Current Diagnosis & Treatment in Infectious Diseases

Section IV - Viral Infections

33. Herpesviruses

Lawrence W. Drew MD, PhD

The herpesvirus group of the family Herpesviridae comprises large, enveloped, double-stranded DNA viruses found in both animals and humans. They are ubiquitous and produce infections ranging from painful skin ulcers to chickenpox to encephalitis. The major members of the group to infect humans are the two herpes simplex viruses (HSV-1 and -2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), herpesvirus 6, and the recently discovered human herpesvirus types 7 and 8. Occasionally, the simian herpesvirus, herpes B virus, has caused human disease.

All herpesviruses are morphologically similar with an overall diameter of 180–200 nm. The nucleic acid core is ~ 30–45 nm in diameter, surrounded by an icosahedral capsid. The capsid is covered by a tegument and a lipoprotein envelope derived from the nuclear membrane of the infected host cell. The envelope contains at least nine glycoproteins that protrude beyond it as spikelike structures, while the tegument is a protein-filled area between the capsid and the envelope. Despite the morphologic similarity between these agents, substantial differences in the molecular composition of their genomes are reflected in their structural glycoproteins and polypeptides. Antigenic analysis is an important means for differentiation among herpesviruses despite some cross-reactions (eg, between HSV and VZV).

Susceptible tissue cultures vary significantly for the individual agents. HSV has the widest range; it replicates in numerous animal and human host cells. VZV is best grown in cells of human origin, although some laboratory-adapted strains can grow in primate cell lines. Human CMV replicates well only in human diploid fibroblast cell lines. EBV does not replicate in most commonly used cell culture systems but can be grown in continuous human or primate lymphoblastoid cell cultures. Human herpesvirus type 6 grows in lymphocyte cell cultures.

Characteristically, all of these agents produce an initial infection followed by a period of latent infection in which the genome of the virus is present in the cell, but infectious virus is not recovered. Reactivation of virus may then result in the first episode of clinically apparent disease or as recurrent disease. Complex host-virus interactions determine the expression of disease. With all of these agents, immunocompromised patients, especially those with altered cellular immunity, have more frequent and severe episodes, including clinically severe disease from reactivation of virus.

HERPES SIMPLEX VIRUS

Essentials of Diagnosis

  • Intranuclear inclusions and multinucleated giant cells in tissue cytology.
  • Grows rapidly in many types of tissue culture.
  • HSV antigen can be detected in tissue by immunofluorescence.
  • Polymerase Chain Reaction (PCR) analysis of cerebrospinal fluid (CSF) now considered best assay for HSV encephalitis.

General Considerations

  1. Epidemiology

The term herpes (from the Greek herpein, to creep) and the clinical description of cold sores date back to Hippocrates. Two distinct epidemiologic and antigenic types of HSVs exist (HSV-1 and HSV-2). HSVs have worldwide distribution. There are no known animal vectors, and humans appear to be the only natural reservoir (Box 33-1 shows the syndromes caused by HSV). Direct contact with infected secretions is the principal mode of spread. Seroepidemiologic studies indicate that the prevalence of HSV antibody varies directly with the age and socioeconomic status of the population studied. In most underdeveloped countries, 90% of the population have HSV-1 antibody by the age of 30. In the United States, HSV-1 antibody is currently found in ~ 50–60% of the middle-class population. Among lower socioeconomic groups, however, the percentage approaches 90%.

Detection of HSV-2 antibody before puberty is unusual. The virus is associated with sexual activity, and direct sexual transmission is the major mode of spread. Approximately 15–30% of sexually active adults in western industrialized countries have HSV-2 antibody. The virus can be isolated from the cervix and urethra of ~ 5–12% of adults attending sexually transmitted disease clinics; many of these patients are asymptomatic or have small, unnoticed lesions on penile or vulvar skin. Genital herpes is not a reportable disease in the United States, but it is estimated that 500,000 new cases occur per year.

  1. Microbiology

The DNA genomes of both types of HSV are linear, double-stranded molecules with molecular weights of ~ 108 and are composed of ~ 160 kilobase pairs. Their nucleic acids demonstrate ~ 50% base sequence homology, which is considerably greater than that shown between these viruses and other herpesviruses. HSV-1 and HSV-2 share antigens in almost all their surface glycoproteins and other structural polypeptides. Numerous strains of both HSV-1 and HSV-2 exist. In fact, by restriction endonuclease analysis of the viral genome, most isolates of HSV-1 or HSV-2 are found to differ somewhat, except in epidemiologically related cases such as mother-infant and sexual partner transfer.

  1. Pathogenesis

Herpes simplex virus produces both acute and latent infections.

  1. Acute Infection.In acute infections, the initial stages entail envelope glycoprotein-mediated attachment of the virus to unidentified receptors and fusion with the host cell membrane. Viral DNA released in the cytoplasm is transported through nuclear pores to the nucleus. New viral DNA synthesis and transcription of mRNA occur in the nucleus. The virus buds through the nuclear membrane; this process adds the envelope material to the virus particles, which are then transported through the cytoplasm and out of the cell in a manner similar to the movement of other proteins.

The molecular events involving synthesis of virus-specific gene products are coordinated and regulated. Three classes of mRNA coding for three groups of virus polypeptides have been identified. The products, designated the alpha or immediate early (IE) polypeptides, are synthesized 2–4 h after infection. These IE polypeptides probably function as regulators of viral transcription. The beta or early (E) polypeptides include virus-specified thymidine kinase (TK) and DNA polymerase (Pol). These virus-specified enzymes differ from host cell enzymes and are therefore important targets of antiviral chemotherapy. The synthesis of early polypeptides shuts off the synthesis of immediate early polypeptides and induces the synthesis of a third group of gamma or late (L) polypeptides. The late polypeptides, synthesized 12–15 h after infection, are the major structural components of the viral particle.

Pathologic changes during acute infections consist of development of multinucleated giant cells, ballooning degeneration of epithelial cells, focal necrosis, eosinophilic intranuclear inclusion bodies, and an inflammatory response characterized by an initial polymorphonuclear neutrophil infiltrate and a subsequent mononuclear cell infiltrate. The virus can spread intra- or interneuronally or through the supporting cellular networks of an axon or nerve, resulting in latent infection of sensory and autonomic nerve ganglia. The spread of virus can occur by cell-to-cell transfer and can therefore be unaffected by circulating immune globulin.

