HERPETIC DISEASES

HERPES SIMPLEX VIRUS

Herpes simplex virus (HSV) infections are among the most common maladies affecting humans. Often they are annoying and troublesome, occasionally they are life-threatening.

Historic reference

The term "herpes" is derived from the Greek word meaning "to creep", and clinical descriptions of herpes labialis go back to the time of Hippocrates. Astruc,physician to the king of France,is credited with the first description of genital herpes in 1736. Between 1910 and 1920, the infectious nature of herpes lesions was demonstrated by producing corneal lesions in rabbits with material derived from herpes keratitis and labialis. As techniques for isolating and characterizing the virus became more simplified and serologic procedures were developed, our understanding of the HSV clinical spectrum has greatly expanded. Studies during the past two decades have brought insights into the molecular biology of HSV. the mechanisms of HSV latency and recurrence, and the first successful approaches to therapy for certain types of HSV infections.

Etiology

Herpes simplex virus {herpesvirus hominis) shares many properties with other members of the herpesvirus groups, which in humans includes varicella-zoster, cytomegalovirus, Epstein-Barr virus, and human herpesviruses type 6 and 7. The members of this group have an internal core containing double-stranded DNA, an icosahedral capsid with 162 hollow capsomeres,and a lipid-containing laminated membrane or envelope. The overall diameters of enveloped herpesviruses are 150-200 nm. Replication occurs primarily within the cell nucleus and is completed by the addition of protein envelopes as the virus passes through the nuclear membrane. Complete virus replication is associated with lysis of the productive cell. All members of the human herpesvirus group can also establish latent states within certain types of cells they infect, although the physical nature of the viruses during periods of latency is unclear.

The development of monoclonal antibody and restriction enzyme technologies have permitted an even finer definition of variations among individual HSV isolates. It is now clear that HSV-1 and HSV-2 share certain glycoprotein antigens (gB) and differ with respect to others (gG). Serologic differentiation between HSV-1 and HSV-2 infections can be readily made by detection of type-specific IgG antibodies.

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Epidemiology

Herpes simplex viruses have a worldwide distribution. There are no known animal vectors for HSV, and although experimental animals can easily be infected, humans appear to be the only natural reservoir. Direct contact, with transmission through infected secretions, is the principal mode of spread. HSV-1 is transmitted primarily by contact with oral secretions and HSV-2 by contact with genital secretions. Transmission can occur both from overtly infected persons or from asymptomatic excretors, although virus titers are higher in persons with active lesions and thus transmissability may be greater. Approximately 15 % of the adults may be excreting HSV-1 or HSV-2 at any given time depending on the population studied. For example, because shedding of HSV-2 is related to sexual activity, prostitutes may have unusually high rates of excretion.

The risk of heterosexual acquisition of HSV is greater in women than men, and previous HSV-1 infection reduces the risk of subsequent HSV-2 infection.

Pathogenesis

On entry into skin sites HSV replicates locally in parabasal and intermediate epithelial cells, which results in the lysis of infected cells and the instigation of a local inflammatory response. This series of events results in the characteristic lesion of superficial HSV infection, that is, a thin-walled vesicle on an inflammatory base. Multinucleated cells are formed with ballooning degeneration, marked edema, and characteristic Cowdry type A intranuclear inclusions. Such lesions are indistinguishable from those caused by Varicella-zoster virus. Lymphatics and regional lymph nodes draining the site of primary infection become involved. Further virus replication may result in viremia and visceral dissemination, depending on the immune competence of the host. In murine models the maturity of macrophages at the site of local infection helps determine whether virus remains localized or disseminates. Subsequently,other host defense mechanisms, for example, the production of interferons, natural killer cells, protective antibodies, and sensitized killer lymphocytes, are elicited to prevent the spread of infection.

