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HERPESVIRUSES Properties of herpesviruses Enveloped double stranded DNA viruses. Genome consisits of long and short fragments which may be orientated in either direction, giving a total of 4 isomers. Three subfamilies: – Alphaherpesviruses - HSV-1, HSV-2, VZV – Betaherpesviruses - CMV, HHV-6, HHV-7 – Gammaherpesviruses - EBV, HHV-8 Set up latent or persistent infection following primary infection Reactivation are more likely to take place during periods of immunosuppression Both primary infection and reactivation are likely to be more serious in immunocompromised patients. Herpesvirus Size: 180-200nm Replication: Nuclear. Assembly: Nuclear. Envelope: Present; associated glycoproteins. Tegument: Protein-filled region between capsid and envelope. Capsid: Icosahedral, 95-105nm diameter; 162 hexagonal capsomers. Core: DNA around protein , ~75nm Genome: Linear, d/s DNA, 105-235kbp Common Antigens:None Herpes viruses can replicate in human diploid cells except of BBV Produce cytopathic effect(CPE) Intranuclear acidophilic inclusion bodies Categories of herpes virus 正式命名 常用名 病毒亚科 重要生物学性状 所致疾病 人类疱疹病毒1型 (HHV-1) 单纯疱疹病毒1型 (HSV-1) 繁殖快、杀细胞性感染 感觉神经节中潜伏 唇疱疹、龈口炎、角膜结膜炎、 脑炎等 人类疱疹病毒2型 (HHV-2) 单纯疱疹病毒2型 (HSV-2) 同上 生殖器疱疹、新生儿疱疹 人类疱疹病毒3型 (HHV-3) 水痘-带状疱疹病毒 (VZV) 同上 水痘、带状疱疹、脑炎 人类疱疹病毒4型 (HHV-4) Epstein-Barr病毒 (EBV) 淋巴细胞中繁殖与潜伏 传染性单核细胞增多症、 Burkitt淋巴瘤、鼻咽癌(?) 等 人类疱疹病毒5型 (HHV-5) 人类巨细胞病毒 常在淋巴细胞、肾脏及 分泌腺体中潜伏 先天性巨细胞包涵体病、单核细 胞增多症、间质性肺炎、先 天性畸形、肝炎 人类疱疹病毒6型 (HHV-6) 人类疱疹病毒6型 同人巨细胞病毒 婴儿急疹、间质性肺炎、骨髓抑 制 人类疱疹病毒7型 (HHV-7) 人类疱疹病毒7型 同人巨细胞病毒 未明确 人类疱疹病毒8型 (HHV-8) 人类疱疹病毒8型 同EB病毒 Kaposi肉瘤 弥猴疱疹病毒1 猿猴B病毒 同HSV 脊髓炎、出血性脑炎 1 Herpes Simplex Viruses Properties Belong to the alphaherpesvirus subfamily of herpesviruses ds DNA enveloped virus with a genome of around 150 kb The genome of HSV-1 and HSV-2 share 50 - 70% homology. They also share several cross-reactive epitopes with each other. There is also antigenic crossreaction with VZV. Man is the only natural host for HSV. Epidemiology (1) HSV is spread by contact, as the virus is shed in saliva, tears, genital and other secretions. By far the most common form of infection results from a kiss given to a child or adult from a person shedding the virus. Primary infection is usually trivial or subclinical in most individuals. It is a disease mainly of very young children ie. those below 5 years. There are 2 peaks of incidence, the first at 0 - 5 years and the second in the late teens, when sexual activity commences. About 10% of the population acquires HSV infection through the genital route and the risk is concentrated in young adulthood. Epidemiology (2) Generally HSV-1 causes infection above the belt and HSV-2 below the belt. In fact, 40% of clinical isolates from genital sores are HSV-1, and 5% of strains isolated from the facial area are HSV-2. This data is complicated by oral sexual practices. Following primary infection, 45% of orally infected individuals and 60% of patients with genital herpes will experience recurrences. The actual frequency of recurrences varies widely between individuals. Pathogenesis During the primary infection, HSV spreads locally and a short-lived viraemia occurs, whereby the virus is disseminated in the body. Spread to the to craniospinal ganglia occurs. The virus then establishes latency in the craniospinal ganglia. The exact mechanism of latency is not known, it may be true latency where there is no viral replication or viral persistence where there is a low level of viral replication. Reactivation - It is well known that many triggers can provoke a recurrence. These include physical or psychological stress, infection; especially pneumococcal and meningococcal, fever, irradiation; including sunlight, and menstruation. Pathogenesis Clinical Manifestations HSV is involved in a variety of clinical manifestations which includes ;1. Acute gingivostomatitis龈口炎 2. Herpes Labialis (cold sore)唇疱疹 3. Ocular Herpes 4. Herpes Genitalis 5. Other forms of cutaneous herpes 7. Meningitis 8. Encephalitis 9. Neonatal herpes Oral-facial Herpes Acute Gingivostomatitis – Acute gingivostomatitis is the commonest manifestation of primary herpetic infection. – The patient experiences pain and bleeding of the gums. 1 - 8 mm ulcers with necrotic bases are present. Neck glands are commonly enlarged accompanied by fever. – Usually a self limiting disease which lasts around 13 days. Herpes labialis (cold sore) – Following primary infection, 45% of orally infected individuals will experience reactivation. The actual frequency of recurrences varies widely between individuals. – Herpes labialis (cold sore) is a recurrence of oral