  1. Latent Infection.In humans, latent infection by HSV-1 has been demonstrated, by co-cultivation techniques, in trigeminal, superior cervical, and vagal nerve ganglia and occasionally in the S2-3 dorsal sensory nerve root ganglia. Latent HSV-2 infection has been demonstrated in the sacral (S2-3) ganglia. Latent infection of neural tissue by HSV does not result in the death of the cell; however, the exact mechanism of viral genome latency is incompletely understood. The HSV genome exists in a circular form in latently infected neuronal cells. Transcription of only a small portion of the viral genome is abortive and does not appear to be associated with detectable amounts of early eg, (Pol) or TK, or late polypeptides. Therefore, unfortunately, antiviral drugs directed at the viral DNA polymerase do not eradicate the virus in its latent state.

Reactivation of virus from latently infected ganglionic cells with subsequent release of infectious virions appears to account for most recurrences of both genital and oralabial infections. The mechanisms by which latent infection is reactivated are unknown. Precipitating factors that initiate reactivation of herpes simplex include fever, trauma (eg, oral intubation), and exposure to ultraviolet light.

  1. Immunity

Host factors have a major effect on clinical manifestations of HSV infection. Many episodes of HSV infection are either asymptomatic or mildly symptomatic. If initial clinical episodes of the disease are symptomatic, they are more severe than recurrent episodes, probably because of the presence of anti-HSV antibodies and immune lymphocytes in persons with recurrent infections.

Neutralizing antibodies directed against HSV envelope glycoproteins appear to be important protective responses, particularly those that mediate antibody-dependent cellular cytotoxicity (ADCC) reactions. ADCC may be important in limiting early spread of HSV. By the second week of infection, cytotoxic T lymphocytes can be detected that are able to destroy HSV-infected cells before completion of the replication cycle. Prior infection with HSV-1 may protect against or shorten the duration of symptoms and lesions during subsequent infection with HSV-2. In immunosuppressed patients, especially those with depressed cell-mediated immunity, reactivation of HSV may be associated with prolonged viral excretion and persistence of lesions.

BOX 33-1 Herpes Simplex Infection

 

Children

Adults

More Common

 

· Mucocutaneous lesions, oral or genital

Less Common

· HSV stomatitis

· HSV encephalitis

· HSV disseminated

· HSV meningitis, encephalitis

CLINICAL SYNDROMES

  1. HERPES SIMPLEX TYPE 1 (HSV-1)

Clinical manifestations of infection with HSV-1 usually are found above the waist. They consist characteristically of grouped or single vesicular lesions that become pustular and coalesce to form single or multiple ulcers. On dry surfaces, these ulcers scab before healing; on mucosal surfaces, they re-epithelialize directly. HSV can be isolated from almost all ulcerative lesions, but the titer of virus decreases as the lesions progress. Infections generally involve ectoderm (skin, mouth, vagina, conjunctiva, and nervous system).

Primary infection with HSV-1 is often asymptomatic. When clinically evident, it appears most frequently as gingivostomatitis with fever, and vesicular or ulcerative lesions involving the buccal mucosa, tongue, gums, and pharynx. The lesions are quite painful, and the illness usually lasts 5–12 days. After this initial infection, HSV may become latent within sensory nerve root ganglia of the trigeminal nerve.

Recurrent lesions usually appear on an area of the lip and the immediately adjacent skin; these lesions are described as mucocutaneous and are commonly called cold sores or fever blisters. Because reactivation is usually from a single latent source, these lesions are typically unilateral. Their recurrence may be signaled by premonitory tingling or burning in the area. Systemic complaints are unusual, and the episode generally lasts approximately 7 days. HSV may be reactivated and excreted into the saliva with no apparent mucosal lesions present. HSV has been isolated from saliva in 5–8% of children and 1–2% of adults who were asymptomatic at the time.

HSV sometimes infects the finger or nail area. This infection, termed herpetic Whitlow, usually results from the inoculation of infected secretions through a small cut in the skin. Painful vesicular lesions of the finger develop and pustulate and are often mistaken for bacterial infection and mistreated accordingly. Health care workers, especially nurses and respiratory therapists, are at particular risk for this entity.

HSV infection of the eye is one of the most common causes of corneal damage and blindness in the developed world. Infections usually involve the conjunctiva and cornea, and characteristic dendritic ulcerations are produced. With recurrence of disease, there may be deeper involvement with corneal scarring. Occasionally there may be extension into deeper structures of the eye, egiritis, especially if topical steroids are used.

HSV encephalitis is a rare result of HSV-1 infection, occurring in ~ 1–10 humans/million/year. Although rare, herpes encephalitis accounts for ~ 10% of all cases of documented viral encephalitis in the United States. Most cases occur in adults with high levels of anti-HSV-1 antibody, suggesting reactivation of latent virus in the trigeminal nerve root ganglion and extension of productive (lytic) infection into the temporoparietal area of the brain.

Since the disease usually affects one temporal lobe, focal neurologic signs are frequent. Clinically, the disease can resemble brain abscess, tumor, or intracerebral hemorrhage.

  1. HERPES SIMPLEX TYPE 2 (HSV-2)

Genital herpes is a common sexually transmitted disease. Both HSV-1 and HSV-2 can cause genital disease, and the symptoms and signs of acute infection are similar for both viruses. Of first episodes of genital HSV infection in the United States, 70% are caused by HSV-2. As with type 1 oral infection, the majority of genital infections are asymptomatic without lesions, and patients do not know they have been infected. Patients with asymptomatic genital HSV may be culture or PCR positive in genital secretions and are able to transmit the virus to sex partners.

