viruses Family Herpesviridae 1  Herpesviruses The herpes viruses are an important group of large DNA enveloped viruses with the following features in common: – Virion morphology, – Basic mode of replication, and – Capacity to est...

Herpes Viruses Family Herpesviridae 1  Herpesviruses The herpes viruses are an important group of large DNA enveloped viruses with the following features in common: – Virion morphology, – Basic mode of replication, and – Capacity to establish latent and recurrent infections. The human herpes viruses are grouped into three subfamilies on the basis of differences in: – Viral characteristics (genome structure, tissue tropism, cytopathologic effect, and site of latent 2  Classification of Human Herpesviruses Family: Herpesviridae Sub family: Herpesvirinae Sub family Genus Official name Common Alpha Simplex HHV 1 Herpes simplex type 1 HHV 2 Herpes simplex type 2 ________________________________________ Varicello HHV 3 Varicella Zoster virus _________________________________________________________ Beta Cytomegalo HHV 5 Cytomegalovirus Roseolo HHV 6 HHV 6 HHV 7 HHV 7 ____________________________________________________________ Gamma Lymhocrypto HHV 4 Epstein-Bar virus Rhadino HHV 8 Kapossi’s sarcoma associated herpes virus 3  Primary Target Site of Means of Subfamily Virus Cell Latency Spread Alpha herpes virinae Human Herpes simplex Mucoepithelial cells Neuron Close contact herpesvirus 1 type 1 Human Herpes simplex Mucoepithelial cells Neuron Close contact herpesvirus 2 type 2 (sexually transmitted disease) Human Varicella-zoster Mucoepithelial and T Neuron Respiratory and herpesvirus 3 virus cells close contact Gamma herpes virinae Human Epstein-Barr B cells and epithelial B cell Saliva (kissing herpesvirus 4 virus cells disease) Human Kaposi Lymphocyte and B cell Close contact herpesvirus 8 sarcoma- other cells (sexual), saliva related virus Beta herpes virinae Human Cytomegaloviru Monocyte, Monocyte, Close contact, herpesvirus 5 s lymphocyte, and lymphocyte transfusions, epithelial cells , tissue transplant, and congenital Human Herpes Like CMV & T cells Saliva herpesvirus 6 lymphotropic salivary glands, virus neurons 4 Human Human Like CMV T cells Saliva  Herpesviruses encode enzymes (DNA polymerase) – that promote viral DNA replication - It easily targets for antiviral drugs. Herpesviruses is released by exocytosis, cell lysis, and through cell-cell bridges. Herpesviruses can cause lytic, persistent, latent – Herpesviruses has capacity to persist in host indefinitely in nucleus of the cell 5  – Varicella zoster and herpes simplex viruses establish latent infections in neurons – Reactivation Varicella zoster(HHV-3) is commonly known as herpes zoster (shingles) Herpesviruses are ubiquitous (present everywhere). Cell-mediated immunity is required for control. Frequently reactivated in immunocompromised host 6  nucleocapsid ER ENDOPLASMIC RETICULUM. 7 Herpes Simplex Viruses HSV 1 & HSV 2 8  Herpes Simplex Viruses HSV was the first human herpesvirus to be recognized. The name "herpes" is derived from a Greek word meaning to creep. Extremely widespread in the human population. Has broad host range, – being able to replicate in many types of cells and to infect many different animals. They grow rapidly and are highly cytolytic. 9  Herpes Simplex Viruses Responsible for a spectrum of diseases, ranging from gingivostomatitis to keratoconjunctivitis, encephalitis, genital disease, and infections of newborns. The herpes simplex viruses establish latent infections in nerve cells; & recurrences are common Properties of the Viruses There are two distinct HSV: type 1 and type 2 (HSV-1, HSV-2). HSV-1 and HSV-2, share many characteristics, including DNA homology, antigenic determinants, tissue tropism, 10 and disease symptoms.  Herpes Simplex Viruses…… They can still be distinguished by slight but significant differences in these properties – They can be distinguished by analysis of viral DNA. – They differ in their mode of transmission. HSV-1 is spread by contact, usually involving infected saliva HSV-2 is transmitted sexually or from a maternal genital infection to a newborn. – Different clinical feature of human infections. – Has Cross react serologically, but some unique protein exist for each type. 11  Pathogenesis HSV-1 is usually associated with infections above the waist, and HSV-2 with infections below the waist HSV-1 and HSV-2 also differ in growth characteristics and antigenicity, – HSV-2 has a greater potential to cause viremia with associated systemic flulike symptoms. 