HSV. – A prodrome of tingling, warmth or itching at the site usually heralds the recurrence. About 12 hours later, redness appears followed by papules and then vesicles. Ocular Herpes HSV causes a broad spectrum of ocular disease, ranging from mild superficial lesions involving the external eye, to severe sight-threatening diseases of the inner eye. Diseases caused include the following:– Primary HSV keratitis – dendritic ulcers – Recurrent HSV keratitis – HSV conjunctivitis – Iridocyclitis虹膜睫状体炎 , chorioretinitis 脉络膜视 网膜炎and cataract白内障 Genital Herpes Genital lesions may be primary, recurrent or initial. Many sites can be involved which includes the penis, vagina, cervix, anus, vulva, bladder, the sacral nerve routes, the spinal and the meninges. The lesions of genital herpes are particularly prone to secondary bacterial infection eg. S.aureus, Streptococcus, Trichomonas and Candida Albicans. Dysuria is a common complaint, in severe cases, there may be urinary retention. Local sensory nerves may be involved leading to the development of a radiculitis. A mild meningitis may be present. Herpes Simplex Encephalitis Herpes Simplex encephalitis is one of the most serious complications of herpes simplex disease. There are two forms: Neonatal – there is global involvement and the brain is almost liquefied. The mortality rate approaches 100%. Focal disease – the temporal lobe is most commonly affected. This form of the disease appears in children and adults. It is possible that many of these cases arise from reactivation of virus. The mortality rate is high (70%) without treatment. It is of utmost importance to make a diagnosis of HSE early. It is general practice that IV acyclovir is given in all cases of suspected HSE before laboratory results are available. Neonatal Herpes Simplex (1) Incidence of neonatal HSV infection varies inexplicably from country to country e.g. from 1 in 4000 live births in the U.S. to 1 in 10000 live births in the UK The baby is usually infected perinatally during passage through the birth canal. Premature rupturing of the membranes is a well recognized risk factor. The risk of perinatal transmission is greatest when there is a florid primary infection in the mother. There is an appreciably smaller risk from recurrent lesions in the mother, probably because of the lower viral load and the presence of specific antibody The baby may also be infected from other sources such as oral lesions from the mother or a herpetic whitlow in a nurse. Neonatal Herpes Simplex (2) The spectrum of neonatal HSV infection varies from a mild disease localized to the skin to a fatal disseminated infection. Infection is particularly dangerous in premature infants. Where dissemination occurs, the organs most commonly involved are the liver, adrenals and the brain. Where the brain is involved, the prognosis is particularly severe. The encephalitis is global and of such severity that the brain may be liquefied. A large proportion of survivors of neonatal HSV infection have residual disabilities. Acyclovir should be promptly given in all suspected cases of neonatal HSV infection. The only means of prevention is to offer caesarean section to mothers with florid genital HSV lesions. Other Manifestations Disseminated herpes simplex are much more likely to occur in immunocompromised individuals. The widespread vesicular resembles that of chickenpox. Many organs other than the skin may be involved e.g. liver, spleen, lungs, and CNS. Other cutaneous manifestations include – eczema herpeticum which is potentially a serious disease that occurs in patients with eczema. – Herpetic whitlow which arise from implantation of the virus into the skin and typically affect the fingers. – “zosteriform herpes simplex". This is a rare presentation of herpes simplex where HSV lesions appear in a dermatomal distribution similar to herpes zoster. Laboratory Diagnosis Direct Detection – 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 – HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes only 1 - 5 days for a result to be available. Serology – Not that useful in the acute phase because it takes 1-2 weeks for before antibodies appear after infection. Used to document to recent infection. Cytopathic Effect of HSV in cell culture: Note the ballooning of cells. (Linda Stannard, University of Cape Town, S.A.) Positive immunofluorescence test for HSV antigen in epithelial cell. (Virology Laboratory, New-Yale Haven Hospital) Management 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 – this the drug of choice for most situations at present. It is available in a number of formulations: 