There are eight Herpesvirus which cause infections in human
| Herpesvirus infections | |
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| Virus | Infection |
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| Cytomegalovirus (CMV) |
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| Epstein-Barr virus (EBV) |
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| Varicella zoster virus (VZV) |
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| Human herpesvirus 6 (HHV 6) and 7 (HHV 7) | Exanthem subitum ? Disease in immunocompromised patients |
| Human herpesvirus 8 (HHV 8) | Associated with Kaposi's sarcoma |
Herpes simplex virus (HSV) type 1, human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are ubiquitous agents which commonly cause asymptomatic infection in early life--hence many adults have serological evidence of infection with these agents. Varicella zoster virus (VZV) usually causes clinical infection (chickenpox) in childhood and 80% of adults will have antibodies to the virus in their blood. Following primary infection all herpesviruses establish latent infection and persist in the body for life; they may subsequently reactivate from latency. In normal people VZV may reactivate to cause herpes zoster (shingles) in later life and HSV may reactivate to produce recurrent lesions on the face (eye and lips) or external genitalia. However, reactivation of CMV and EBV usually only causes disease if the patient has become immunosuppressed. HHV 6 and HHV 8 have only been isolated in the last decade.
HERPES SIMPLEX VIRUS INFECTIONS
Herpes simplex virus (HSV) is a common virus which frequently causes asymptomatic infection, often in childhood; hence many people have serum antibodies to the organism. It has assumed greater importance as a cause of serious, and sometimes fatal, infections in immunocompromised patients. There are two strains of HSV, type 1 and type 2, the latter being principally responsible for sexually transmitted anogenital infections Infections caused by these viruses can be categorised as primary or recurrent.
Clinical features
Primary infectionThis may produce gingivostomatitis and pharyngitis (most common in infants), keratitis (dendritic ulcer), finger infections (whitlows), vulvovaginitis, balanitis and encephalitis.
Recurrent infectionHSV becomes latent in sensory ganglia, from where it may reactivate. HSV recurrent infections are most common on the lips and adjoining skin (herpes labialis or cold sore'). The lesions start as macules, and become vesicular and then pustular . Attacks of herpes labialis may be precipitated by various stimuli including sunlight, menstruation and viral and bacterial infections. Genital lesions (usually due to HSV 2) also commonly recur.
ComplicationsIn neonates HSV infection may be disseminated, involving many organs and tissues, and can be fatal. In the immunosuppressed (patients with lymphoma, leukaemia or AIDS) progressive mucocutaneous, and occasionally disseminated, infection may occur. The newborn may contract the infection from the mother's genital tract during birth and active genital HSV infection may be an indication for Caesarean section. although aciclovir treatment may now be an alternative.
HSV encephalitis is the most serious complication of HSV infection; it may occur with primary or recurrent infection and is characterised by a necrotising haemorrhagic encephalitis, mainly affecting the temporal lobes. Although not common, it is one of the most common causes of acute viral encephalitis in the UK and it is striking that most cases are seen in apparently normal immunocompetent patients. Untreated, it carries a high mortality (around 80%) and, if suspected, is an indication for immediate high-dose intravenous aciclovir.
InvestigationsThe virus can be cultured from lesions, or identified by electron microscopy. Detection by PCR from cerebrospinal fluid is increasingly used, and shows good specificity for HSV encephalitis. Serology is of limited use except in primary infection.
ManagementHSV is sensitive to aciclovir and the newer related nucleoside analogues, famciclovir and valaciclovir (a prodrug of aciclovir), although most infections in the immunocompetent resolve spontaneously. Drops containing aciclovir are effective in eye infections. Intravenous aciclovir is indicated for disseminated infections in immunocompromised patients and also for HSV encephalitis. The adult dose for intravenous infusion is from 5-10 mg/kg 8-hourly, the higher dose being indicated for encephalitis and the immunosuppressed. Oral aciclovir is available for infections of the skin and mucous membranes; the dose is 200-400 mg 4–5 times daily. Aciclovir will not eradicate latent HSV from posterior root ganglia, but recurrent attacks can usually be prevented by giving continuous aciclovir 200-400 mg 12-hourly, with a drug-free period every 6-12 months. Resistance of HSV to aciclovir has only been seen in immunosuppressed patients who have been given the drug for long periods.
VARICELLA ZOSTER VIRUS INFECTIONSChickenpox (varicella) is caused by the varicella zoster virus (VZV) which spreads by droplets from the upper respiratory tract, or from the discharge from ruptured lesions on the skin, or through contact with herpes zoster. Herpes zoster is due to reactivation of VZV from a dorsal root ganglion. Although it can occur at all ages it is increasingly common with age and will eventually affect about 20% of the population.