12  infectionof HSV-1 infections are usually limited to the oropharynx 13  Comparison based on disease HSV-1 HSV-2 Primary infection: Gingivostomatitis + - Pharyngotonsillitis + - Keratoconjunctivitis + - Neonatal infections ± + Recurrent infection: Cold sores, fever blisters + - Keratitis + - Primary or recurrent infection: Cutaneous herpes – Skin above the waist + ± – Skin below the waist ± + – Hands or arms + + Herpetic whitlow + + Eczema herpeticum + - Genital herpes ± + Herpes encephalitis + - Herpes meningitis ± + 14  Pathogenesis  HSV can cause lytic infections of most cells, persistent infections of lymphocytes and macrophages, and latent infection of neurons.  Lesions induced in the skin and mucous membranes by HSV-1 and HSV-2 are the same and resemble those of varicella-zoster virus.  Changes induced by HSV are similar for primary and recurrent infections.  Characteristic histopathologic changes include – Ballooning of infected cells 15 – Production of Cowdry type A intranuclear inclusion  Pathogenesis – Formation of multinucleated giant cells. Many strains of HSV also initiate syncytia formation. – Cell fusion provides an efficient method for cell-to-cell spread of HSV, even in the presence of neutralizing antibody. HSV has several ways to escape host protective responses. – The virus blocks the interferon-induced inhibition of viral protein synthesis and block antigen presentation in association with class I Major histocompatibility complex (MHC) – The virus can escape antibody neutralization and clearance by direct cell-to-cell spread and by going into hiding during latent infection of the neuron. 16  Pathogenesis Latent infection occurs in neurons and results in no detectable damage. A recurrence can be activated by various stimuli (e.g., stress, trauma, fever, sunlight [ultraviolet ]). The virus can be reactivated despite the presence of antibody. However, recurrent infections are generally less severe, more localized, and of shorter duration than the primary episodes because of the nature of the spread and the existence of memory immune responses 17  Epidemiology Transmission Virus is transmitted in saliva, in vaginal secretions, and by direct contact with lesion fluid Virus is transmitted orally and sexually and by placement into eyes and breaks in skin. N.B. HSV-1 is generally transmitted orally; HSV-2 is generally transmitted sexually. Who Is at Risk? Children and sexually active people: – At risk for classic presentations of HSV-1 and HSV-2, respectively. 18  Epidemiology Health workers in contact with oral and genital secretions: – At risk for infections of fingers (herpetic whitlow). Immunocompromised people and neonates: – At risk for disseminated, life-threatening disease HSV-1 infections are usually limited to the oropharynx, and virus is spread by respiratory droplets or by direct contact with infected saliva. Viral replication occurs first at the site of infection. 19  Clinical findings Oropharyngeal Disease Primary HSV-1 infections are usually asymptomatic. Symptomatic disease occurs most frequently in small children (1–5 years of age) and involves the buccal and gingival mucosa of the mouth The incubation period is short (about 3–5 days, with a range of 2–12 days), and clinical illness lasts 2–3 weeks. Symptoms include fever, sore throat, vesicular and ulcerative lesions, gingivostomatitis, and malaise. Gingivitis (swollen, tender gums) is the most striking and common lesion. Primary infections in adults commonly cause pharyngitis and 20 tonsillitis. Localized lymphadenopathy may occur.  involves the buccal and gingival mucosa of the mouth vesicular and ulcerative lesions of oropharynx 21 sore throat, vesicular and ulcerative lesions, 22 Eczema - An inflammatory condition of the skin involving redness, itching, development of papules and vesicles 23 A Primary herpes Clinical findings gingvostoma titis Gingivitis(swo llen, tender gums) is the most striking and common lesion B. HSV latent infection- trigeminal ganglia 24  Clinical findings Skin Infections  Intact skin is resistant to HSV, so cutaneous HSV infections are uncommon in healthy persons.  