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 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 2 Varicella- Zoster Virus Properties Belong to the alphaherpesvirus subfamily of herpesviruses ds DNA enveloped virus Genome size 125 kbp, long and short fragments with a total of 4 isometric forms. One antigenic serotype only, although there is some cross reaction with HSV. Epidemiology Primary varicella is an endemic disease. Varicella is one of the classic diseases of childhood, with the highest prevalence occurring in the 4 - 10 years old age group. Varicella is highly communicable, with an attack rate of 90% in close contacts. Most people become infected before adulthood but 10% of young adults remain susceptible. Herpes zoster, in contrast, occurs sporadically and evenly throughout the year. Pathogenesis The virus is thought to gain entry via the respiratory tract and spreads shortly after to the lymphoid system. After an incubation period of 14 days, the virus arrives at its main target organ, the skin. Following the primary infection, the virus remains latent in the cerebral or posterior root ganglia. In 10 - 20% of individuals, a single recurrent infection occurs after several decades. The virus reactivates in the ganglion and tracks down the sensory nerve to the area of the skin innervated by the nerve, producing a varicellaform Pathogenesis shingles Varicella Primary infection results in varicella (chicken-pox) Incubation period of 14-21 days Presents fever, lymphadadenopathy. a widespread vesicular rash. The features are so characteristic that a diagnosis can usually be made on clinical grounds alone. Complications are rare but occurs more frequently and with greater severity in adults and immunocompromised patients. Most common complication is secondary bacterial infection of the vesicles. Severe complications which may be life threatening Rash of Chickenpox Herpes Zoster (Shingles) Herpes Zoster mainly affect a single dermatome of the skin. It may occur at any age but the vast majority of patients are more than 50 years of age. The latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment. There is a characteristic eruption of vesicles in the dermatome which is often accompanied by intensive pain which may last for months (postherpetic neuralgia) Herpes zoster affecting the eye and face may pose great problems. As with varicella, herpes zoster in a far greater problem in immunocompromised patients in whom the reactivation occurs earlier in life and multiple attacks occur as well as complications. Complications are rare and include encephalitis and disseminated herpes zoster. Shingles Congenital VZV Infection 90% of pregnant women already immune, therefore primary infection is rare during pregnancy. Primary infection during pregnancy carries a greater risk of severe disease, in particular pneumonia. First 20 weeks of Pregnancy Up to 3% chance of transmission to the fetus, recognised congenital varicella syndrome; – – – – Scarring of skin Hypoplasia of limbs CNS and eye defects Death in infancy normal Neonatal Varicella VZV can cross the placenta in the late stages of pregnancy to infect the fetus congenitally. Neonatal varicella may vary from a mild disease to a fatal disseminated infection. If rash in mother occurs more than 1 week before delivery, then sufficient immunity would have been transferred to the fetus. Zoster immunoglobulin should be given to susceptible pregnant women who had contact with suspected cases of varicella. Zoster immunoglobulin should also be given to infants whose mothers develop varicella Laboratory Diagnosis The clinical presentations of varicella or zoster are so characteristic that laboratory confirmation is rarely required. Laboratory diagnosis is required only for atypical presentations, particularly in the immunocompromised. – – – Virus Isolation - rarely carried out as it requires 2-3 weeks for a results. Direct detection - electron microscopy may be used for vesicle fluids but cannot distinguish between HSV and VZV. Immunofluorescense on skin scrappings can distinguish between the two. Serology - the presence of VZV IgG is indicative of past infection and immunity. The presence of IgM is indicative of recent primary infection. Cytopathic Effect of VZV Cytopathic Effect of VZV in cell culture: Note the ballooning of cells. (Coutesy of Linda Stannard, University of Cape Town, S.A.) Management Uncomplicated varicella is a self limited disease and requires no specific treatment. However, acyclovir had been shown to accelerate the resolution of the disease and is prescribed by some doctors. Acyclovir should be given promptly immunocompromised