Management of herpes simplex and varicella-zoster virus infections.

Herpes simplex virus and varicella-zoster virus are common infections and are seen frequently in clinical practice. Infection with these viruses results in cutaneous lesions that may be diagnosed clinically, but widely available laboratory testing is useful for confirmation. Asymptomatic herpes simplex virus shedding, or "subclinical reactivation," likely occurs in all persons infected with herpes simplex virus and results in the transmission of virus despite the absence of signs or symptoms that suggest active infection. Oral and intravenous acyclovir are effective in treating initial and recurrent herpes simplex and varicella-zoster virus infections. The daily administration of oral acyclovir as suppressive therapy is effective in patients with frequently recurring genital infection with herpes simplex virus by reducing the number of symptomatic recurrences and the frequency of asymptomatic virus shedding. Two new antiviral agents, famciclovir and valacyclovir hydrochloride, have been approved for the short-term treatment of recurrent genital herpes simplex virus and recurrent zoster in nonimmunocompromised hosts. Famciclovir and valacyclovir demonstrate superior pharmacokinetics compared with acyclovir and allow for less frequent daily dosing with higher achievable serum drug concentrations. The attenuated live varicella virus vaccine is now available in the United States and prevents primary varicella-zoster virus infection in susceptible children and adults.

Effects of selective depletion of L3T4+ T-lymphocytes on herpes simplex virus encephalitis.

The L3T4 surface molecule defines a subset of murine lymphocytes which are homologous to CD4+ lymphocytes in humans, and are functionally characterized as "helper/inducer" cells. To determine the role of helper/inducer lymphocytes in the host defense against herpes simplex virus type 1 (HSV-1) encephalitis, we utilized a monoclonal antibody to selectively deplete L3T4+ lymphocytes from BALB/c mice prior to experimental HSV infection. Susceptibility to HSV was only minimally increased by the depletion of L3T4+ cells, although mice receiving anti-L3T4 were profoundly immunosuppressed; splenic lymphocytes did not respond to stimulation by virus antigen in vitro, and L3T4+ lymphocyte-depleted mice failed to produce antibodies to HSV-1. However, mice receiving anti-L3T4 had a prolonged increase in natural killer cell activity following HSV infection as compared to controls. These data demonstrate that L3T4+ lymphocytes contribute minimally to host resistance to acute neural HSV infection, even though elimination of these lymphocytes markedly inhibits the genesis of immune responses.

Effects of L3T4+ lymphocyte depletion on acute murine cytomegalovirus infection.

We examined the role of T lymphocytes bearing the L3T4 phenotype in acute murine cytomegalovirus (MCMV) infection. In vivo administration of rat IgG2b monoclonal antibody (MAb) GK 1.5 was used to deplete mice of L3T4+ lymphocytes during acute MCMV infection. Unlike the saline-treated controls that resolved their infections, mice receiving the MAb developed persistent and high levels of virus in the salivary gland, lung and spleen. The production of antibody to MCMV was delayed and the titres achieved were markedly less than in the controls. Despite the higher levels of virus replication, there was no increase in mortality seen in animals treated with the MAb. Following intraperitoneal challenge with MCMV, depletion of L3T4+ lymphocytes was protective, increasing the dose of MCMV required to produce death. These data indicate that T lymphocytes of the L3T4 phenotype influence the degree of MCMV replication during acute infection and may contribute to mortality following intraperitoneal virus challenge.

Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). An uncontrolled trial.

STUDY OBJECTIVE: To determine whether trisodium phosphonoformate (foscarnet) is efficacious in treating severe mucocutaneous disease due to acyclovir-resistant herpes simplex virus type-2 (HSV-2) infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Open-labeled drug administration to patients with AIDS and severe ulcerative disease due to acyclovir-resistant HSV-2 infection. SETTING: Medical floors of acute care hospital. PATIENTS: Four patients with AIDS who developed progressive ulcerative mucocutaneous lesions of the genitals, perineum, perianal region, or finger due to acyclovir-resistant, thymidine-kinase (TK)-negative strains of HSV-2. INTERVENTION: Foscarnet, 60 mg/kg body weight intravenously every 8 hours (with reduced dosage for renal impairment), for 12 to 50 days. MEASUREMENT AND MAIN RESULTS: All patients receiving foscarnet had dramatic improvement in their clinical findings with marked clearing of mucocutaneous lesions and eradication of HSV from mucosal surfaces. CONCLUSION: Foscarnet may be an effective treatment for severe mucocutaneous disease due to acyclovir-resistant, TK-negative strains of HSV-2.