Skin Infections is mainly among the health care workers  Localized lesions caused by HSV-1 or HSV-2 may occur in abrasions that become contaminated with the virus (traumatic herpes).  These lesions are seen on the fingers of dentists and hospital personnel (herpetic whitlow) and on the bodies of wrestlers (herpes gladiatorum). Herpetic whitlow - an abscess of a fingertip 25  Clinical findings Herpes whitlow (Herpes skin infection) An abscess affecting the pulp of a fingertip 26  ECZEMA HERPETICUM Eczema - An inflammatory condition of the skin involving redness, itching, development of papules and 27 vesicles  Clinical findings Keratoconjunctivitis  HSV-1 infections may occur in the eye, producing severe keratoconjunctivitis.  Recurrent lesions of the eye are common and appear as dendritic keratitis or corneal ulcers or as vesicles on the eyelids.  With recurrent keratitis, there may be progressive involvement of the corneal stroma, with permanent opacification and blindness. 28  Clinical findings HSV Keratitis- Dendritic ulcers keratitis - Inflammation of the cornea. 29 With recurrent keratitis, there may be progressive involvement of the corneal stroma, with permanent opacification and blindness keratitis or corneal ulcers or as vesicles on the eyelids 30  Laboratory Diagnosis Cytology: Characteristic CPEs can be identified in a Tzank smear (a scraping of the base of a lesion), Pap smear, or biopsy specimen. Giemsa can also be used to stain scraping of lesions. – CPEs include syncytia, "ballooning" cytoplasm, and Cowdry type A intranuclear inclusions. 31  Laboratory Diagnosis – Cowdry type A inclusion bodies are eosinophilic/ acidophilic nuclear inclusions composed of nucleic acid and protein seen in cells infected with Herpes simplex virus; It form Droplet like masses of material surrounded by clear halos within nuclei, with margination of chromatin on the nuclear membrane as seen in human herpesvirus–infected cells. 32 Cytopathic Effect of HSV in cell culture: Note the ballooning of Cowdry type A cells. (Linda Stannard, University Productioninclusions of Cowdry type A intranuclear of Cape Town, S.A.) inclusion bodies: droplet like masses 33 of acidophilic material surrounded by clear  Direct Detection Lab Dx – Electron microscopy of vesicle fluid - rapid result but cannot distinguish between HSV and VZV – Immunofluorescence of skin scrappings can distinguish between HSV and VZV – PCR - now used routinely for the diagnosis of herpes simple encephalitis Virus Isolation in cell culture – HSV-1 and HSV-2 are among the easiest viruses to cultivate. – It usually takes only 1 - 5 days for a result to be 34  Serology – Useful only for diagnosing a primary HSV infection and for epidemiological studies. – Antibody Appear in 4-7 days after infection, reach peak in 2-4 weeks, persist for life of the host – It Has Limited value due to multiple antigenic share b/n HSV 1 and HSV 2 and also other herpes viruses. 35  Treatment At present, there are only a few indications of antiviral chemo­therapy, with the high cost of antiviral drugs being a main consideration. Generally, antiviral chemotherapy is indicated where –the primary infection is especially severe, where –there is dissemination, where sight is threatened, and herpes simplex encephalitis. Acyclovir : drug of choice for most situations at present. I.V. (HSV infection in normal and immunocompromised patients) Oral (treatment and long term suppression of mucocutaneous herpes and prophylaxis of HSV in immunocompromised patients) Cream (HSV infection of the skin and mucous membranes) Ophthalmic ointment 36  Treatment Famciclovir and valacyclovir – oral only, more expensive than acyclovir. Other older agents – e.g. idoxuridine, trifluorothymidine, Vidarabine (ara-A). These agents are highly toxic and is suitable for topical use for opthalmic infection only 37 Varicella-Zoster virus 38  Varicella-Zoster virus VZV causes two almost universal human diseases – Chickenpox (varicella) and, – Herpes zoster, or shingles upon recurrence disease. VZV shares many characteristics with HSV, including: 1. The ability to establish latent infection of neurons and recurrent disease, 2. The importance of cell-mediated immunity in controlling and preventing serious disease, and 3. The characteristic blister like lesions. Like HSV, VZV is susceptible to antiviral drugs. Unlike HSV, VZV spreads predominantly by the 39 respiratory route.  