individuals with varicella infection and normal individuals with serious complications such as pneumonia and encephalitis. herpes zoster in a healthy individual is not normally a cause for concern. The main problem is the management of the postherpetic neuralgia. The International Herpes Management Forum recommends that antiviral therapy should be offered routinely to all patients over 50 years of age presenting with herpes zoster. Three drugs can be used for the treatment of herpes zoster: acyclovir, valicyclovir, and famciclovir. There appears to be little difference in efficacy between them. Prevention Preventive measures should be considered for individuals at risk of contracting severe varicella infection e.g. leukaemic children, neonates, and pregnant women Where urgent protection is needed, passive immunization should be given. Zoster immunoglobulin (ZIG) is the preparation of choice but it is very expensive. Where ZIG is not available, HNIG should be given instead. A live attenuated vaccine is available. There had been great reluctance to use it in the past, especially in immunocompromised individuals since the vaccine virus can become latent and reactivate later on. However, recent data suggests that the vaccine is safe, even in children with leukaemia provided that they are in remission. It is highly debatable whether universal vaccination should be offered since chickenpox and shingles are normally mild diseases. 3 Cytomegalovirus Properties Belong to the betaherpesvirus subfamily of herpesviruses ds DNA enveloped virus Nucleocapsid 105nm in diameter, 162 capsomers The structure of the genome of CMV is similar to other herpesviruses, consisting of long and short segments which may be orientated in either direction, giving a total of 4 isomers. A large no. of proteins are encoded for, the precise number is unknown. Epidemiology CMV is one of the most successful human pathogens, it can be transmitted vertically or horizontally usually with little effect on the host. Transmission may occur in utero, perinatally or postnatally. Once infected, the person carries the virus for life which may be activated from time to time, during which infectious virions appear in the urine and the saliva. Reactivation can also lead to vertical transmission. It is also possible for people who have experienced primary infection to be reinfected with another or the same strain of CMV, this reinfection does not differ clinically from reactivation. In developed countries with a high standard of hygiene, 40% of adolescents are infected and ultimately 70% of the population is infected. In developing countries, over 90% of people are ultimately infected. Pathogenesis Once infected, the virus remains in the person for life and my be reactivated from time to time, especially in immunocompromised individuals. The virus may be transmitted in utero, perinatally, or postnatally. Perinatal transmission occurs. Perinatal infection is acquired mainly through infected genital secretions, or breast milk. Overall, 2 10% of infants are infected by the age of 6 months worldwide. Perinatal infection is thought to be 10 times more common than congenital infection. Postnatal infection mainly occurs through saliva. Sexual transmission may occur as well as through blood and blood products and transplanted organ. Clinical Manifestations Congenital infection - may result in cytomegalic inclusion disease Perinatal infection - usually asymptomatic Postnatal infection - usually asymptomatic. However, in a minority of cases, the syndrome of infectious mononucleosis may develop which consists of fever, lymphadenopathy, and splenomegaly. The heterophil antibody test is negative although atypical lymphocytes may be found in the blood. Immunocompromised patients such as transplant recipients and AIDS patients are prone to severe CMV disease such as pneumonitis, retinitis, colitis, and encephalopathy. Reactivation or reinfection with CMV is usually asymptomatic except in immunocompromised patients. Congenital Infection Defined as the isolation of CMV from the saliva or urine within 3 weeks of birth. Commonest congenital viral infection, affects 0.3 - 1% of all live births. The second most common cause of mental handicap after Down's syndrome and is responsible for more cases of congenital damage than rubella. Transmission to the fetus may occur following primary or recurrent CMV infection. 