  1. Primary Genital Herpes Infection.The mean incubation period from sexual contact to onset of lesions is 5 days. Lesions begin as small erythematous papules that soon form vesicles and then pustules. Within 3 to 5 days the vesiculopustular lesions break to form painful coalesced ulcers that subsequently dry; some form crusts and heal without scarring. With primary disease the genital lesions are usually multiple, bilateral, and extensive. The urethra and cervix are also infected frequently, with discrete or coalesced ulcers on the exocervix. Bilateral enlarged tender inguinal lymph nodes are usually present and may persist for weeks to months. About one-third of patients show systemic symptoms such as fever, malaise, and myalgia, and 1–10% develop aseptic meningitis with neck rigidity and severe headache. First episodes of disease usually last 20–30 days.
  2. Recurrent Genital Infection.In contrast to primary infection, recurrent genital herpes is a disease of shorter duration, usually localized in the genital region, without systemic symptoms. Prodromal paresthesias in the perineum, genitalia, or buttocks occur 12–24 h before the appearance of lesions. Recurrent genital herpes usually presents with grouped vesicular lesions in the external genital region. Local symptoms such as pain and itching are mild, lasting 4–5 days, and lesions usually last 10–14 days. Recurrent meningitis due to HSV-2 does occur.

 

  1. NEONATAL HERPES

Neonatal herpes usually results from transmission of virus during delivery, as the neonate passes through infected genital secretions of the mother. True congenital in utero infection, although possible, is uncommon. The prevalence rate of neonatal herpes varies greatly among populations but is estimated at ~ 1/2500 live births in the United States. This estimate is based on the observation that ~ 0.5–1.0% of women excrete HSV from the cervix at the onset of labor and ~ 6% of babies born through infected birth canals develop neonatal HSV.

Manifestations of neonatal herpes vary. To a considerable degree, this is determined by the mother's antibody status. If she is experiencing primary HSV infection and has no antibody to pass to the baby, the consequences can be severe. If she is experiencing a reactivation, the baby can be completely protected by maternal antibody. Some infants show disseminated skin lesions only; others have widespread internal organ involvement; still others have involvement of the central nervous system only, with listlessness and seizures. Less commonly, HSV-1 causes neonatal herpes infection, usually resulting from genital HSV-1 lesions or colonization.

Diagnosis

Herpes simplex virus is easily isolated from lesions or tissue by using fibroblasts or a variety of other tissue culture cells. The cytopathic effects of HSV can usually be demonstrated 24–48 h after inoculation. Isolates of HSV-1 and HSV-2 (see below) can be differentiated by staining virus-infected cells with type-specific monoclonal antibodies to the two types or by analyzing restriction enzyme digests of purified viral DNA. Restriction endonuclease digests can also be used to define epidemiologic relationships, that is, identify strains acquired between sexual partners or through mother-infant transmission. A direct smear prepared from the base of a suspected lesion and stained by either the Giemsa or Papanicolaou method may show intranuclear inclusions or multinucleated giant cells typical of herpes (as demonstrated by the Tzanck test) but is less sensitive than a viral culture and doesn't distinguish HSV-1 from HSV-2. Enzyme immunoassays have been developed for direct detection of herpes antigen in lesions. Although early versions of these noncultural tests lacked sensitivity, more recent assessments show ~ 90% correlation with results from cultures. Rapid diagnosis of HSV mucocutaneous lesions can be accomplished with immunofluorescence or other antigen detection methods. Serology should not be used to diagnose active HSV infection, for example, genital or encephalitis; frequently there is no change in antibody titer when reactivation occurs. PCR on CSF is now the test of choice to diagnose HSV encephalitis. PCR positivity eliminates the need for brain biopsy, but the latter should still be performed if PCR is negative in a patient with highly suggestive clinical findings.

BOX 33-2 Treatment of Herpes Simplex Infection

 

Children

Adults

First Choice

· Acyclovir

· Acyclovir

Second Choice

 

· Valacyclovir

· Famciclovir

Treatment

Several antiviral drugs have been developed that inhibit HSV (Box 33-2). The most commonly used is the nucleoside analog acyclovir, which is converted by a viral enzyme (thymidine kinase) to a monophosphate and then by cellular enzymes to the triphosphate form, which is a potent inhibitor of the viral DNA polymerase. Acyclovir significantly decreases the duration of primary infection but has much less effect when used for treating recurrent infection. Valacyclovir is a prodrug of acyclovir that is better absorbed and can be used in lower and less frequent doses. Famciclovir is an oral drug that is converted to penciclovir, has good bioavailability, is equivalent to acyclovir but can also be given less frequently.

Prognosis

At least 80% of patients with clinically evident primary HSV infection develop recurrent episodes of herpes within 12 months. In patients whose lesions recur, the median number of recurrences is four or five per year. They are not evenly spaced, and some patients experience a succession of monthly attacks followed by a period of quiescence. Most recurrences result from reactivation of virus from dorsal root ganglia. Rarely, recurrent diseases may be caused by reinfection with a different strain of HSV. Ultimately recurrences of herpes diminish in frequency, especially with genital HSV-2 infection. Genital HSV-1 infection recurs to recur less frequently.

If untreated, HSV-1 encephalitis has a mortality of 70%, but intravenous acyclovir reduces mortality especially if given before coma occurs.

Because a normal immune response is absent in the neonate, neonatal HSV infection is an extremely severe disease with an overall mortality of ~ 60%, and neurologic sequelae are high in those who survive.

Prevention & Control

Avoiding contact with individuals with lesions reduces the risk of spread; however, virus may still be spread by individuals shedding virus asymptomatically from the saliva, urethra, and cervix. When lesions are present, sexual intercourse should be avoided. Condoms should be used when individuals with a history of type 2 HSV or antibodies have sexual contact with susceptible people, even when lesions are absent. Daily acyclovir, valacyclovir, or famciclovir suppresses recurrences of HSV infections and is indicated for patients who have frequent attacks (Box 33-3). Because of the high morbidity and mortality of neonatal infection, special attention must be paid to preventing transmission during delivery. In some cases Cesarean section may be used to minimize contact of the infant with infected maternal genital lesions; however, Cesarean section may not be effective if rupture of the membranes precedes delivery by several hours. A recently completed trial of a recombinant HSV-2 vaccine in HSV-2–infected patients had no impact on the rate of recurrences. It is not known whether a vaccine would prevent primary infection, although an effective vaccine offers the best hope for controlling the spread of genital herpes infections. Several different vaccines are at various stages of development and testing. Subsequently a recombinant HSV vaccine was similarly ineffective in preventing primary genital HSV-2 infection.