Chickenpox is highly infectious and chiefly affects children under 10 years of age. Most children tolerate this disease well but, as often happens with viral infections, adults may develop a more severe illness. In patients who are immunocompromised, the disease may be severe or even fatal. The incubation period is 14–21 days.
Clinical features
ChickenpoxConstitutional symptoms are usually brief and mild in children but can be severe in adults. Lesions are sometimes present on the palate before the characteristic rash appears on the trunk on the second day of the illness, Then the face and finally the limbs are involved. The spots reach their maximum density upon the trunk, and are more sparse on the periphery of the limbs. Macules appear first, and within a few hours the lesions become papular, then vesicular and, within 24 hours, pustular. Damage from scratching is frequent, since itching may be troublesome. Whether or not the pustules rupture, they dry up in a few days to form scabs. The spots appear in crops, so that lesions at all stages of development are seen in any area at the same time.
Herpes zosterThis is characterised first by pain and then by a vesicular rash in a dermatomal distribution; it may be accompanied by a scanty varicelliform rash in the immunocompetent.
ComplicationsThe course of chickenpox is usually uneventful but complications occasionally occur and are more common in adults. Pneumonia may be severe in adults, especially in pregnant women, patients who smoke and the immunosuppressed; it is not always accompanied by clinical chickenpox.
| COMPLICATIONS OF CHICKENPOX |
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| Viral effects |
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| Secondary bacterial infection |
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| Intrauterine infection |
| Congenital limb defects (varicella embryopathy-rare) |
No specific treatment is required for chickenpox in the majority of patients. Aciclovir is indicated for the immunocompromised (10 mg/kg 8-hourly by intravenous infusion) and (orally or intravenously) for chickenpox in adults and older adolescents in whom the infection can be more severe than in children. If there is secondary infection a local antiseptic should be applied to the skin, e.g. chlorhexidine. If bacterial infection progresses, antibiotic such as flucloxacillin 500 mg 6-hourly should be prescribed.
For herpes zoster aciclovir, famciclovir and valaciclovir are all licensed; they shorten the disease if give early in the normal adult and are required to limit dissemination in the immunosuppressed.
PreventionImmunosuppressed patients, neonates and pregnant women who have no antibody to VZV and have had significant contact with chickenpox should be given an injection of human varicella zoster immunoglobulin. A live attenuated vaccine is available but is not yet licensed in the UK.
EPSTEIN-BARR VIRUS AND INFECTIOUS MONONUCLEOSIS (GLANDULAR FEVER)Infectious mononucleosis (glandular fever) is an acute infectious disease caused by primary infection with Epstein-Barr virus. It principally occurs in teenagers and young adults, although occasionally other age groups may be affected. The age at which primary infection occurs influences the likelihood of symptoms, seroconversion in young children is usually asymptomatic. The virus infects, and replicates primarily in, B lymphocytes and is shed in the throat following the acute disease. Transmission is, therefore, usually by oral contact, with exchange of saliva. The incubation period is probably between 7 and 10 days.
Clinical featuresThe infection usually presents with malaise, tiredness, headache, abdominal discomfort, anorexia and fever.The clinical features can be variable. The rash is especially common if ampicillin or amoxycillin has been given, occurring in around 90% of patients conditions to be excluded in the differential diagnosis include
| CLINICAL FEATURES OF INFECTIOUS MONONUCLEOSIS |
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| Acute illness |
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| Abnormal laboratory test |
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| Complications |
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cytomegalovirus infection, which toxoplasmosis and acute HIV infection, which can all present with lymphadenopathy, splenomegaly and fever with an atypically not usually sore throat).
InvestigationsThe diagnosis is suspected by the finding of a predominance of atypical lymphocytes in the peripheral blood and confirmed hy a positive Monospot or Paul-Bunnell test; these detect the presence of heterophile antibody (able to agglutinate ox or horse red cells). Specific virus serological tests are also available for diagnosis but are not required in most cases; IgM antibody to virus capsid antigen (VCA) indicates primary infection, whilst EBV carriers have IgG antibodies to VCA and EBV nuclear antigen (EBNA).
ComplicationsThese are listed in the information box. Chronic fatigue with prolonged debility, inability to concentrate, depression, tiredness and low-grade fever may follow infectious mononucleosis. However, in most cases the chronic fatigue syndrome, sometimes referred to as myalgic encephalomyelitis (ME), develops without preceding EBV mononucleosis, or indeed any other defined virus infection; it is believed there is frequently an underlying psychological component.