40% chance of transmission to the fetus following a primary infection. May be transmitted to the fetus during all stages of pregnancy. Cytomegalic Inclusion Disease CNS abnormalities - microcephaly, mental retardation, spasticity, epilepsy, periventricular calcification. Eye - choroidoretinitis and optic atrophy Ear - sensorineural deafness Liver - hepatosplenomegaly and jaundice which is due to hepatitis. Lung - pneumonitis Heart - myocarditis Thrombocytopenic purpura, Haemolytic anaemia Late sequelae in individuals asymptomatic at birth - Incidence of Cytomegalic Disease Laboratory Diagnosis (1) Direct detection – biopsy specimens may be examined histologically for CMV inclusion antibodies or for the presence of CMV antigens. However, the sensitivity may be low. – The pp65 CMV antigenaemia test is now routinely used for the rapid diagnosis of CMV infection in immunocompromised patients. – PCR for CMV-DNA is used in some centers but there may be problems with interpretation. CMV pp65 antigenaemia test (Virology Laboratory, New-Yale Haven Hospital) Laboratory Diagnosis (2) Virus Isolation – conventional cell culture is regarded as gold standard but requires up to 4 weeks for result. – More useful are rapid culture methods such as the DEAFF test which can provide a result in 24-48 hours. Serology – the presence of CMV IgG antibody indicates past infection. – The detection of IgM is indicative of primary infection although it may also be found in immunocompromised patients with reactivation. Cytopathic Effect of CMV DEAFF test for CMV Specimens for Laboratory Diagnosis Treatment Congenital infections - it is not usually possible to detect congenital infection unless the mother has symptoms of primary infection. If so, then the mother should be told of the chances of her baby having cytomegalic inclusion disease and perhaps offered the choice of an abortion. Perinatal and postnatal infection - it is usually not necessary to treat such patients. Immunocompromised patients - it is necessary to make a diagnosis of CMV infection early and give prompt antiviral therapy. Anti-CMV agents in current use are ganciclovir, forscarnet, and cidofovir. Prevention No licensed vaccine is available. There is a candidate live attenuated vaccine known as the Towne strain but there are concerns about administering a live vaccine which could become latent and reactivates. Prevention of CMV disease in transplant recipients is a very complicated subject and varies from center to center. It may include the following measures. – 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 – Give antiviral agents such as acyclovir and ganciclovir prophylactically. 4 Epstein-Barr Virus Pathogenesis Transformation of B cells Burkitt's lymphoma Nasopharyngeal cancer Oral hairy leukoplakia Infectious mononucleosis Epstein-Barr Virus (EBV) Belong to the gammaherpesvirus subfamily of herpesviruses Nucleocapsid 100 nm in diameter, with 162 capsomers Membrane is derived by budding of immature particles through cell membrane and is required for infectivity. Genome is a linear double stranded DNA molecule with 172 kbp The viral genome does not normally integrate into the cellular DNA but forms circular episomes which reside in the nucleus. The genome is large enough to code for 100 - 200 proteins but only a few have been identified. Epidemiology Two epidemiological patterns are seen with EBV. In developed countries, 2 peaks of infection are seen : the first in very young preschool children aged 1 - 6 and the second in 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 Once infected, a lifelong carrier state develops whereby a low grade infection is kept in check by the immune defenses. 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 Furthermore 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 where it may act directly or one of several co-factors. Disease Association 1. Infectious Mononucleosis(IM) 2. Burkitt's lymphoma( BL) 3. Nasopharyngeal carcinoma( NPC) 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. Infectious Mononuclosis Primary EBV infection is usually subclinical in childhood. However in adolescents and adults, there is a 50% chance that the syndrome of infectious mononucleosis (IM) will develop. IM is usually a self-limited disease which consists of fever, lymphadenopathy and splenomegaly. In some patients jaundice may be seen which is due to hepatitis. Atypical lymphocytes are present in the blood. Complications occur rarely but may be serious e.g. splenic rupture, meningoencephalitis, and pharyngeal obstruction. In some patients, chronic IM may occur where eventually the patient dies of lymphoproliferative disease or lymphoma. Burkitt’s Lymphoma (1) Burkitt's lymphoma (BL) 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 and patients with BL have high titres of antibodies against various EBV antigens. Burkitt’s