Nancy L. Stitt, RN, BSN


April 03, 2003

Viral Infection

The viruses most responsible for infection in transplant recipients belong to the family of HHVs. Herpesviridae are classified according to their biologic properties into 3 families: alpha herpesviruses, which include herpes simplex virus (HSV) 1, HSV 2, and VZV; the beta herpesvirus, cytomegalovirus (CMV); and the gamma herpesvirus, Epstein-Barr virus (EBV). Risk assessment and prevention of HHV infection is dependent on assessment of the serologic status of the donor and recipient for viruses.

Viruses are totally dependent on host cells for survival. After the virus enters the host cell it is uncoated, and the viral DNA enters the host nucleus, where it orders transcription of messenger RNA and synthesis of viral proteins in the cytoplasm. Viral proteins take part in DNA synthesis within the nucleus of the host cell, and it is here that maturation of the virus occurs.

Viral infections can be primary (de novo) or secondary (reactivation). Most viral infections in transplant recipients are secondary infections because most individuals have had a primary infection with a herpesvirus (the species of virus most responsible for infection in transplant recipients), usually in early childhood. By puberty, it is estimated that 40% to 80% of individuals have been infected by a herpesvirus and that by age 25, almost all adults have.[26] In primary HSV infection, the virus enters the host organism through mucocutaneous surfaces and begins to multiply and migrate toward sensory ganglia. An individual who has experienced a primary infection by a particular virus will have antibodies to that virus in their serum and is said to be seropositive for that virus. The individual who has never experienced a primary viral infection by a particular virus is seronegative for that virus. A primary infection is defined as an active infection in a previously seronegative recipient.

Secondary viral infections are called latent or reactivation infections. After the initial or primary infection, long-lasting humoral and cellular immunity occurs and the virus establishes permanent residence in the host, either in the lymphocyte pool or in the corresponding sensory ganglia. In latency, for example, CMV attaches to C3 receptors on B cells where viral proteins are produced, but complete viral replication is inhibited. The virus "sets up residence" in the cell, but outside of the chromosome, which prevents the virus from ever being fully "packaged" and allows for peaceful coexistence of the virus within the cell. Virus that resides in a neuron or lymphocyte is in effect protected from antiviral antibodies, because antibodies do not penetrate human cells.

Although recurrence or reactivation of latent virus infection occurs during or after therapeutic immunosuppression, the association between reactivation and decreased cellular immunity is unclear. During recurrence, complete viral replication occurs. The areas in which the greatest differences are seen between HSV infection in normal persons and HSV infection in immunosuppressed individuals are the severity and chronicity of disease. Even localized infections may be severe in the immunosuppressed individual.


By serologic assessment, approximately 90% of the population is infected with HSV at one time or another, and in the majority of the general population, the virus establishes a latent and permanent residence.[27,28] Reactivation occurs in 10% to 15% of the general population, but is much more prevalent in transplant recipients. Primary HSV-1 infection usually occurs during childhood, and primary HSV-2 infections usually occur after puberty. Recurrence can lead to aseptic meningitis, transverse myelitis, and secondary fungal and bacterial infections. Crossover of both types of HSV infection occurs from auto-inoculation and orogenital sexual contact.

HSV infections are prevalent in the solid organ transplant population. Viral shedding can be detected within 5 to 14 days after transplantation in 50% to 66% of seropositive renal allograft recipients.[29] However, symptomatic ulcers or vesicles develop in only 15% to 45% of cases. The most common manifestation of HSV infection in the immunosuppressed patient is mucocutaneous lesions of the oropharynx or genital regions. Lesions may persist for months, and dissemination to internal organs, including the esophagus, colon, and bladder, as well as the eye (corneal and retinal infection), may occur. Cutaneous manifestations are uncommon and the mortality rate is high, up to 67%.[29] HSV hepatitis can occur, and when it does, the onset is within 4 to 20 days after transplantation.

