Cellular and humoral immunity in the pathogenesis of recurrent herpes viral infections in patients with lymphoma.

86 patients with lymphoma were evaluated prospectively for clinical and laboratory evidence of recurrent varicella-zoster, herpes simplex, and cytomegalovirus infections during the first 16 mo of treatment. Cellular immunity to the viral antigens was measured by in vitro lymphocyte transformation and interferon production. Antibody titers and nonspecific measures of cellular immunity, including T-cell quantitation and transformation to phytohemagglutinin, were also assessed. The patients treated with radiation and chemotherapy had the highest incidence of reactivation of each of the viruses (15-19%). Greater susceptibility to herpes viral reactivation in these patients correlated with suppression of cell-mediated immunity to the specific virus. In individual patients, suppression of cellular immunity to the specific herpes viral antigen preceded each episode of reactivation, but recurrent infection did not occur in all patients with diminished specific lymphocyte transformation. Absence of the response appears to be a necessary but not a sufficient condition for the recrudescence of latent infection. Better preservation of cellular immunity to herpes simplex antigen during treatment was associated with infrequent reactivation of herpes simplex. In 25 patients with acute herpes zoster, uncomplicated recovery from the infection was accompanied by the development of lymphocyte transformation and interferon production to varicella-zoster antigen. Quantitation of T-cell numbers and phytohemagglutinin transformation did not correlate with the presence of viral cellular immunity in treated patients. Responses returned while T-cell numbers were low, and the recovery of phytohemagglutinin transformation often preceded recovery of the responses to viral antigens. Although some patients had deficiencies in viral cellular immunity at diagnosis, the duration of the suppression of specific antiviral responses resulting from treatment appears to be the most important factor predisposing to the recurrence of herpes infections in lymphoma patients.

Varicella-zoster virus: molecular virology and virus-host interactions.

Cosmid-based mutagenesis and methods to examine varicella-zoster virus (VZV) tropism for differentiated human cells in vivo provide new information about molecular mechanisms of VZV infection. How specific VZV gene products contribute to viral replication has been further defined, and effects of VZV on expression of cellular genes have been demonstrated.

Specific cell-mediated immunity and infections with herpes viruses in cardiac transplant recipients.

Immune responses and infections with herpes viruses were studied prospectively in 36 cardiac transplant recipients. Specific lymphocyte transformation and interferon production in response to viral antigens, viral culture results, antibody levels, responses to phytohemagglutinin, and T-cell numbers were determined. Responses to phytohemagglutinin and T-cell numbers were depressed for six to 12 weeks. Cytomegalovirus infection occurred in 100 percent of seropositive patients and in 62 percent of seronegative patients. Primary infection was more frequently symptomatic. Heart implantation from a seropositive patient wwas significantly correlated with subsequent infection in seronegative patients. Depression of transformation in response to cytomegalovirus correlated with prolonged shedding. Herpes simplex infection occurred in 95 percent of seropositive patients but decreased after 12 weeks. Asymptomatic shedding was rare, and primary infection did not occur. Return of transformation in response to herpes simplex was associated with decreased infection. Herpes zoster occurred in 22 percent during the first year, and transformation responses to varicella-zoster returned thereafter. Depression of interferon production in response to viruses did not correlate with infection as well as did lymphocyte transformation.

Varicella zoster antibody titers after the administration of intravenous immune serum globulin or varicella zoster immune globulin.

Varicella is a serious infection in the immunocompromised patient. Prophylaxis with varicella zoster immune globulin is known to decrease the incidence of severe varicella infection. The titers of antibody to varicella zoster virus were compared in patients who received either varicella zoster immune globulin or intravenous immune globulin, 4 ml or 6 ml/kg per dose. The titers of antibody to varicella zoster virus were comparable in each group.

Reasons for the absence of a history of recurrent genital infections in mothers of neonates infected with herpes simplex virus.