BOX 33-3 Control of Herpes Simplex Infection

Prophylactic Measures

· Avoidance of contact with HSV positive lesions, secretions

· Daily acyclovir (OR valaciclovir, famiciclovir) suppresses recurrences of HSV infections

· Vaccine ineffective for treatment; under study for prophylaxis

VARICELLA-ZOSTER VIRUS

Essentials of Diagnosis

  • Vesiculopustular, generalized rash in a febrile child (varicella or chicken pox)
  • Dermatomal pustular eruption in elderly or immunocompromised patient (herpes zoster or shingles)
  • Multinucleated, giant epithelial cells with intranuclear inclusions in skin scrapings, tissue biopsy Slow growth of virus (5–7 days) in diploid fibroblast cells if fresh vesicles are cultured
  • Detection of VZV antigen by immunofluorescence of skin vesicles (best diagnostic test)

General Considerations

  1. Epidemiology

VZV infection, the cause of both varicella (chickenpox) and herpes zoster, is ubiquitous (Box 33-4). Nearly all persons contract chickenpox before adulthood, and 90% of cases occur before the age of 10. The virus is highly contagious, with attack rates among susceptible contacts of 75%. Varicella occurs most frequently during the winter and spring months. The incubation period is 11–21 days. The major mode of transmission is respiratory, although direct contact with vesicular or pustular lesions may result in transmission. Infectivity is greatest 24–48 h before the onset of rash and lasts 3–4 days into the rash. Virus is rarely isolated from crusted lesions.

  1. Microbiology

VZV has the same general structure as HSV but has its own DNA sequence and envelope glycoproteins. Cellular features of infected cells, such as multinucleated giant cells and intranuclear eosinophilic inclusion bodies, are similar to those of HSV-infected cells. VZV is more difficult to isolate in cell culture than HSV and grows best but slowly in human diploid fibroblast cells.

  1. Pathogenesis

The viruses isolated from lesions of chickenpox and zoster (or shingles) are identical. Latency of VZV occurs in sensory ganglia, as shown by in situ hybridization detection of viral DNA in dorsal root ganglia of adults many years after varicella infection.

  1. Immunity

Both humoral immunity and cell-mediated immunity are important factors in determining the frequency of reactivation and severity of varicella-zoster. Circulating antibody prevents reinfection, and cell-mediated immunity appears to control reactivation. In patients with depressed cell-mediated immune responses, especially those who have received bone marrow transplants or have Hodgkin's disease, AIDS, or lymphoproliferative disorders, reactivation can occur, and be severe.

BOX 33-4 Syndromes Caused by Varicella Infection

 

Children

Adults

More Common

· Varicella

· Zoster (shingles)

Less Common

· Zoster (shin gles)

· VZ encephalitis

· Varicella

· VZ encephalitis

Clinical Findings

VZV produces a primary infection in healthy children which is characterized by a generalized vesicular rash termed chickenpox. Chickenpox lesions generally appear on the head and ears, then spread centrifugally to the face, neck, trunk, and extremities. Lesions appear in different stages of evolution; this characteristic was one of the major features to differentiate varicella from smallpox, in which lesions were concentrated on the extremities and appeared at the same stage of disease. Varicella lesions are pruritic, and the number of vesicles may vary from 10 to several hundred. Involvement of mucous membranes is common, and fever may occur early in the course of disease.

Immunocompromised children may develop progressive varicella, which is associated with prolonged viremia, visceral dissemination, and the development of pneumonia, encephalitis, hepatitis, and nephritis. Progressive varicella has an estimated mortality of ~ 20%. In thrombocytopenic patients, the lesions may be hemorrhagic. Adult patients with varicella are more ill and may develop pneumonia.

Reactivation of VZV is associated with the disease herpes zoster. Although zoster is seen in patients of all ages, it increases in frequency with advancing age, when cell-mediated immunity is waning. Clinically, pain in a sensory nerve distribution may herald the onset of the eruption, which occurs several days to a week or two later. The vesicular eruption is usually unilateral, involving one to three dermatomes. New lesions may appear over the first 5–7 days. Multiple attacks of VZV infection are uncommon; if recurrent attacks of a vesicular eruption occur in one area of the body, HSV infection should be considered.

Complications

The complications of VZV infection are varied and depend on age and host immune factors. Post-herpetic neuralgia is a common complication of herpes zoster in elderly adults. It involves persistence of severe pain in the dermatome after resolution of the skin lesions and appears to result from damage to the involved nerve root. Immunosuppressed patients may develop disseminated lesions with visceral infection, which resembles progressive varicella. Bacterial superinfection of varicella occurs and is usually caused by gram-positive cocci. Encephalitis may complicate varicella or zoster and may be associated with seizures and in some cases cerebellar signs.

Diagnosis

Varicella or herpes zoster lesions can usually be diagnosed clinically. Scrapings or swabs from the base of lesions may reveal characteristic cells with intranuclear inclusions or multinucleated giant cells identical to those produced by HSV. VZ virus can be isolated from aspirated vesicular fluid inoculated onto human diploid fibroblasts; however, the virus is difficult to grow from zoster (shingles) lesions older than 5 days, and cytopathic effects are usually not seen for 5–9 days. For rapid viral diagnosis, varicella zoster antigen may be demonstrated in cells from lesions by immunofluorescent antibody staining. PCR analysis of CSF may be useful to diagnose VZV encephalitis; cultures are rarely positive.

Treatment

Acyclovir has been shown to reduce fever and skin lesions in patients with varicella (Box 33-5), and its use is recommended in healthy patients over 18 years of age if treatment is begun within 24–48 h of onset of rash. There is insufficient data to justify universal treatment of all healthy children and teenagers with antiviral agents. In immunosuppressed patients, controlled trials of acyclovir have shown efficacy in reducing dissemination, and its use is definitely indicated. In addition, controlled trials of acyclovir have demonstrated effectiveness in the treatment of herpes zoster in immunocompromised patients. Acyclovir may be used to treat herpes zoster in immunocompetent adults, but it appears to have little or no impact on the development of post-herpetic neuralgia, the most important complication of zoster. Treatment should be started within 3 days of the onset of zoster. VZ virus is less susceptible than HSV to acyclovir, so the dosage for treatment is substantially higher. Famciclovir or valacyclovir are more convenient and may be more effective in preventing post-herpetic neuralgia. Some authorities recommend systemic corticosteroids for patients with zoster who are over 60 and have no contraindications. Although steroids do not prevent post-herpetic neuralgia, patients feel better and return to activity faster.