Clinical manifestations

Primary HSV-1 infection is frequently asymptomatic but may present as gingivostomatitis and pharyngitis most commonly in children under the age of 5 years but occasionally in older persons. Incubation periods range from 2 to 12 days and are followed by fever and sore throat with pharyngeal edema and erythema. Shortly after its onset, small vesicles develop on the pharyngeal and oral mucosa: these rapidly ulcerate and increase in number, often involving the soft palate, buccal mucosa, tongue, and floor of the mouth. Gums are tender and bleed easily and lesions may extend to the lips and cheeks. Fever and toxicity may persist for many days, and the patient complains of severe mouth pain. Breath is fetid, and cervical adenopathy is present. In children, dehydration may result from poor intake, drooling,

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and fever. In college-aged persons, primary HSV infection often presents as a posterior pharyngitis or tonsilitis. Included in the age-related differential diagnosis are streptococcal or diphtheritic pharyngitis, herpangina. aphthous stomatitis, Stevens-Johnson's syndrome, Vincent's infection and infectious mononucleosis.

Herpes simplex virus infections of the eye are usually caused by HSV-1. Primary infections may be manifested by a unilateral follicular conjunctivitis with regional adenopathy and/or blepharitis with vesicles on the lid margin. Photophobia, chemosis, excessive tearing, and edema of the eyelids may be present. Some patients develop dendritic figures or coarse, punctate, epithelial opacities. If disease is limited to the conjunctiva, healing takes place within 2-3 weeks. However, if systemic symptoms and signs of stromal involvement are present, the healing phase may be delayed. Spontaneous healing of the conjunctiva and cornea is usually complete.

Primary genital infection is most common in adolescents and in young adults and is usually (in 70-95 % of the cases) caused by HSV-2. Incubation periods are 2-7 days. In men, vesicular lesions on an erythematous base usually appear on the glans penis or the penile shaft. In the female, lesions may involve the vulva,perineum,buttocks,cervix,and vagina and are frequently accompanied by a vaginal discharge). Extra-genital lesions occur during the course of primary infection in 10-20 % of patients. Primary infection in both sexes may be associated with fever, malaise, anorexia, and tender bilateral inguinal adenopathy. Although vesicular lesions may persist for several days in men, in women they rapidly ulcerate and become covered by a grayish-white exudate. Such lesions may be exquisitely tender, and urethral involvement may result in dysuria or urinary retention. Herpetic sacral radiculomyelitis accompanying genital infection may also lead to urinary retention,neuralgias,and obstipation; in such patients a loss of anal tone, diminished bulbocavernosus reflex, and cystometrographic evidence of lower motor neuron dysfunction can sometimes be demonstrated. Lesions of primary genital herpes may persist for several weeks before healing is complete. Previous HSV-1 infection may reduce the severity and duration of a first episode of genital herpes caused by HSV-2. In the diagnosis of genital herpes, other sexually transmitted infections such as chancroid or syphilis, erosions secondary to excoriation, genital manifestations of Behcet syndrome or erythema multiforme, and local candidiasis must all be distinguished.

Although primary infections are usually in perioral (Fig. 8), ocular or genital areas, any skin site may be initially involved. Primary HSV skin infections may be extensive and mimic herpes zoster, although a dermatomal distribution is not usually maintained and the pain is less severe.

Primary perianal and anal HSV-2 infection is becoming increasingly well recognized, both in women and in male homosexuals. Pain is the primary symptom, with itching, tenesmus, and discharge also noted. Systemic complaints of fever, chills, malaise, headache, difficulty in urinating, and sacral paresthesias may be present. On examination, vesicles and ulcerations may be seen in perianal and sometimes in

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anal areas. They may become confluent and result in a grayish ulcerating cryptitis surrounded by a red edematous mucosa. Bilateral inguinal adenopathy is common. The course is generally self-limited unless bacterial infection supervenes, with healing occurring in 1-3 weeks. However, m the setting of the acquired immunodeficiency syndrome (AIDS), herpes proctitis as well as other cutaneous manifestations of HSV infection may be prolonged and progressive.

Recourse herpes labialis is frequently heralded by prodromal symptoms (pain, burning, tingling, or itching) generally lasting for less than 6 hours but occasionally as long as 24-48 hours. Vesicles appear most commonly at the vermillion border of the outer lip and are associated with considerable pain. The lower lip is more frequently involved, although individual patients may have stereotyped lesions at similar sites during each recurrence. The lesion area is usually less than 100 mm3, and lesions progress from the vesicle to the ulcer/crust stage within 48 hours. Pain is most severe within the first 24 hours after the appearance of lesions. Healing is generally complete within 8-10 days. Rarely, recurrences may occur in the mouth or on the nose, chin or cheek. Systemic complaints do not usually accompany recourse herpes labialis, although local adenopathy may occur.