Mucocutaneous dissemination of acyclovir-resistant herpes simplex virus in a patient with AIDS.

Infections caused by herpes simplex virus (HSV) are a significant source of morbidity in immunocompromised patients. Acyclovir is often used prophylactically and therapeutically in patients with human immunodeficiency virus infection. The emergence of acyclovir-resistant strains of HSV capable of causing disease has been recognized. We report a case in which a thymidine kinase-deficient mutant of HSV caused extensive disease in a patient with AIDS. This case emphasizes that virus recovered from nonhealing lesions should be submitted for further study, which may advance our understanding of the interaction between host defense and drug-resistant strains.

Effects of long-term acyclovir chemosuppression on serum IgG antibody to herpes simplex virus.

Patients with severe or frequent recurrent genital herpes simplex virus (HSV) infection can be managed either by treating each recurrence with acyclovir or by suppressing recurrences with daily administration of the drug. To determine the effects of long-term acyclovir therapy on the immune response to HSV, we studied the change in IgG antibody concentration to HSV in 46 individuals with recurrent genital HSV-2 infection who received acyclovir for 1 year, Twenty-seven subjects received daily acyclovir chemosuppression, while 19 subjects received daily placebo (with acyclovir administered intermittently only during recurrences). Immunoglobulin G (IgG) antibody to HSV was determined before medication began, at completion of 1 year of therapy, and 22 weeks following the first untreated HSV recurrence. Daily acyclovir chemosuppression for 1 year reduced mean IgG antibody concentration by 10% from baseline values (P less than 0.01), whereas in patients receiving intermittent therapy no significant decline was observed. In both groups, however, the first untreated recurrence produced a rise in mean antibody concentrations. We conclude that prolonged daily acyclovir chemosuppression reduces humoral immunity to HSV, but antibody concentrations increase following the first untreated recurrence.

Herpesvirus infections (cytomegalovirus, herpes simplex virus, varicella-zoster virus). How to use ganciclovir (DHPG) and acyclovir.

Herpes viruses (HSV, CMV, VZ) are very frequent in AIDS patients and often exist in a chronic or progressive form. Clinically evident CMV retinitis occurs in approximately 10 per cent of AIDS patients but can be effectively treated with a new nucleoside analogue DHPG (Gancyclovir). Perianal ulcers, proctitis, and other clinical syndromes caused by HSV can be effectively treated with acyclovir (ACV) and HSV recurrences can be prevented by daily administration of ACV. Zoster in a young adult may be the first indication of immunodeficiency due to HIV. Because VZV is less susceptible to ACV than HSV, intravenous ACV or high-dose oral therapy is required to achieve inhibitory blood levels.

Laboratory diagnosis of herpesvirus infections.

The diagnosis of infection due to herpesviruses can be performed by several laboratory techniques, including virus culture, demonstration of virus-specific cellular antigens, detection of virus-induced serum antibodies, detection of viral nucleic acids (using radiolabeled probes), or visualization of histologic changes in infected tissue. Virus culture is the most sensitive technique for diagnosis of most infections due to herpes simplex virus (HSV) and cytomegalovirus (CMV), but is insensitive for the diagnosis of varicella-zoster (VZV) infection and not routinely available for Epstein-Barr virus (EBV). Identification of viral antigens on infected cells with monoclonal antibodies is useful for definitive identification of virus in cell culture and for rapid diagnosis of infection due to HSV, VZV, or CMV. Serologic studies are useful for the diagnosis of EBV infection, because clinical symptoms and an antibody response occur simultaneously, and other diagnostic tests are generally unavailable. Although serologic studies may be used retrospectively to diagnose infections due to HSV, VZV, or CMV, these results are seldom available in time to be useful in managing the acute infection or in guiding antiviral chemotherapy. Newer diagnostic techniques, such as detection of viral nucleic acids using radiolabeled probes, may become useful in the future for the rapid diagnosis of EBV or CMV infection.

Prevention and treatment of experimental herpes simplex virus encephalitis with human immune serum globulin.