BOX 33-5 Treatment of Varicella Infection

 

Children

Adults

First Choice

· Acyclovir for children > 12 years who have varicella but no definite consensus

· Varicella: acyclovir, 800 mg 5 times/day

· Zoster: acyclovir, 800 mg 5 times/ day; famciclovir, 500 mg/8 h; or valacyclovir, 1.0 g 3 times/day

Pediatric Considerations

· An antiviral agent is not recommended for children <12 years

 

Prevention & Control

High-titer immune globulin administered within 72–96 h of exposure is useful in preventing infection or ameliorating disease in patients at risk for primary infection (ie, varicella) and serious complications (Box 33-6). Immunosuppressed children who are household or play contacts of patients with primary varicella are candidates for this immunoprophylaxis.

 

BOX 33-6 Control of Varicella Infection

Prophylactic Measures

An attenuated VZV vaccine is now recommended for healthy children >1 year of age
VZ-specific immune globulin can diminish illness if given within 72 h of exposure. This is reserved for immunocompromised susceptible patients or other special circumstances

Isolation Precautions

If at all possible, patients with varicella or disseminated zoster should not be admitted to hospital; if unavoidable, these patients should be in strict isolation.

Once infection has occurred, high-titer immune globulin has not proved useful in ameliorating disease or preventing dissemination. Immune globulin is also not indicated for the treatment or prevention of reactivation (ie, zoster or shingles). In nonimmunosuppressed children, varicella is a relatively mild disease, and passive immunization is not indicated. Patients with varicella spread the virus by the respiratory route. In both syndromes virus is also present in the skin lesions. Varicella is a highly contagious disease, and rigid isolation precautions must be instituted in all hospitalized patients.

A live vaccine developed by a group of Japanese workers is effective and a single dose is now recommended for healthy children aged 12 months to 12 years and for selected healthy adults who are susceptible.

In immunocompromised children, chickenpox can be extremely serious, even fatal. For these children, the live vaccine is being evaluated and is not currently recommended.

CYTOMEGALOVIRUS

Essentials of Diagnosis

  • “Owl eye” cells in tissue biopsy, cytology
  • Cultured in diploid fibroblast cells
  • Antibody detection of those patients seroconverting or at risk for reactivation
  • CMV detection in blood or bodily fluids by antigenemia, PCR, or other DNA-based assays, eg hybrid capture, or by culture

General Considerations

  1. Epidemiology

CMV is ubiquitous, and in developed countries ~50% of adults have developed antibody (Box 33-7). Age-specific prevalence rates show that ~ 10–15% of children are infected by CMV during the first 5 years of life, after which the rate of new infections levels off. The rate subsequently increases during young adulthood, probably through close personal contact or sexual transmission of the virus. CMV has been isolated from saliva, cervical secretions, semen, urine, and white blood cells.

Excretion of virus is prolonged after congenital and perinatal infections, probably because of immunologic tolerance, and high titers of virus may be shed for more than 5 years after birth. Transmission of infection in daycare centers has been shown to occur from asymptomatic excretors to other children and, in turn, to seronegative parents. Infected adults, especially immunocompromised adults, also excrete virus for prolonged periods after primary infection or reactivation of latent infection. Latent infection, which may reside in leukocytes and their precursors, can be transmitted by transfusion and organ transplantation.

  1. Microbiology

Human CMV possesses the largest genome of the herpesviruses (~240 kilobase pairs), and its replication, although slow, is similar to that of HSV with the sequential appearance of immediate early, early, and late gene products. Strains of CMV demonstrate considerable genomic and phenotypic heterogeneity, and restriction endonuclease analysis of viral DNA has been useful for distinguishing strains epidemiologically. Antigenic variations have been observed but are not of clinical importance.

  1. Pathogenesis and Immunity.Cytomegalovirus infects epithelial cells and leukocytes. In vitro, CMV DNA can be demonstrated in monocytes showing no cytopathology, indicating a restricted growth potential in these cells. In addition to nuclear inclusions (“owl eye cells”), CMV produces perinuclear cytoplasmic inclusions and enlargement of the cell (cytomegaly), a property which gives the virus its name.

After primary CMV infection, the virus becomes latent. The exact site(s) of latency and the mechanisms of persistence are not completely understood, but leukocytes, especially mononuclear leukocytes, are suspected to contain latent virus and account for transmission of the virus by blood and leukocyte transfusions. Also, organs such as the kidneys and heart harbor the virus, but the exact cell is not known. Latent CMV infection appears to be reactivated by immunosuppression (eg, by corticosteroids or HIV infection) and possibly by allogeneic stimulation (ie, the host response to transfused or transplanted cells). Cellular damage appears to be caused directly by the viral lytic infection or indirectly by the immune response of the host. An example of cellular damage resulting from a direct cytopathic effect is retinitis in severely immunocompromised AIDS patients, in which blindness occurs as a result of a necrotizing infection by the virus. The beneficial effects of ganciclovir therapy support this notion. In contrast, HCMV pneumonitis in transplant recipients frequently manifests subtle histologic alterations in the face of life-threatening clinical symptomatology and extensive inflammation accompanied by mild viral replication, suggesting that immune-mediated injury is the primary pathologic mechanism. In other instances, both direct and immunopathogenic mechanisms seem to be at work.