Pathogenesis Initial replication is in the respiratory tract. VZV infects epithelial cells, fibroblasts, T cells, and neurons. VZV can form syncytia – spread directly from cell to cell. spread by viremia to skin and causes lesions in successive crops (SEASON). VZV can escape antibody clearance, – cell-mediated immune response is essential to control infection. – Disseminated, life-threatening disease can occur in immunocompromised people. 40  Pathogenesis Varicella-Zoster virus can establishes latent infection of neurons – Usually at dorsal root and cranial nerve ganglia. Herpes zoster is a recurrent disease; – it results from virus replication along the entire dermatome. Herpes zoster may result from depression of cell- mediated immunity and other mechanisms of viral activation. 41  Epidemiology VZV is extremely communicable, – with rates of infection exceeding 90% among susceptible household contacts. The disease is spread principally by the respiratory route – but may also be spread through contact with skin vesicles. Who Is at Risk? – Children (ages 5 to 9): Mild classic disease. – Teens and adults: 42  Epidemiology – Immunocompromised people and newborns: At risk for life-threatening pneumonia, encephalitis, and progressive-disseminated varicella. – Elderly and immunocompromised people: At risk for recurrent disease (herpes zoster [shingles]) Normal individuals Primary infection (chickenpox) – ` one of the classical rash diseases of childhood. Following primary infection, 43  Reactivation leading to the appearance of shingles – occurs in 10-20% of infected individuals and usually occurs after the fourth decade of life. Primary infection Varicella Highly contagious disease of children Teens and adults Life-threatening complications such as disseminated varicella, pneumonia, and encephalitis are much more likely to be seen. Reactivation Immuno compromised: herpes zoster, appear at an earlier age and more than one episode may occur. Severe, disseminated disease may occur but fatality 44 is  Clinical feature  Varicella or Chicken pox  is one of the five classic childhood disease (along with rubella, roseola, fifth disease, and measles) IP 7-23 days-infectious 2 days before rash Always acute disease and mostly symptomatic Varicella characteristics include fever and a maculopapular rash – Rash-face, neck, trunk, axillae, limbs, shoulder blades Duration of disease-7 and 10 days, up to 2-4 wks 45  Clinical feature Chicken pox-neonatal Varicella from mother- Congenital Varicella Varicella in pregnancy rarely crosses placenta “Congenital varicella syndrome” Virus –affect different organs It has high mortality about 30 % 46  Clinical feature Chicken pox-adults (Primary) Primary infection is usually more severe in adults than in children. Interstitial pneumonia is the most common complication that – occur in 20% to 30% of adult patients and may be fatal. The pneumonia results from inflammatory reactions at this primary site of infection Mortality 10-40 % 47  Rash of Chickenpox maculopapular rash Rash-trunk, shoulder blades 48 maculopapular rash Rash-face, neck, trunk, axillae, limbs, shoulder 49 blades  Herpes Zoster or Shingles Herpes zoster, a sporadic disease, is the consequence of reactivation of latent VZV from the dorsal root ganglia. No history of recent exposure Incidence is highest among individuals in the sixth decade of life and beyond. Recurrent herpes zoster is exceedingly rare except in immunocompromised hosts There is Unilateral vesicular eruption within a dermatome, often associated with severe pain. 50  Herpes zoster -Shingles Vesicle lesion - In skin or mucous membranes: a raised lesion containing a clear watery fluid. face, trunk, shoulder 51 Vesicle lesion - In skin or mucous membranes: 52  Clinical feature VZV infection in immunocompromised patients or neonates can result in serious, progressive, and potentially fatal disease. Risk for dissemination of the virus to the lungs, brain, and liver, which may be fatal. The disease may occur in response to a primary exposure or recurrence. 