ManagementThis is entirely symptomatic. Rest is important during the acute illness. A 48-hour course of corticosteroids (e.g. intravenous hydrocortisone 200 mg 6-hourly or prednisolone 10 m 6-hourly if the patient can swallow) is indicated for severe tonsillar enlargement causing dysphagia or difficulty in breathing.
EBV-associated lymphomas and immunosuppressionCDV is associated with African Burkitt's lymphoma and with B-cell lymphomas in immunosuppressed patients (transplant recipients and AIDS patients). However, these tumours are also characterised by chromosomal translocations which result in increased expression of the c-myc oncogene, indicating that other factors besides EBV are involved in malignant transformation. Before this translocation and consequent clonal proliferation occur, some EBV-associated post-transplant lymphomas are initially polyclonal and may regress with cessation of immunosuppressive therapy alone, without requiring chemotherapy. This indicates the important role of antiviral T-cell responses in controlling the oncogenic potential of EBV in normal virus carriers.
EBV is associated with the proliferative epithelial lesion seen on the tongue of patients with AIDS-oral hairy leucoplakia. EBV DNA is also found in the cells of nasopharyngeal carcinoma , an epithelial malignancy with which it is believed to be causally associated, although the mechanism is unknown.
CYTOMEGALOVIRUS INFECTIONCMV is present in more than 50% of normal adults, and its seroprevalence increases with age. Primary infection may be asymptomatic or associated with a mononucleosis syndrome. CMV then becomes latent, probably mainly in monocytes, and symptomatic reactivation only occurs in the context of immunosuppression. It is shed in saliva and urine and from the genital tract; transmission is thus from contact with infected saliva or urine, or by sexual contact.
Clinical featuresThe various features of CMV infection are listed in the information box. CMV mononucleosis is similar to EBV mononucleosis without the prominent pharyngitis seen with the latter. Cytomegalovirus is a particularly important pathogen in immunosuppressed patients (organ and bone marrow allograft recipients and especially those with AIDS); primary infection and reactivation of latent infection cause much morbidity and mortality in these patients. CMV (along with rubella, toxoplasmosis and syphilis) is an important although rare (less than 0.5% of live births) cause of congenital infection which is acquired during a pregnancy in which the mother develops symptomatic or asymptomatic CMV infection-particularly primary infection. The child may be stillborn, or have features listed in the information box, although only about 20% of congenital CMV infection is symptomatic in the infant.
InvestigationsCMV may be cultured from blood and urine of infected
| CYTOMEGALOVIRUS INFECTION |
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| Congenital infection |
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| Acquired infection |
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patients--viraemia is usually associated with disease due to CMV. The DEAFF (detection of early antigen fluorescent foci) test allows quicker detection of virus in blood, and PCR-based methods are now becoming quite wide used to detect CMV in plasma. Rapid diagnosis is important in immunosuppressed patients. Diagnosis may also be confirmed by biopsy of infected tissue (e.g. lung or bowel). IgM antibody to CMV usually indicates primary infection but serology is less useful in immunosuppressed patients.
ManagementTwo main drugs are currently used to treat CMV disease in immunosuppressed patients (infection in normal people requires no treatment). Ganciclovir (a nucleoside analogue) is given by intravenous infusion over 1 hour, initially in a dose of 5 mg/kg 12-hourly for 14–21 days; it is myelotoxic and expensive. Foscarnet (trisodium phosphonoformate, a non-nucleoside inhibitor of the virus DNA polymerase) is generally just as effective as ganciclovir and also has to be given intravenously. An oral preparation of ganciclovir is available but is only appropriate for prevention of recurrent CMV disease in the immunosuppressed. Aciclovir is not effective for treatment of CMV. Patients with advanced AIDS usually require life-long prophylaxis after CMV disease, particularly retinitis, usually with ganciclovir.
HHV 6, HHV 7 AND HHV 8 INFECTIONHuman herpesvirus 6 (HHV 6) is a relatively recently discovered virus which is the cause of exanthem subitum (roseola infantum), a benign febrile illness of children, associated with a maculo-papular rash. It has also been associated with lymphadenopathy and may cause disease in the immunosuppressed. HHV 7 is a distinct but closely related herpesvirus to HHV 6 which probably produces a similar spectrum of disease.
Human herpesvirus 8 (HHV 8) has recently been isolated from patients with Kaposi's sarcoma (KS) associated with AIDS. It is present in the KS tumour cells (in AIDS and non-AIDS-associated forms of KS) and postulated, but not proven, to have a causal association. The seroepidemiology of this newly discovered virus is still being defined; present evidence suggests it is acquired mainly by sexual transmission in those populations at risk of KS, and is less widely prevalent than other herpesviruses.