BOX 33-7 Cytomegalovirus Disease Syndromes

 

Children

Adults

More Common

Perinatal infection, “Daycare” infection

 

Less Common

Congenital infection

CMV retinitis (AIDS)

· pneumonia (transplant recipients)

· CMV enteritis, neurologic disease (all immunocompromised patients)

· CMV mononucleosis

Clinical Findings

  • D. Congenital.Worldwide, 1% of infants excrete CMV in urine at delivery, as a result of infection in utero. On physical examination, 90% of these infants appear normal; however, long-term follow-up has indicated that up to 20% go on to develop sensory nerve hearing loss, psychomotor mental retardation, or both. The infants with symptomatic illness (~ 0.1% of all births) may have a variety of congenital defects or other disorders (such as hepatosplenomegaly, jaundice, anemia, thrombocytopenia, low birth weight, microcephaly, and chorioretinitis). Almost all babies with clinically evident congenital CMV infection are born of mothers who experience primary CMV infection during the pregnancy. Congenital infection frequently also results from reactivation in the mother with spread to the fetus, but such infection rarely leads to congenital abnormalities due to protection by passively transferred maternal antibody.
  • E. Perinatal.Most population-based studies have indicated that 10–15% of all mothers are excreting CMV from the cervix at delivery. Approximately one-third to one-half of all infants born to these mothers acquire infection. Almost all of these perinatally infected infants have no discernible illness unless the baby is premature or immunocompromised. CMV can also be efficiently transmitted from mother to child by breast milk, but these postpartum infections are also usually benign.
  • F. Post neonatal.As with intrapartum acquisition of infection, most CMV infections during childhood and adulthood are totally asymptomatic. In adults, CMV may cause a mononucleosis-like syndrome. In immunosuppressed patients, latent CMV may be reactivated and cause very serious disease. In patients receiving bone marrow transplants, interstitial pneumonia caused by CMV is the leading cause of death (90% mortality). In AIDS patients with low CD4 lymphocyte counts CMV often disseminates to visceral organs, causing chorioretinitis, gastroenteritis, neurologic disorders, and disease in other organs.

Diagnosis

Laboratory diagnosis of CMV infection depends on (1) detecting CMV cytopathology, antigen, or DNA in infected tissues or bodily fluids, (2) isolating the virus from tissue or bodily fluids, or (3) demonstrating seroconversion. CMV can be grown in serially propagated diploid fibroblast cell lines but generally requires 3–14 days, depending on the concentration of virus in the specimen. The time for detection can be shortened by centrifugation and immune staining, but culture of blood is less sensitive than antigenemia or DNA-based assays.

Because of the high prevalence of asymptomatic carriers and the known tendency of CMV to persist weeks or months in infected individuals, it may be difficult to attribute a specific disease to CMV by isolation of the virus from a peripheral site. Thus, the isolation of CMV from urine of immunosuppressed patients with interstitial pneumonia does not constitute evidence for CMV as the etiology of that illness. CMV pneumonia or gastrointestinal disease is best diagnosed by demonstrating CMV inclusions in biopsy tissue.

Treatment

Ganciclovir, a nucleoside analog of acyclovir, inhibits CMV replication and reduces the severity of CMV syndromes, such as retinitis and gastrointestinal disease (Box 33-8). When given with hyper immune globulin, ganciclovir is thought to reduce the mortality of CMV pneumonia in transplant recipients.

Foscarnet is an approved drug for therapy of CMV retinitis. Its toxic effects are primarily renal with electrolyte disturbances, whereas ganciclovir is most apt to inhibit bone marrow function. Ganciclovir inhibits CMV DNA polymerase as does foscarnet, but they act on different sites and cross-resistance is rare. Cidofovir is a third approved anti-CMV drug and is the first nucleotide analog to be used in clinical practice. It has a long half-life, which allows it to be given every 2 weeks during maintenance treatment of CMV retinitis, but it is significantly nephrotoxic.

Prevention & Control

The use of blood from CMV seronegative donors or blood that is treated to remove white cells decreases transfusion-associated CMV (Box 33-9).


Similarly, the disease can be avoided in seronegative transplant recipients by using organs from CMV-seronegative donors. Hyperimmune human anti-CMV globulin has been used to ameliorate CMV disease associated with renal and hepatic transplants. Prophylactic or preemptive ganciclovir and valacyclovir reduce the frequency of CMV disease in both transplant and AIDS patients. There are experimental and clinical data indicating that the use of condoms decreases sexual transmission of CMV. CMV vaccines are being evaluated in clinical trials.

BOX 33-8 Treament of Cytomegalovirus Disease

 

Children

Adults

First Choice

Ganciclovir

Ganciclovir, 5 mg/kg/d IV or valgauciclovir 900-1800 mg orally

Second Choice

· Foscarnet, 90-120 mg/kg/d IV

· Cidofovir, 5 mg/kg/q 2 weeks IV

Pediatric Considerations

No experience with treat ments other than ganciclovir

 

BOX 33-9 Control of Cytomegalovirus Disease

Prophylactic Measures

· Avoid organ transplantation or blood donation from CMV seropositive to CMV seronegative

· Preemptive ganciclovir diminishes CMV disease in seropositive AIDS patients. Prophylactic ganciclovir or valacyclovir diminshes CMV disease in seropositive or mismatched transplant recipients. Preemptive ganciclovir disminshes CMV disease in seropositive or mismatched transplant recipients.

· Vaccine trials are in progress

EPSTEIN-BARR VIRUS

Essentials of Diagnosis

  • Atypical lymphocytes in peripheral blood smear
  • Heterophile antibody present in high titer in serum
  • Immunoglobulin G (IgG) seroconversion or development of antibody to EB nuclear antigen
  • Adolescent, young adult with fever, lymphadenopathy, splenomegaly, pharyngitis, and prolonged fatigue
  • Infectious mononucleosis may be complicated by laryngeal obstruction, CNS disease, splenic rupture

General Considerations

EBV is the etiologic agent of infectious mononucleosis and certain lymphoproliferative syndromes (Box 33-10).

  1. Epidemiology

EBV can be cultured from the saliva of 10–20% of healthy adults. Excretion may persist weeks to months. Infection with EBV is by contact with infected secretions such as saliva. It is of low contagiousness, and most cases of infectious mononucleosis are contracted after repeated contact between susceptible persons and those asymptomatically shedding the virus. Secondary attack rates of infectious mononucleosis are low (< 10%), because most family or household contacts already have antibody to the agent. Antibodies to EBV are found in up to 90% of adults, although the percentage of susceptible adults is increasing in developed countries.

  1. Microbiology

The complete 172-kilobase-pair nucleotide sequence of EBV has been mapped. At present there appear to be many fewer genomic strain variations among EBV isolates than among other herpesviruses. Although morphologically similar to the other herpesviruses, EBV can be cultured easily only in lymphoblastoid cell lines derived from B-lymphocytes of humans and higher primates. The virus generally does not produce cytopathic effects or the characteristic intranuclear inclusions of other herpesvirus infections. After infection with EBV, lymphoblastoid cells containing the viral genome can be cultivated continuously in vitro; they are thus transformed or immortalized.