Ocular infection may recur as keratitis, blepharitis or keratoconjunctivitis. Recourse keratitis is usually unilateral but is rarely (in 2-6 % of the cases) bilateral. Two main types of keratitis may develop: dendritic ulceration or stromal involvement. Branching dendritic ulcers that strain with fluorescein are virtually diagnostic and are often accompanied by a loss in corneal sensation. Visual acuity may be decreased because the ulcers frequently involve the pupillary portion of the cornea. They may be accompanied by minimal anterior opacification or deep stroma involvement. Occasionally, extensive ameboid corneal ulcers may evolve, particularly if topical steroids have been applied. Superficial keratitis usually heals, but recourse infection may lead to deep stromal involvement and uveitis, which may in part be mediated by hypersensitivity reactions to viral or altered cellular antigens. A gradual diminution in visual acuity takes place, and individual attacks may last for several months with the formation of dense scars, corneal thinning, and neovascularization. Permanent visual loss may result, and rarely, rupture of the eyeball develops.

Recourse genital lesions in both sexes are generally associated with less severe systemic symptoms and less extensive local involvement than are primary attacks. A prodrome of tenderness, itching, burning or tingling is often noted for several hours before a recurrence. Lesions in women are most often noted on the labia minora, labia majora, and perineum and less commonly on the mons pubis or buttocks. Lesions in men are most often found on the glans or penile shaft. In women recurrences tend to be more severe. Healing generally occurs in 6-10 days. Virus shedding diminishes more slowly in women and can occur between recurrences in both sexes. Occasionally, genital recurrences are associated with headache and even with aseptic meningitis. Urethral stricture and labial fusion have also been reported after recourse genital infections.

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Recourse HSV-1 *or HSV-2 infections may develop on extremities; occasionally such lesions are associated with severe local neuralgia. Local edema and lymphangitis may also occur during recurrences on extremities.

Relationship to other diseases

Erythema multiforme. Allergic cutaneous and mucous membrane disorders may accompany or follow acute HSV infections. Up to 75 % of all cases of erythema multiforme are regularly preceded by an attack of herpes simplex. Both HSV-1 and HSV-2 may be involved, and the cutaneous manifestations range from mild to severe (Stevens-Johnson syndrome) and may be recourse. Inactivated HSV antigens injected intra-dermally into persons subject to erythema multiforme have induced such attacks, and HSV antigen has been identified in skin biopsy specimens from affected lesions.

Cancer. Although HSV has been suspected as a cause of cervical and other cancers on the basis of both epidemiologic and laboratory studies, many recent studies do not support its etiologic role in human cancers.

Idiopathic neurologic syndromes. Herpes simplex virus infections have been implicated as possible factors involved in the pathogenesis of various neurologic disorders of unknown etiology, including idiopathic facial paralysis (Bell's palsy), multiple sclerosis,atypical pain syndromes,ascending myelitis,trigeminal neuralgia, Mollaret's meningitis, and temporal lobe epilepsy. The associations are based on the known predilection of HSV for nerve tissue, on serologic or nucleic acid studies, and on the occasional observations of temporal relationships between attacks of herpes labialis or genitalis and attacks of the neurologic syndrome.

Complications

Herpes simplex encephalitis is a rare complication of herpetic infection and yet is one of the most common acute sporadic viral diseases of the brain. Although little is known about the pathogenesis of HSV-1 encephalitis in humans, the virus is believed to spread by neural routes into the brain during either primary or recourse infection. Temporal lobes are the principal target areas of the virus, and a necrotizing hemorrhagic encephalitis results.