53  Laboratory Diagnosis Cytology- similar with HSV-multinucleated giant cells and syncytia. – These cells may be seen in skin lesions, respiratory specimens, or organ biopsy specimens Molecular methods-PCR Serology-CF, Nt, ELISA Intracellular viral antigen-IF Virus isolation in culture – Virus very labile in transportation – Virus poor in vitro replication 54  Treatment and Prevention Treatment may be appropriate for – adults and immunocompromised patients with VZV infections – people with shingles. Anciclovir (ACV), famciclovir, and valacyclovir have been approved for the treatment of VZV infections. A live attenuated vaccine at child age. VZIg can be used to prevent primary infection in susceptible individuals. 55 Cytomegalovirus 56  Cytomegalovirus CMV is – a member of the subfamily Beta herpes virinae – considered lymphotropic. – has the largest genome of the human herpesviruses. – The name of the virus is derived from massive enlargement of cytomegalovirus-infected cells. In contrast to the traditional definition of a virus -CMV carries specific mRNAs into the cell in the virion particle to facilitate infection. Human CMV replicates only in human cells. It is very species-specific and cell type-specific. CMV establishes latent infection in mononuclear lymphocytes, 57  Cytomegalovirus CMV infection is common – more than 50 % population experienced infection by the age of 40 Most infections occurs are asymptomatic except in people with immune defects (T-cell defects) /pregnancy/ newborns (congenital) CMV produces a characteristic cytopathic effects. Intranuclear inclusion typical of herpesviruses and also perinuclear inclusions can be seen. 58  Pathogenesis of CMV CMV is acquired from blood, tissue, and most body secretions. CMV causes productive infection of epithelial and other cells. CMV establishes latency in T cells, macrophages, and other cells. Cell-mediated immunity is required for resolution and contributes to symptoms; – role of antibody is limited. Suppression of cell-mediated immunity allows recurrence and severe presentation. CMV generally causes subclinical infection. 59 Normal individuals Primary infection is usually asymptomatic, – occasionally systemic infection- an infectious mononucleosis- like illness may be seen. Can establish lifelong latent infection. Reactivations or re-infections are common throughout life and are usually asymptomatic. 60 Immunocompromised individuals Both primary and recurrent infection may lead to symptomatic disease. Primary CMV infection is usually more severe than recurrent infection, – with the exception of bone marrow transplant recipients, where primary and recurrent infections are just as severe. 61  Epidemiology of CMV Transmission occurs via blood, organ transplants, and all secretions (urine, saliva, semen, cervical secretions, breast milk, and tears). Virus is transmitted orally and sexually, in blood transfusions, in tissue transplants, in utero, and at birth CMVAge Group is the agent of most common Source congenital infection. Neonate Transplacental transmission, Sources of CMV infections intrauterine infections, cervical secretions Baby or child Body secretions: breast milk, saliva, tears, urine Adult Sexual transmission (semen, 62  Clinical Manifestations Fever Pneumonitis Hepatitis Gastrointestinal manifestations eg. colitis Encephalopathy Poor graft function Pneumonitis is the most severe manifestation, and carries a mortality rate of 85% in the absence of treatment. 63  Clinical Manifestations Solid organ transplant recipients CMV is the most common infection, leading cause of morbidity and mortality. Occurs within 1 - 3 months following transplant. Primary infection more severe than recurrent infection. Patients may present with fever, pneumonitis, GI manifestations, hepatitis, and poor graft function. Does not appear to be associated with organ rejection. 