Recent studies suggest that most of the viral DNA in transformed cells remains in circular, nonintegrated form as an episome, and a lesser amount is integrated into the host cell genome. Viral antigen expression has been studied by immunofluorescent staining of transformed cell lines under various conditions. One group of proteins called EBV nuclear antigens (EBNAs) appears in the nucleus before virus-directed protein synthesis. Viral capsid antigen (VCA) can be detected in cell lines that produce mature virions. Other cell lines, called nonproducers, contain no mature virions, but express certain virus-associated antigens called early antigens (EA). The latter may be seen as diffuse (D), and as restricted (R) aggregates of staining. Antibodies against these antigens can be detected by serological tests.

  1. Pathogenesis

Although EBV initially infects epithelial cells, the hallmark of EBV disease is infection of B-lymphocytes. The virus enters B-lymphocytes by means of envelope glycoprotein binding to surface complement (C3d) receptor; 18 to 24 h later, EBV nuclear antigens are detectable within the nucleus of infected cells. Expression of the viral genome is associated with immortalization and proliferation of the cell. The EBV-infected B-lymphocytes are polyclonally activated to produce immunoglobulin and express a lymphocyte-determined membrane antigen that is the target of host cellular immune responses. During the acute phase of infectious mononucleosis, ~ 20% of circulating B-lymphocytes demonstrate EBV antigens. After infection subsides, EBV can be isolated from only ~ 1% of such cells.

EBV has been associated with several lymphoproliferative diseases including African Burkitt's lymphoma, nasopharyngeal carcinoma, and lymphomas in immunocompromised patients. The factors that render the EBV infections oncogenic in these cases are obscure. The distribution of EBV infections in Africa has suggested an infectious cofactor, such as malaria, which may cause immunosuppression and predispose to EBV-related malignancy. In the case of nasopharyngeal carcinoma, environmental carcinogens probably create the precancerous lesion, which then stimulates the EBV to reactivate. EBV-associated lymphomas have been shown to be of both monoclonal and polyclonal origin. Chromosomal translocations in B cells are characteristic of Burkitt's lymphoma and involve specific breaks in chromosomes at sites of genes encoding immunoglobulins. These translocations lead to expression of oncogenes that may contribute to clonal activation and ultimately to malignancy. Some breakdown in immune surveillance also appears to play a role in the development of malignancy because immunosuppressed patients are more prone to develop B-cell lymphomas. Transplant recipients may develop a lympho-proliferative syndrome with very high titers of EBV in blood.

  1. Immunity

EBV-infectious mononucleosis results in the synthesis of circulating antibodies against viral antigens, as well as against unrelated antigens found in sheep, horse, and some beef red blood cells. These heterophile antibodies, a heterogeneous group of predominantly IgM antibodies, are commonly used as diagnostic tests for the disease. Some other immunologic functions are also affected by EBV infection. Cutaneous anergy and decreased cellular immune responses to mitogens and antigens are seen early in the course of mononucleosis.

Although EBV infects B-lymphocytes, the lymphocytosis associated with infectious mononucleosis is caused by an increase in the number of circulating T cells, which appear to be activated cells developed in response to the virus-infected B-lymphocytes. With recovery from illness, the atypical lymphocytosis gradually resolves, and cell-mediated immune functions return to preinfection levels.

BOX 33-10 Epstein-Barr Virus Infection

 

Children

Adults

More Common

Infectious mononucleosis

Less Common

EBV lymphoproliferaliferative disease

EBV lymphoproliferative disease

Clinical Findings

As with most of the herpesviruses (except varicella), most primary EBV infections are asymptomatic. The clinical syndrome of infectious mononucleosis is characterized by fever, malaise, pharyngitis, tender lymphadenitis, and splenomegaly. These symptoms persist for days to one or more weeks but slowly resolve. Complication such as laryngeal obstruction, ruptured spleen, or a variety of CNS manifestations(aseptic meningitis, encephalitis, etc.) may occur in 1–5% of patients.

Patients with primary or secondary immunodeficiency are susceptible to EBV-induced lymphoproliferative disease. The risk is greatest in those experiencing primary EBV infection rather than reactivation. The most characteristic clinical findings are persistent fever, lymphadenopathy, and hepatosplenomegaly. In AIDS patients, several distinct additional EBV-associated syndromes occur, including hairy leukoplakia of the tongue interstitial lymphocytic pneumonia, especially in infants and lymphoma of the CNS and elsewhere.

Diagnosis

Laboratory confirmation of EBV infectious mononucleosis is usually documented by the demonstration of atypical lymphocytes, heterophile antibodies, or positive EBV-specific serologic findings. Hematologic examination reveals a markedly raised lymphocyte and monocyte count with > 10% atypical lymphocytes. Atypical lymphocytes, although not specific for EBV, are present with the onset of symptoms and disappear with resolution of disease. Alterations in liver function tests may also occur.

Although not specific for EBV, tests for heterophile antibodies are used most commonly for diagnosis of infectious mononucleosis. In commercial kits, animal erythrocytes are used in simple slide agglutination methods, which incorporate absorption to remove cross-reacting antibodies that may develop in other situations, such as serum sickness. The infectious mononucleosis heterophile antibody is absorbed by sheep erythrocytes but not by guinea pig kidney cells. Heterophile antibodies can usually be demonstrated by the end of the first week of illness but may occasionally be delayed until the third or fourth week. They may persist many months.

Approximately 5–15% of EBV-induced cases of infectious mononucleosis in adults and a much greater proportion in young children and infants fail to induce detectable levels of heterophile antibodies. In these cases EBV-specific serologic tests may be used to establish the diagnosis. Antibodies to VCA rise quickly and persist for life. The presence of IgM antibody to VCA is theoretically diagnostic of acute, primary EBV infection, but low levels may occur during reactivation of EBV, and cross-reactivation with antigens of other herpesviruses occur. Antibodies to EBNAs rise later in disease (after ~ 1 month) and also persist in low titers for life. Thus, a high titer to VCA and no titer to EBNAs suggest recent EBV infection, whereas antibody titers to both antigens are indicative of past infection. Persistent antibody to early antigens (anti-EA, -D, or -R) may be correlated with severe disease, nasopharyngeal carcinoma (anti-D), or African Burkitt's lymphoma (anti-R) but are not useful in diagnosing infectious mononucleosis. Isolation of EBV from clinical specimens is not practical because it requires fresh human B cells or fetal lymphocytes obtained from cord blood. PCR is being developed to assay EBV DNA in blood.