Herpes simplex encephalitis occurs at all ages in both sexes, and in all seasons. The clinical course may begin suddenly or after a brief influenzalike prodrome. Headache, fever, behavioral disorders, speech difficulties, and focal seizures are prominent features; olfactory hallucinations may be present. Cerebrospinal fluid examination is variable but frequently shows a moderate pleocytosis with mononuclear and polymorphonuclear leukocytes: protein levels are slightly elevated, and glucose is generally normal. Infectious virus is rarely present in cerebrospinal fluid during encephalitis, and brain biopsy with appropriate histologic and cultural techniques is coursely the most reliable way to make the diagnosis. Although various antibody and antigen assays may provide adjunctive information, they are not sensitive enough to provide a sufficiently early diagnosis.

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Rapid diagnosis of Herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid has been reported by certain research laboratories. Herpes simplex virus encephalitis must be distinguished from other forms of viral encephalitis, tuberculous and fungal meningitis, brain abscesses, cerebrovascular accidents, and brain tumors.

The course in untreated patients is usually one of rapid deterioration over several days that progresses to coma and death. Mortality in untreated biopsy-proven cases is 60-80 %, and fewer than 10 % of the patients are left without significant neurologic sequelae.

Diagnosis

Although experimental animals and embryonated eggs are susceptible to infection with HSV strains, tissue cultures have largely replaced these hosts for diagnostic purposes. Primary human embryonic kidney, rabbit kidney, and human amnion cells readily support the replication of HSV. Continuous cell strains or cell lines of human diploid origin and certain continuous monkey kidney cell lines also support HSV replication, but to a lesser extent. Cytopathic effects usually appear rapidly, within 24-48 hours if the virus inoculum is high. Cells become rounded and clump, with rapid progression of cytopathic effects throughout the cell monolayer. Ballooning degeneration and the formation of multinucleated syncytial giant cells may be observed, particularly with HSV-2 isolates. Vesicles contain their highest titers of virus within the first 24-48 hours, and specimens should be collected early and promptly inoculated into tissue cultures. If a delay is unavoidable, specimens can be stored in appropriate carrying medium at 4-9 °Ñ for a few hours, but for longer period they should be stored at -70 °Ñ. Typing of isolates can be accomplished by using a variety of serologic techniques including immunohistochemistry or microneutralization. When tissue specimens such as neural ganglia are being studied for the presence of virus, tissue explantation or cell cocultivation techniques have proved useful in facilitating virus isolation.

The recent development of monoclonal antibodies to individual herpes virus antigens should allow for the more precise identification and typing of HSV isolates. HSV-1 and HSV-2 have both type-specific and cross-reactive antigens that are useful for both grouping and type discrimination. Moreover, the cloning of herpes DNA fragments in recombinant bacteria may permit the production of probes to identify herpes genomes in the absence of infectious virus.

For a rapid diagnosis of skin or mucous membrane lesions, scrapings from suspect lesions may be smeared, fixed with ethanol or methanol and stained with Giemsa or Wright preparation. The presence of multinucleated giant cells indicates infection with HSV or varicella-zoster virus. When using cytologic techniques, e.g. the Papanicolaou cervicovaginal stain or the Paragon multiple stain, intranuclear inclusions may also be seen. Alternatively, such material can be examined for herpes antigens by immunohistochemical techniques or by in situ DNA hybridization.

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Serologic techniques may be helpful in diagnosing primary HSV infections but are rarely of value in recourse infections. A variety of assays have been used including neutralization, complement fixation, passive hemagglutination, indirect immunofluorescence, radioimmunoassay, enzyme immunoassays, complement-mediated cytolysis, and antibody-dependent cellular cytolysis. During primary infections, a fourfold or greater rise in titer is observed between acute and convalescent sera. In recourse infections such rises may or may not be observed. Many licensed enzyme immunoassays appear to give inaccurate information concerning HSV-infecting subtypes.

Measurement of IgM HSV antibodies in infants may be helpful in the diagnosis of neonatal infection. Such antibodies usually appear within the first 4 weeks of life in infected infants and persist for many months. Measurement of IgM antibodies in older persons has not proved useful in separating primary from recourse infections.

Approaches to detect specific HSV antigens, antibodies, or DNA in cerebrospinal fluid are under development. Such techniques may circumvent the need for invasive procedures such as brain biopsy to make the diagnosis of herpes encephalitis.