Pooled human immunoglobulin suitable for intravenous administration (IGIV) was evaluated in the prophylaxis and treatment of herpes simplex virus (HSV) type 1 encephalitis in a murine model. Four-week-old BALB/c mice received a single intraperitoneal injection of IGIV or saline 24 h before or up to 24 h after intranasal infection with 10(4.6) PFU of HSV type 1. Treatment with IGIV was protective against death, and the protective effects were dose and time dependent. Treatment with IGIV blocked the production of HSV antibody by infected mice and reduced the number of trigeminal ganglia containing latent virus. Removal of neutralizing antibody from the IGIV pool did not eliminate the protective effect, whereas F(ab)2 fragments of IGIV, which had virus-neutralizing activity that was identical to that of native IGIV, conferred no protection against death. Pooled human IGIV was effective for the prevention and treatment of HSV encephalitis in mice. Antibody-mediated protection required the Fc portion of the immunoglobulin molecule but did not require the direct neutralization of virus.

Passive immunotherapy for encephalitis caused by herpes simplex virus.

Passive administration of antiviral antibody has been assessed in animal models as a potential form of treatment for infections due to herpes simplex virus (HSV). Previous investigative work has demonstrated the beneficial effect of immune serum administered either before or after HSV infection of mice. In some studies the protective effect of antibody was abrogated in the absence of T lymphocytes, an observation suggesting that cellular effector mechanisms may be necessary for antibody efficacy. In the present study of a mouse model of encephalitis caused by HSV type 2, a 0.5-ml dose of human immunoglobulin (1,250 mg of immunoglobulin G/kg of body weight) prepared at pH 4.25 for intravenous administration reduced mortality and prolonged survival when administered by intraperitoneal injection 24 hr before or up to 8 hr after intranasal viral challenge. The serum titer of HSV-neutralizing antibody and the response to therapy were dose dependent. Clinical trials of passive immunotherapy for severe HSV infections may be warranted.

Recovery of herpesviruses from cerebrospinal fluid of immunodeficient homosexual men.

Over a one-year period the cerebrospinal fluid (CSF) obtained from a series of homosexual men immunocompromised with either Hodgkin's disease or acquired immune deficiency syndrome (AIDS) was cultured to assess the frequency with which infectious viruses could be recovered. Of 58 patients examined, 4 (6.9%) had CSF cultures that showed a cytopathology consistent with a virus infection. All isolates proved to be herpesviruses. Cytomegalovirus (CMV) and varicella-zoster virus were isolated from CSF obtained from 2 patients with neurological features consistent with a subacute encephalitis common among AIDS patients. CMV was also recovered from the CSF of an AIDS patient who developed an ascending myelitis of herpesvirus origin. Finally, a CSF sample obtained from an immunodeficient homosexual man who showed no detectable neurological abnormalities consistently yielded herpes simplex virus type 1 in culture. These results suggest that seeding of the CSF with infectious virus is an uncommon event in this patient population. However, our experience should not dissuade attempts to culture viruses from CSF in similar cases. Successful isolations may prove beneficial in the diagnosis of an accompanying neurological illness and facilitate treatment with antiviral therapy when indicated.

IgG antibody to purified protein derivative by enzyme-linked immunosorbent assay in the diagnosis of pulmonary tuberculosis.

We studied the diagnostic utility of an enzyme-linked immunosorbent assay (ELISA) in hospitalized patients with suspected pulmonary tuberculosis (TB). A positive culture for M. tuberculosis identified active disease, and 3 negative cultures and smears defined the negative group. IgG antibody activity was determined by adding a 1:1,000 dilution of serum to plates coated with PPD antigen. Alkaline phosphatase labeled anti-IgG was added, color developed, and an optical density index (ODI) was determined. Twenty-one patients with M. tuberculosis TB had a mean ODI of 0.27, which was higher than 99 patients without TB, ODI 0.10 (p less than 0.001). An ODI of 0.15 or greater was established as a positive ELISA test. For patients with M. tuberculosis TB, the ELISA had a sensitivity of 67 and a specificity of 79%. The first smear had a sensitivity of 57 and a specificity of 99%. With the first smear and the ELISA test results, a combined sensitivity of 86% was achieved. When both ELISA and the first smear were negative (101 cases), active TB caused by M. tuberculosis was found in only three patients (3.0%).