Thirty-one cases of neonatal herpes simplex (HSV) infection were evaluated to determine how often mothers of infected infants lacked a history of recurrent genital infections and the reasons for its absence. A history of recurrent genital infections was elicited from eight (26%) of the mothers. Nine (29%) of the mothers had primary infections; three of these were oral and six were genital. The mother was not the source of infection in three (9.6%) cases. In eleven (35%) cases, the mother had antibody to HSV but did not have a history or findings of primary or recurrent infection. Two of these mothers had positive cervical or vaginal cultures, but neither had genital lesions typical of HSV in the perinatal period. Two mothers had recurrent HSV infections documented later. The source of the HSV infection remained uncertain in 23% of cases including two in which only the father had a history of recurrent genital infection. When mothers with primary infections in the perinatal period were excluded, the HSV neutralization titers of the mothers of infected infants were similar to the titers of the mothers with recurrent genital infections whose infants were not infected. In contrast, the infected infants had titers fourfold lower than their mother's titer as well as fourfold lower than the 16 infants exposed to HSV who remained uninfected. This discrepancy suggests that the mothers may have had a rise in titer late in pregnancy or that placental transport of antibody was limited. Although 26% of the mothers of infected infants had recurrent genital infections, only three (9.6%) had an easily elicitable history.(ABSTRACT TRUNCATED AT 250 WORDS)

Nocardia farcinica pneumonia in chronic granulomatous disease.

Infection with Nocardia poses a diagnostic challenge in patients with chronic granulomatous disease (CGD) because the signs and symptoms are often nonspecific, delay in diagnosis is common, and invasive procedures are frequently required to obtain appropriate tissue specimens. We present the first reported case of N farcinica pneumonia in an adolescent with X-linked CGD. Differentiation of N farcinica from other members of N asteroides complex is important because of its propensity for causing disseminated infection and antimicrobial resistance. Physicians caring for patients with CGD should maintain a high index of suspicion for nocardiosis, especially in those receiving chronic steroid therapy. Early diagnosis remains critical for decreased morbidity and occasional mortality.

Lack of transmission of the live attenuated varicella vaccine virus to immunocompromised children after immunization of their siblings.

The safety of administering the live attenuated Oka/Merck varicella vaccine to the well siblings of children with malignancy was evaluated as a strategy for reducing the risk of household exposure to varicella among immunocompromised children. Susceptible well children were eligible for vaccination if the child with malignancy had leukemia, lymphoma, or solid tumor in remission for 3 months or longer. No evidence of vaccine virus transmission was found among 30 children with malignancy whose 37 healthy susceptible siblings were immunized with varicella vaccine. Varicella-zoster virus was not isolated from the oropharyngeal secretions taken from 17 vaccinees or their 14 immunocompromised siblings. None of the 30 immunocompromised children had vaccine-related rashes or showed immunologic evidence of subclinical varicella-zoster virus infection based on testing for varicella-zoster virus IgG antibodies and T-lymphocyte proliferation to varicella-zoster virus. Four healthy vaccinees eventually had mild breakthrough cases of varicella, with transmission to the high-risk sibling in 3 cases. However, even in these families, the immunocompromised children had been protected from household exposure varicella for at least 20 months early in the course of their immunosuppressive treatment.

Human T cells recognize multiple epitopes of an immediate early/tegument protein (IE62) and glycoprotein I of varicella zoster virus.

Infection with varicella zoster virus (VZV) elicits persistent cell-mediated immunity directed against the immediate early (IE62) protein and the glycoprotein I (gp I) in most healthy subjects. In these experiments, synthetic peptides corresponding to residues of the IE62 protein and gp I were used to identify linear amino acid sequences of these immunogenic VZV proteins that were recognized by peripheral blood T lymphocytes from VZV-immune individuals of known major histocompatibility complex (MHC) type. All of 12 VZV-immune donors had T-cell proliferative responses, defined as a stimulation index (SI) greater than or equal to 2.0, to at least two of ten synthetic IE62 peptides; the mean number of IE62 peptides recognized by T cells from VZV-immune donors was seven. Five of the ten IE62 peptides stimulated T cells from 75% to 83% of the VZV-immune donors; the other five IE62 peptides were recognized by T cells from 42% to 67% of the subjects. All VZV-immune donors also had T proliferation responses to at least two of ten synthetic gp I peptides; the mean number of peptides recognized was six. Six of the ten gp I peptides were recognized by T cells from 67% to 92% of the VZV-immune donors; the frequency of donors responding to the other gp I peptides ranged from 42% to 58%. None of five nonimmune donors demonstrated T-cell proliferation to any of the IE62 or gp I peptides. A combination of two IE62 peptides provided epitopes that could be recognized by T cells from all twelve VZV-immune donors, regardless of DR type. Similarly, one gp I peptide in combination with either of two other gp I peptides induced proliferation of T cells from all immune subjects. Memory T cells with specificity for multiple short amino acid sequences of the IE62 protein and gp I were detected in subjects who had had primary VZV infection more than 20 years earlier. These observations indicate that natural VZV infection elicits a diverse cell-mediated immune response to viral proteins that is not restricted to only one or two immunodominant regions. Although the usefulness of peptide vaccines remains to be established, multiple epitopes of the IE62 protein and gp I were identified that could be presented by antigen-presenting cells (APC) and recognized by T cells from most subjects in an "outbred" human population.