Differential diagnosis

HSV causes various pathologies, which clinical manifestations can differ a lot. Sometimes only complicated laboratory research helps to verify diagnosis of HSV infection. The most common sign of HSV infection is vesicular eruption, so differential diagnostics is necessary with diseases, which can be accomponied by the same eruptive lesions. They are chicken-pox, VZV-infection, enterovirus herpangina, Hand-Fuss-Mund Krankheit (HFMK), erysipelas, anthrax.

Treatment

A number of nucleoside derivatives interfere with the synthesis of HSV DNA. Some of these (trifluorothymidine, vidarabine) are useful in and licensed for the topical treatment of herpes keratitis. Vidarabine and acyclovir are also useful for systemic HSV infections. None of these agents affects latent virus.

In the immunocompromised host, acyclovir is useful as both treatment and suppression of recourse mucocutaneous HSV lesions. For the treatment of acute episodes, virus shedding, local symptoms (pain), and time to healing can be reduced by intravenous or oral regimens (400 mg five times per day). Acyclovir is also useful in the prevention of herpetic recurrences in immunocompromised hosts including transplant recipients,leukemics undergoing induction chemotherapy, and patients with AIDS. Regimens of 200-400 mg from two to five times per day have been satisfactory in preventing recurrences among seropositive patients.

Parenteral acyclovir is indicated for disseminated or central nervous system HSV infections. In patients with biopsy-proven HSV encephalitis, acyclovir was compared with vidarabine and found to be superior in reducing mortality. Doses of 10 mg/kg every 8 hours for 14-21 days are recommended. In newborns with

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disseminated HSV- infections, acyclovir and vidarabine appear equivalent but because of ease of administration, acyclovir is recommended.

Acyclovir has little acute toxicity. Drug-related neurotoxicity (disorientation, hallucinations, tremors, ataxia, seizures) has been described rarely, and reversible renal dysfunction may occur, particularly following a rapid bolus infusion.

Prophylaxis

Experimental vaccines against HSV have shown promise in animal models, and some are undergoing human trials. Limited trials in humans, however, have been unsuccessful, and it is unlikely that a human HSV vaccine will be generally available in the near future.

The prevention of neonatal disease in the offspring of mothers with genital infection presents special problems.

VARICELLA-ZOSTER VIRUS

Varicella-zoster virus (VZV) causes two distinct clinical diseases. Varicella, or more commonly chickenpox, is the primary infection and results from exposure of a susceptible individual to the virus. Chickenpox is ubiquitous and extremely contagious, but for the most part, it is a benign illness characterized by a generalized exanthematous rash. It occurs seasonally and in epidemics. Recurrence of infection results in the more localized phenomenon known as herpes zoster, often referred to as shingles, a common infection among the elderly.

Historic reference

Shingles has been recognized since ancient times as a unique clinical entity because of the dermatomal vesicular rash; however, chickenpox was often confused with smallpox. In 1875, Steiner successfully transmitted VZV by inoculation of the vesicular fluid from an individual suffering from chickenpox to volunteers. The infectious nature of VZV was further defined by von Bokay who observed chickenpox in individuals who had close contact with others suffering from herpes zoster. He correctly described the mean incubation period for the development of chickenpox in susceptible patients as well as the average range in days. Kundratitz in 1925 showed that the inoculation of vesicular fluid from patients with herpes zoster into susceptible individuals resulted in chickenpox. Similar observations were reported by Brunsgaard and others, and in 1943 Garland suggested that herpes zoster was the consequence of the reactivation of latent VZV.

Since early in the twentieth century, similarities in the histopathologic findings of skin lesions and in epidemiologic and immunologic studies indicated that varicella and herpes zoster were caused by the same agent. Tyzzer described the histopathology of skin lesions resulting from VZV infections and noted the development of intranuclear inclusions and multinucleated giant cells. The histopathologic descriptions were amplified by Lipschutz in 1921 for herpes zoster.