64  Congenital CMV Infection CMV is the most prevalent viral cause of congenital disease. Mother infected in pregnancy : fetus at high risk Fetuses are infected by virus in the mother's blood (primary infection) or – by virus ascending from the cervix (after a recurrence) Maternal infection usually asymptomatic Fetal infection can be asymptomatic to severe and disseminated Congenital CMV Infection can cause Fetus damaged at any stage which results in severe developmental defects- Unilateral or bilateral hearing loss and mental retardation are 65 common consequences of congenital CMV infection  Perinatal CMV Infection Approximately half the neonates born through an infected cervix acquire CMV infection and become excreters of the virus at 3 to 4 weeks of age. Neonates may also acquire CMV from – maternal milk. – through blood transfusions. Effects – Protracted interstitial pneumonitis – Poor weight gain, adenopathy, rash. – Hepatitis and anemia persist for months to years 66  AIDS Patients CMV disease is present in 7.4% to 30% of all AIDS patient. retinitis, colitis, and encephalopathy are the most common manifestations of CMV disease in AIDS patients. Pneumonitis is extremely rare. 67 Clinical manifestations of CMV Tissue Children/Adults Immunosuppress ed Patients Predominant Asymptomatic Disseminated presentation disease, severe disease Eyes - Chorioretinitis Lungs - Pneumonia,pneumo nitis Gastrointestinal - Esophagitis, colitis tract Nervous system myelitis Meningitis and encephalitis, myelitis Lymphoid system Mononucleosis Leukopenia, syndrome, post- lymphocytosis transfusion syndrome 68 Major organs hepatitis Hepatitis  Laboratory Diagnosis (CMV) The histologic hallmark of CMV infection is – the cytomegalic cell, which is an enlarged cell (25 to 35 mm in diameter) that contains a dense, central, "owl's eye," basophilic intranuclear inclusion body Samples taken for analysis include – urine, saliva, blood, bronchoalveolar lavage specimens, and tissue biopsy specimens. 69 Test Finding Cytology and "Owl's-eye" inclusion body histology Antigen detection In situ DNA probe hybridization Polymerase chain reaction (PCR) Cell culture Cytologic effect in human diploid fibroblasts Immunofluorescence detection of early antigens (most common) PCR Serology Primary infection 70  Treatment of CMV Ganciclovir - is the drug of choice. – However, it is associated with neutropenia and trombocytopenia. Forscarnet - can be used as the 2nd line drug. – Again it is very toxic and is associated with renal toxicity. Cifofovir - approved for the treatment of CMV retinitis. – It is also associated with renal toxicity. Fomivirsen - is approved for the treatment of CMV retinitis. CMV hyperimmune globulin - found to be effective against CMV pneumonitis. 71 Epstein-Barr Virus 72  Epstein-Barr Virus EBV is a member of the subfamily Gamma herpes virinae, – with a very limited host range and a tissue tropism defined by the limited cellular expression of its receptor. – Dual cell tropism human B-lymphocytes (generally non-productive infection) epithelial cells (productive infection). B cells of humans and New World monkeys and on some epithelial cells of the oropharynx and nasopharynx. 73  EBV infection has the following three potential outcomes: – EBV can replicate in B cells or epithelial cells permissive for EBV replication. – EBV can cause latent infection of B cells in the presence of competent T cells. It can directly enters a latent state in the lymphocyte without undergoing a period of viral replication. – EBV can stimulate and immortalize B cells. When virus binds to the cell surface, cells are activated to enter the cell cycle. – Subsequently, a limited repertoire of EBV genes are expressed, and the cells are able to proliferate indefinitely. 74  Epstein-Barr Virus EBV causes – Heterophile antibody-positive infectious mononucleosis – Endemic Burkitt's lymphoma, – Hodgkin's disease, and – Nasopharyngeal carcinoma. EBV has also been associated with B-cell lymphomas in patients with acquired or congenital immunodeficiencies. – EBV stimulates the growth and immortalizes B cells in tissue culture. 