Lymphoma (2) BL cells show a reciprocal translocation between the long arm of chromosome 8 and chromosomes 14, 2 or 22. This translocation result in the c-myc oncogene being transferred to the Immunoglobulin gene regions. This results in the deregulation of the c-myc gene. It is thought that this translocation is probably already present by the time of EBV infection and is not caused by EBV. Sporadic cases of BL occur, especially in AIDS patients which may or may not be associated with EBV. In theory BL can be controlled by the eradication of malaria (as has happened in Papua New Guinea) or vaccination against EBV. Burkitt's Lymphoma 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. Multiple copies of EBV genome and EBV EBNA-1 antigen can be found in cells of undifferentiated NPC. Patients with NPC have high titres of antibodies against various EBV antigens. Besides EBV there appears to be a number of environmental and genetic cofactors in NPC. NPC usually presents late and thus the prognosis is poor. 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. AIDS patients - EBV is 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 . This condition accounts for half of the fatal cases of IM. Diagnosis Acute EBV infection is usually made by the heterophil antibody test and/or detection of anti-EBV VCA IgM. 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. Cases of NPC should be diagnosed by histology. The determination of the titre of anti-EBV VCA IgA in screening for early lesions of NPC and also for monitoring treatment. A patient with with non-specific ENT symptoms who have elevated titres of EBV IgA should be given a thorough examination. Vaccination 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 organ transplant recipients and those developing severe IM, such as the male offspring of X-linked proliferative syndrome carriers. The vaccine should not preferably be a subunit vaccine since there is a danger that a live vaccine may still have tumorigenic properties. The antigen chosen for vaccine development is the MA antigen gp 340/220 as antibodies against this antigen are virus neutralizing. This vaccine is being tried in Africa. Epidemiology and Pathogenesis HHV-6 and HHV-7 are ubiquitous and are found worldwide. They are transmitted mainly through contact with saliva and through breast feeding. HHV-6 and HHV-7 infection are acquired rapidly after the age of 4 months when the effect of maternal antibody wears off. By the time of adulthood, 90-99% of the population had been infected by both viruses. Like other herpesviruses, HHV-6 and HHV-7 remains latent in the body after primary infection and reactivates from time to time. Roseala Infantum Kaposi’s Sarcoma Human herpes virus 6 Worldwide In the saliva of the majority of adults (>90%). It infects almost all children by the age of two and the infection is life-long. Again, it replicates in B and T lymphocytes, megakaryocytes, etc Latent infection in T cells . Infected cells are larger than normal with inclusions in both cytoplasm and nucleus. Cell-mediated immunity is essential in control, although infection is life-long, and the virus can reactivate in immune-suppression. Pathogenesis Two forms: HHV-6A and HHV-6B. The latter causes exanthem subitum, otherwise known as roseola infantum. This a common disease of young children (in the US >45% of children are seropositive for HHV-6 by two years of age) and symptoms include fever and sometimes upper respiratory tract infection and lymphadenopathy. Incubation period : 14 days. Pathogenesis The fever subsides leaving a macropapular rash on the trunk and neck that last a few days longer. In adults, primary infection is associated with a mononucleosis. Patients with HIV have a higher infection rate than the normal population. HHV-6 has been associated with a number of neurological disorders, including encephalitis and seizures. It has been postulated to play a role in multiple sclerosis and chronic fatigue immunodeficiency syndrome. Human herpes virus 7 This virus binds to the CD4 antigen and replicates in T4 (CD4+) cells and is found in the saliva of the majority of the adult population (>75%). Most people acquire the infection as children and it remains with them for the rest of their lives. It is similar to HHV-6 and may be responsible for some cases of exanthem subitum Human herpes virus 8 This was formerly known as Kaposi`s sarcoma associated herpes virus and is found in the saliva of many AIDS patients. It infects peripheral blood lymphocytes. The distribution of the virus may explain why some populations of HIV-infected people go down with Kaposi`s sarcoma