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Etiology

Isolation of VZV in 1958 permitted a definition of the biology of this virus. Viral isolates from patients with chickenpox and herpes zoster demonstrated similar changes in tissue culture, specifically the appearance of eosinophilic intranuclear inclusions and multinucleated giant cells. These findings are virtually identical to those encountered with clinically available biopsy material. Taken together, these data provided a universal acceptance that both diseases were caused by VZV. By 1958, Weller and colleagues had been able to establish that there were no differences between the viral agents isolated from patients with these two clinical entities from either a biologic or immunologic standpoint.

Varicella-zoster virus is a member of the Herpesviridae family and shares structural characteristics with other members of the family. The virus has icosahedral symmetry containing centrally located double-stranded DNA with a surrounding envelope. The size of the virus is approximately 150-200 nm and has a lipid-containing envelope with glycoprotein spikes. The organization of the viral genome is similar to other herpesviruses.

Varicella-zoster virus is highly cell associated and spreads from cell to cell by direct contact. Virus can be isolated in a variety of continuous and discontinuous cell culture systems of human and simian origin. Approximately 8-Þ hours after infection, virus-specific immunofluorescence can be detected in the cells immediately adjacent to the initial focus of infection. This parallels the microscopic observation of the radial spread of cytopathology.

Epidemiology

The epidemiology of herpes zoster is somewhat different. Varicella-zoster virus characteristically becomes latent after primary infection. It is presumed that VZV establishes latency within the dorsal root ganglia. Reactivation leads to herpes zoster, a sporadic disease. Histopathologic examination of the nerve root after infection with VZV demonstrates characteristics indicative of VZV infection. In those individuals who die after recent herpes zoster infection, an examination of the dorsal root ganglia reveals satellitosis lymphocytic infiltration in the nerve root, and degeneration of the ganglia cells. Intranuclear inclusions can be found within the ganglia cells. Although it is possible to demonstrate the presence of VZV by electron microscopy, it has not been possible to isolate this virus in cultures usually from explants of dorsal root ganglia, as has been done after herpes simplex virus infection. The biologic mechanism by which VZV establishes latency remains a mystery at this time.

Herpes zoster is a disease that occurs at all ages, but it will afflict about 20 % or more of the population overall, mainly among the elderly. Herpes zoster, known also as shingles, occurs in individuals who are seropositive for VZV or more specifically, in individuals who have had prior chickenpox. Herpes zoster has occurred within the first 2 years of life in children born in women who have had chickenpox during pregnancy. These particular cases likely reflect in utero chickenpox with reactivation early in life.

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Pathogenesis

The pathogenesis of VZV infection that results in chickenpox reflects the natural history of the disease. Chickenpox occurs in susceptible individuals who are exposed to virus after intimate contact. The appearance of a diffuse vesicular rash has been well studied from a pathologic standpoint. Histopathologic findings in human VZV infection, whether chickenpox or herpes zoster, are virtually identical. The vesicles involve the corium and dermis. As viral replication progresses, the epithelial cells undergo degenerative changes characterized by ballooning, with the subsequent appearance of multinucleated giant cells and prominent eosinophilic intranuclear inclusions. Under unusual circumstances, necrosis and hemorrhage may appear in the upper portion of the dermis. As the vesicle evolves, the collected fluid becomes cloudy as a consequence of the appearance of polymorphonuclear leukocytes, degenerated cells, and fibrin. Ultimately, the vesicles either rupture and release infectious fluid or gradually become reabsorbed.

Transmission is likely by the respiratory route, followed by localized replication at an undefined site, which leads to seeding of the reticuloendothelial system and, ultimately, viremia. The occurrence of viremia in patients with chickenpox is supported by the diffuse and scattered nature of the skin lesions and can be verified in selected cases by the recovery of virus from the blood. As noted, the mechanism of the reactivation of VZV that results in herpes zoster is unknown.