Diagnosis of HSV infection can usually be made by direct observation of the characteristic lesions, but the definitive diagnosis of active infection relies on culture of vesicular fluid, mucosal swabs, cerebrospinal fluid, or urine. PCR testing is the preferred technique for cerebrospinal fluid. A positive Tzanck smear signifies herpesvirus infection, but is not specific for HSV. The preferred method is immunofluorescence staining with specific antisera.[29]

HSV-1. HSV-1 is responsible for most herpesvirus infections above the waist (eg, herpetic lesions of the lips [herpes labialis]), face, and mouth. Most of the US population develops antibodies to HSV-1 by the age of 50.[30] Following a primary infection, the virus establishes latency in the dorsal root of the trigeminal ganglion and recurs as herpes labialis. Recurrence sites are those innervated by the trigeminal nerve (eyes, nose, and mouth), and recurrence can lead to keratoconjunctivitis, blindness, and encephalitis. More than 5000 cases of adult HSV encephalitis and more than 500,000 cases of herpes keratitis occur annually in the United states.[31] Although HSV-1 can occasionally extend below the oropharynx to involve the esophagus or trachea, resulting in focal necrotizing pneumonia, and can disseminate through the bloodstream to involve the CNS, liver, colon, and adrenal glands, infection is usually localized and manifested by recurrent vesicles and shallow ulcerations.

Herpetic lesions heal in approximately 10 to 14 days. Primary and secondary localized infections of the cornea can develop and are a major cause of blindness. With immunosuppression, small perioral lesions may enlarge and produce extensive and painful oropharyngeal ulcerations associated with gingivitis, stomatitis, and pharyngitis, and a rash indistinguishable from HZV may develop. Large, painful ulcerations can interfere with nutritional intake.

HSV-2. HSV-2 is responsible for most herpesvirus infections below the waist (eg, herpes genitalis). Primary HSV-2 genital infections are usually acquired during sexually active periods of life. There are approximately 500,000 new cases of HSV-2 and 20-30 million people have recurrent herpes genitalis each year in the United States.[31] A primary HSV-2 infection begins with local symptoms, such as soreness, itching, and discharge, and is accompanied by the following symptoms: fever; general malaise; lymphadenopathy; neuralgia radiating to the thighs, buttocks, and groin; numerous clusters of painful vesicular lesions; and erythema on the penis, vulva, vaginal mucosa, or cervix. Herpetic vesicles break and form shallow ulcerations that take up to 3 weeks to heal.

Genital herpes frequently flares up as a latent infection. Recurrent episodes are milder than primary infection, with prodromal symptoms of tingling, itching, and burning. Associated complications include aseptic meningitis, transverse myelitis, urethral stricture and dysuria, erythema multiforme, and secondary bacterial and fungal infections. Factors associated with recurrence of HSV-2 infection include fever, respiratory tract infection, sleep deprivation, menstruation, malnutrition, stress, hormonal imbalance, and mechanical friction from tight clothing.

HSV-2 infection can be diagnosed by observation of the characteristic lesions, but the only definitive diagnostic test is isolation of the virus in cell cultures. Often, however, a Tzanck smear of scrapings from the base of the vesicle is used for a simple, quick diagnosis.

Treatment of HSV Infection

Primary and recurrent oral or genital herpes infection should be treated. Prompt treatment of primary infections can reduce the amount of virus invading the ganglia and limit the reservoir of virus that can potentially be reactivated. Therapeutic goals include: (1) containment of infection, (2) prevention of spread of lesions, particularly to other people, (3) rapid healing, (4) alleviation of symptoms, (5) prevention of bacterial superinfection, (6) prevention of systemic disease, and (7) prevention of permanent blindness. Treatment regimens for mucocutaneous HSV infections in renal transplant recipients are similar to those used in immunocompetent individuals except that dosages are tailored to renal function ( Table 1 ).

Symptomatic treatment of mucocutaneous lesions also includes use of drying agents such as 4% zinc sulfate solution, antibiotic ointments to prevent bacterial superinfection, and topical anesthetics and analgesics for pain relief.


VZV is a highly communicable pathogen that causes chickenpox in childhood. Spread occurs by droplet infection or contact with involved mucocutaneous lesions. The virus remains in a latent state in dorsal root ganglia and can be reactivated after years to produce the clinical syndromes of HZV infection. Approximately 5% to 10% of renal transplant recipients develop reactivation to HZV infection. Reactivation of HZV is seen primarily as a vesicular infection in thoracic nerve dermatome distributions and is commonly referred to as shingles. A primary VZV infection in the transplant recipient can be devastating. Up to 33% of untreated cases disseminate, causing hemorrhagic pneumonia and skin lesions, encephalitis, disseminated intravascular coagulation, pancreatitis, and hepatitis.

In healthy individuals, only the primary dermatome is involved, and the major morbidity is postherpetic neuralgia. Renal transplant recipients however, may develop localized dermatomal HZV involving up to 3 dermatomes, disseminated cutaneous zoster that crosses the midline or involves more than 3 dermatomes, or visceral HZV infection with lung or liver involvement. Treatment of VZV infection is outlined in Table 2 .


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