75  Epidemiology Transmission – Transmission occurs via saliva, close oral contact ("kissing disease"), or sharing of items such as toothbrushes and cups. Risk Groups – Children: Asymptomatic disease or mild symptoms. – Teenagers and adults: At risk for infectious mononucleosis. – Immunocompromised people: At highest risk for life- threatening neoplastic disease. There are no modes of control. 76  Pathogenesis Virus in saliva initiates infection of oral epithelia and spreads to B cells in lymphatic tissue. There is productive infection of epithelial and B cells. Virus promotes growth of B cells (immortalizes). T cells kill and limit B-cell outgrowth. T cells are required for controlling infection. Antibody role is limited. EBV establishes latency in memory B cells and is reactivated when the B cell is activated. 77  Pathogenesis T-cell response (lymphocytosis) contributes to symptoms of infectious mononucleosis. There is causative association with lymphoma in immunosuppressed people and African children living in malarial regions (African Burkitt's lymphoma) and with nasopharyngeal carcinoma in China 78  Disease Association 1. Infectious Mononucleosis 2. Burkitt's lymphoma 3. Nasopharyngeal carcinoma 4. Lymphoproliferative disease and lymphoma in the immunosuppressed. 5. X-linked lymphoproliferative syndrome 6. Chronic infectious mononucleosis 7. Oral leukoplakia in AIDS patients 8. Chronic interstitial pneumonitis in AIDS patients. 79  Infectious Mononuclosis In some patients, chronic IM may occur where eventually the patient dies of lymphoproliferative disease or lymphoma. Diagnosis of IM is usually made by the heterophil antibody test and/or detection of EBV IgM. There is no specific treatment. 80  Infectious Mononuclosis Atypical T-cell (Downey cell) characteristic of infectious mononucleosis. The cells have a more basophilic and vacuolated cytoplasm than normal lymphocytes the nucleus may be oval, kidney shaped, or lobulated. 81 Infectious Mononuclosis 82  Burkitt’s Lymphoma (1) Burkitt's lymphoma (BL) is a tumor of the jaw that occurs endemically in parts of Africa (where it is the commonest childhood tumour) and Papua New Guinea. It usually occurs in children aged 3-14 years. It respond favorably to chemotherapy. It is restricted to areas with holoendemic malaria. Therefore it appears that malaria infection is a cofactor. Multiple copies of EBV genome and some EBV antigens can be found in BL cells patients with BL have high titres of antibodies against various EBV antigens. Sporadic cases of BL occur, especially in AIDS patients which may or may not be associated with EBV. 83  Nasopharyngeal Carcinoma Nasopharyngeal carcinoma (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. The tumour is rare in most parts of the world, though pockets occur in N. and C. Africa, Malaysia, Alaska, and Iceland. 84  Hairy leukoplakia Often presents as white plaques or warts on the lateral surface of the tongue and is associated with EBV infection. 85  Immunocompromised Patients After primary infection, EBV maintains a steady low grade latent infection in the body. Should the person become immunocompromised – the virus will reactivate. In a few cases, lymphoproliferative lesions and lymphoma may develop. These lesions tend to be extranodal and in unusual sites such as the GI tract or the CNS. Transplant recipients e.g. renal - EBV is associated with the development of lymphoproliferative disease and lymphoma. 86  Laboratory Diagnosis Acute EBV infection is usually made by the heterophil antibody test and/or detection of anti-EBV VCA IgM. (VCA – Viral Capsid Antigen) Cases of Burkitt’s lymphoma should be diagnosed by histology. The tumour can be stained with antibodies to lambda light chains which should reveal a monoclonal tumour of B-cell origin. In over 90% of cases, the cells express IgM at the cell surface. 87  Treatment and prevention Vaccination – Under trial There is no effective EBV vaccine available. A vaccine against EBV which prevents primary EBV infection should be able to control both BL and NPC. Such a vaccine must be given early in life. Such a vaccine would also be useful in seronegative organtransplant recipients and those developing severe IM, such as the male offspring of X-linked proliferative syndrome carriers. 88