Clinical manifestations

Herpes zoster, or shingles, is characterized by a unilateral vesicular eruption with a dermatomal distribution. Thoracic and lumbar dermatomes are most commonly involved (Fig. 9). Herpes zoster may involve the eyelids when the first or second branch of the fifth cranial nerves is affected, but keratitis heralds a sight-threatening condition,herpes zoster ophthalmicus. Although lesions on the tip of the nose are said to presage corneal lesions, absence of such skin lesions does not guarantee corneal sparing. Keratitis may be followed by severe iridocyclitis, secondary glaucoma, or neuroparalytic keratitis. Ophthalmologic consultation should be requested for any patient with suspected herpes zoster ophthalmicus. Generally, the onset of disease is heralded by pain within the dermatome that precedes the lesions by 48-72 hours. Early in the disease course erythematous, macropapular lesions will appear that rapidly evolve into a vesicular rash. Vesicles may coalesce to form bullous lesions. In the normal host these lesions continue to form over a period of 3-5 days, with the total duration of disease being 10-15 days. However, it may take as long as 1 month before the skin returns to normal.

Unusual cutaneous manifestations of herpes zoster, in addition to herpes zoster ophthalmicus, include the involvement of the maxillary or mandibular branch of the trigeminal nerve, which results in intraoral involvement with lesions on the pallet, tonsillar fossa, floor of the mouth, and tongue. When the geniculate ganglion is involved, the Ramsay-Hunt syndrome may occur, with pain and vesicles in the external auditory meatus, loss of taste in the anterior two-thirds of the tongue.

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No known factors are responsible for the precipitation of the events of herpes zoster. If herpes zoster occurs in children, the course is generally benign and not associated with progressive pain or discomfort. In adults, systemic manifestations are mainly those associated with pain, as noted below.

The most significant clinical manifestations of herpes zoster are the associated acute neuritis and, later, post-herpetic neuralgia. Post-herpetic neuralgia, although uncommon in young individuals, may occur in as many as 25-50 % of patients over the age of 50 years. It is estimated that as many as 50 % of individuals over 50 years of age will have debilitating pain that persists for over 1 month. Postherpetic neuralgia may cause constant pain in the involved dermatome or consist of intermittent stabbing pain. Pain may be worse at night or on expose to temperature changes. At its worst, the neuralgia can be incapacitating.

Extracutaneous sites of involvement include the central nervous system as manifested by meningoencephalitis or encephalitis. The clinical manifestations are similar to that of other viral infections of the central nervous system. However, a rare manifestation of central nervous system involvement by herpes zoster is granulomatous cerebral angiitis which usually follows zoster ophthalmicus. It should be noted that involvement of the central nervous system in cutaneous herpes zoster probably is more common than is recognized clinically. Frequently,patients who undergo cerebrospinal fluid examination for other reasons during episodes of shingles are found to have evidence of pleocytosis without elevated cerebrospinal fluid protein levels. These patients are without signs of meningeal irritation and frequently complain of headaches.

Classically, VZV infection involves dorsal root ganglia. Motor paralysis can occur as a consequence of the involvement of the anterior horn cells in a manner similar to that encountered with polio. Patients with involvement of the anterior horn cells are particularly likely to have excruciating pain. Other neuromuscular disorders associated with herpes zoster include Guillain-Barre syndrome, transverse myelitis, and myositis.

Herpes zoster in the immunocompromised host is more severe than in the normal individual. Lesion formation continues for up to 2 weeks, and scabbing may not take place until 3-4 weeks into the disease course. Patients with lymphoproliferative malignancies are at risk for cutaneous dissemination and visceral involvement, including varicella pneumonitis, hepatitis, and meningoencephalitis. However, even in the immunocompromised patient disseminated herpes zoster is rarely fatal.

In recent years,herpes zoster has been recognized as a frequent infection in individuals with human immunodeficiency virus (HIV) infection, occurring in 8-11 percent of patients. Although the occurrence of cutaneous dissemination is infrequent,complications such as VZV retinitis,acute retinal necrosis,and chronic, progressive encephalitis have been reported.

Chronic herpes zoster may also occur in the immunocompromised host particularly those individuals with a diagnosis of HIV infection. Individuals have

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sustained new legion formation with an absence of healing of the existing lesions. These syndromes can be particularly debilitating and, interestingly, have been associated with the isolation of VZV isolates resistant to acyclovir.

Diagnosis

The diagnosis of shingles is usually made by history and physical examination. The recent development of monoclonal antibodies to individual herpes virus antigens should allow for the more precise identification and typing of HSV isolates.