Treatment

Treatment of infectious mononucleosis is largely supportive. More than 95% of patients recover uneventfully. In a small percentage of patients, splenic rupture may occur; thus, restriction of contact sports or heavy lifting during the acute illness is recommended. The DNA polymerase enzyme of EBV has been shown to be sensitive to acyclovir, and acyclovir can decrease the amount of replication of EBV in tissue culture and in vivo (Box 33-11). Despite this antiviral activity, systemic acyclovir makes little impact on the clinical illness. Corticosteroids appear to be beneficial in reducing laryngeal edema and severe toxicity. They may also be indicated for CNS complications. Treatment of EBV lymphoproliferative disease includes diminution of immunosuppression as much as possible; acyclovir is also used.

BOX 33-11 Treatment of Epstein-Barr Virus Infection

First Choice

None

Second Choice

Corticosteroids if severe toxicity or airway obstruction

Acyclovir and/or decrease immunosuppression for post transplant lymphoproliferative disease

Prevention & Control

Because EBV may be spread by direct person-to-person contact from even asymptomatic individuals, it is unavoidable. Isolation is not practiced owing to ubiquitous infection. The occurrence of Burkitt's lymphoma and nasopharyngeal carcinomas in restricted geographic areas offers the possibility of prevention by immunization with virus-specific antigen(s). This approach is under exploration at present. A subunit vaccine has proved effective in preventing the development of tumors in tamarind monkeys, which are highly susceptible to the oncogenic effects of the virus under experimental conditions.

HUMAN HERPESVIRUS TYPE 6

Essentials of Diagnosis

  • Infant with high fever for several days; maculopapular rash after defervescence
  • Can be isolated in cultures of monocytes but takes 10–30 days and may be false negative
  • Detection of specific IgG and IgM by indirect immunofluorescence are diagnostic tests of choice
  • Blood or saliva PCR for HHV-6 DNA may be positive, but diagnostic significance uncertain due to intermittent excretion in asymptomatic patients
  • PCR positively in CSF diagnostic of encephalitis

General Considerations

In 1986 a human herpesvirus, now called human herpesvirus type 6 (HHV-6), was identified in cultures of peripheral blood lymphocytes from patients with lymphoproliferative diseases (Box 33-12). The virus, which is genetically distinct but morphologically similar to other herpesviruses, replicates in lymphoid tissue, especially CD4+ T lymphocytes, and has two distinct variants, A and B.

BOX 33-12 Exanthem Subitum Syndromes

More Common

Exanthem subitum

Less Common

Meningitis, encephalitis fever in transplant recipients

Initially it was thought that HHV-6 would grow only in freshly isolated B-lymphocytes, and the virus was referred to as the human B-lymphotropic virus (HBLV); now it is clear that the virus is preferentially tropic for CD4+ T lymphocytes. HHV-6 establishes a latent infection in T cells but may be activated to a productive lytic infection by mitogenic stimulation. Resting lymphocytes and lymphocytes from healthy immune individuals are resistant to HHV-6 infection. In vivo, HHV6 replication is controlled by cell-mediated immune factors. It appears to be capable of reactivating in immunosuppressed patients, but its clinical significance in this situation is unknown.

Serologic studies indicate that almost all children are infected by age 2. This makes HHV-6 the most communicable of all human herpesviruses. Most adults shed HHV-6 in saliva, and close personal contact is the most likely route of spread; vertical transmission also occurs.

Clinical Findings

Exanthem subitum occurs in infants and is characterized by fever, eg, 39°C for several days followed by defervescence and a light maculopapular rash spreading from the trunk to the extremities. CNS complications may occur with febrile seizures, meningitis and encephalitis. HHV-6 may also be a cause of febrile episodes in transplant recipients.

Diagnosis

Virus infection is best documented by seroconversion. Active virus infection can be documented by culture, antigenemia, or DNAemia, but since reactivation or is common, it is very difficult to use these tools to diagnose HHV-6 as the cause of disease. Also, culture takes 10–30 days.

Treatment

HHV-6 appears to be susceptible in vitro to ganciclovir and foscarnet and less susceptible to acyclovir, but no clinical data are available.

Prevention & Control

Because HHV-6 infection is ubiquitous and almost all infants excrete the virus by 2 years of age, no preventative measure is practical. No vaccine is in development, and isolation is not practical owing to ubiquitous infection.

OTHER HERPESVIRUSES

  1. HERPESVIRUS TYPE 7

Isolation of human herpesvirus type 7 (HHV-7) was first reported in 1990. The virus was isolated from activated CD4+ T lymphocytes of a healthy individual. HHV-7 is distinct from all other known human herpesviruses but is most closely related to HHV-6. Seroepidemiologic studies indicate that this virus usually does not infect children until after infancy, and ~ 50% of infants are antibody positive by 2–4 years of age. As with HHV-6 this virus is frequently isolated from saliva, and close personal contact is the probable means of transmission. Also like HHV-6 this virus appears to be a cause of exanthem subitum. The diagnosis of acute infection can be made by the demonstration of seroconversion. No treatment has been identified.

  1. HUMAN HERPESVIRUS TYPE 8 (Kaposi's sarcoma-associated herpes virus [KSHV])

KSHV was discovered in 1994 by identification of unique viral DNA sequences in an AIDS patient's Kaposi's sarcoma (KS) tissue. The method used was representational difference analysis. Specific HHV-8 DNA sequences are found in the great majority of KS tissues in the United States, including those from non-AIDS cases, and occasionally in other specimens including lymphomas. Recently the virus was isolated in culture and, when characterized, seemed most closely related to EBV. Serologic and virologic data suggest that this virus is at least a cofactor in the pathogenesis of KS.

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