Differential diagnosis

Differential diagnosis of varicella and herpes zoster is less confusing than it was 20-30 years ago. Smallpox or disseminated vaccinia was confused with varicella because of the similar appearance of the cutaneous lesions. With the worldwide eradication of smallpox and the discontinuation of vaccination, these disease entities no longer confound the clinical diagnosis. For the most part the characteristic skin rash with lesions in all stages of development provides the basis for the clinical diagnosis of infection. The localization and distribution of a vesicular rash makes the diagnosis of herpes zoster highly likely; however, other viral exanthems can occasionally be confused with this disease.

Impetigo and varicella can also be confused clinically. Impetigo is usually caused by group A (p-hemolytic) streptococci and often follows an abrasion of the skin or inoculation of bacteria at the site of the skin break, and can lead to small vesicles in the surrounding area. Systemic signs of disease may be present if progressive cellulitis or secondary bacteremia develops. Unroofing these lesions and careful Gram staining of the scraping of the base of the lesion should reveal gram-positive cocci in chains, which are streptococci presumably, or gram-positive cocci in clusters, which are staphylococci presumably, another cause of vesicular skin lesions. Treatment for these latter infections is distinctly different from that of chickenpox and requires administration of an appropriate antibacterial remedies.

In a smaller number of cases, disseminated vesicular lesions can be caused by herpes simplex virus. In these cases, disseminated herpes simplex virus infection is usually a consequence of an underlying skin disease such as atopic dermatitis or eczema. In this situation,an unequivocal diagnosis can only be confirmed by isolation of the virus in tissue culture.

More recently, it has been-recognized that disseminated enteroviral infections, particulary those caused by group A coxsackieviruses, can cause widespread distal vesicular lesions. These rashes are more commonly morbilliform in nature with a hemorrhagic component rather than vesicular or vesiculopustular appearance. Generally these infections occur during the enterovirus season in late summer and early fall and are associated with lesions of the oropharynx, palms, and soles. This latter finding is most helpful in distinguishing enteroviral disease from chickenpox.

Infectious diseases

Treatment

Acyclovir is approved for the treatment of herpes zoster in the normal host. Adolescents and adults can receive up to 800 mg 5 times a day. Oral therapy of herpes zoster in the normal host accelerates cutaneous healing and reduces acute neuritis. The effect of therapy on post-herpetic neuralgia is marginal at best. Properly designed and controlled clinical trials have not supported the utility of corticosteroids as an adjunct to antiviral therapy.

Corticosteroid therapy alone has been suggested to be useful for decreasing both acute neuritis and the frequency of post-herpetic neuralgia: however, these data are controversial. In the immunocompromised host or with the appearance of visceral complications such as varicella pneumonitis in the normal host, the use of either intravenous acyclovir or vidarabine is of value. Vidarabine has been extensively studied for the treatment of herpes zoster in the immunocompromised hosts. Although efficacy is apparent, it has been replaced by acyclovir.

The management of acute neuritis and/or post-herpetic neuralgia can be particularly problematic. It requires the judicious use of analgesics ranging from non-narcotic to narcotic derivatives and may include the deployment of such drugs as amitriptyline hydrochloride and fluphenazine hydrochloride.

Prophylaxis

Disease can be prevented by administering zoster immune globulin (ZIG), derived from the sera of patients recovering from herpes zoster, or varicella zoster immune globulin (VZIG) prepared from pooled plasma containing high titers of specific antibody. Such preparations should be given within 96 hours after exposure to be effective.

Control questions:

1. Etiology, epidemiology and incidence of herpes simplex virus infections.

2. Pathogenesis of herpes simplex virus (HSV) infections.

3. Main clinical symptoms and signs of primary HSV infections.

4. Clinical manifestations of recourse HSV infections.

5. Complications of HSV infections.

6. Etiology of Varicella-zoster virus (VZV) infections.

7. Pathogenesis of VZV infections.

8. Clinical manifestations of VZV infections.

9. Complications of VZV infections.

10. Laboratory methods of herpetic diseases diagnosis.

11. Differential diagnosis of herpetic infections.

12. Treatment of herpetic infections.

13. Herpetic diseases prophylaxis.

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Date: 2014-12-21; view: 1165