Granulysin blocks replication of varicella-zoster virus and triggers apoptosis of infected cells.

Granulysin, a lytic protein present in cytolytic granules of human natural killer and cytotoxic T cells, entered cells infected with varicella-zoster virus (VZV). Exposure to granulysin accelerated death of infected cells as assessed by apoptosis markers. The functional domain of granulysin that mediated its antiviral effects was amino acid 23-51; this domain also mediates the additional antitumor cell effects of granulysin. Because granulysin is a product of natural killer cells and T lymphocytes, it is possible that its antiviral activity may act as a mediator of innate and adaptive immune mechanisms.

A concurrent epidemic of respiratory syncytial virus and echovirus 7 infections in an intensive care nursery.

We describe concurrent outbreaks of respiratory syncytial virus (RSV) and Echovirus 7 (Echo 7) infections in a neonatal intensive care unit, including infants who had dual infections. Seventy-three infants were identified as having RSV from January through June, 1984. During the same surveillance period Echo 7 was cultured from 20 infants, and 6 infants had concurrent RSV and Echo 7 and RSV were isolated, but not concurrently. This dual outbreak of RSV and Echo 7 infections persisted for months despite infection control measures. Control procedures were complicated by: (1) cases of RSV infection at less than 72 hours of age, which had not previously been reported and which led to the reintroduction of RSV into "clean" areas; (2) the lack of a rapid diagnostic test for enterovirus infection; (3) the number of infants who were asymptomatic with each infection; and (4) the logistical problems of handling a dual pathogen outbreak in a confined setting. These problems were compounded by the many risk factors associated with nosocomial infections found in neonatal intensive care settings such as prolonged hospitalizations, endotracheal or nasogastric tubes and contact with many ancillary care personnel.

Antiviral susceptibilities of herpes simplex virus isolates from infants with recurrent mucocutaneous lesions after neonatal infection.

Recurrent mucocutaneous lesions occur in many infants after completion of antiviral therapy of neonatal herpes simplex virus (HSV) infection. To determine whether these recurrences were caused by viruses that had become resistant to acyclovir or vidarabine, we tested the antiviral susceptibilities of 22 pretherapy and 32 posttherapy HSV isolates from 22 infants younger than 3 months of age. Sixteen had been treated with acyclovir and six with vidarabine. Antiviral susceptibilities were measured by an enzyme-linked immunosorbent assay and are expressed as the 50% inhibitory dose. All HSV isolates had a 50% inhibitory dose for acyclovir of less than 1.0 micrograms/ml. The mean vidarabine 50% inhibitory dose was 11.4 micrograms/ml for pretherapy isolates and 8.9 micrograms/ml for posttherapy isolates. Antiviral therapy did not select for recurrences with HSV resistant to acyclovir or vidarabine.

A prospective evaluation of primary genital herpes simplex virus type 2 infections acquired during pregnancy.

In order to study the epidemiology of herpes simplex type 2 (HSV-2) infections during pregnancy, we used an enzyme immunoassay to detect type-specific antibodies to HSV-2 glycoprotein G in serial blood samples obtained from a cohort of 1891 pregnant women. Blood samples obtained at about 17 and 32 weeks of gestation and at the time of delivery were assessed for antibody to HSV-2 glycoprotein G in order to evaluate the prevalence of past infections with HSV-2 and the rate of acquisition of HSV-2 infection during pregnancy. Three hundred eleven pregnant women (16.5%) were found to have had past infections with HSV-2. Four of the 1580 women who were initially seronegative developed antibodies to HSV-2 during pregnancy. The annualized rate of acquisition of HSV-2 infection in pregnant women was 0.58%. Three of four women had asymptomatic primary infections; all of the women had preexisting HSV-1 immunity. None of the women or their infants experienced any adverse consequences of gestational herpes. Based upon our very limited number of observations to date, asymptomatic primary episodes occurring in women with previous HSV-1 immunity may be of less consequence to the fetus and neonate than symptomatic true primary HSV-2 infections.

Safety and immunogenicity of one vs. two injections of Oka/Merck varicella vaccine in healthy children.

OBJECTIVE: To compare the safety and immunogenicity of a one- vs. two-dose regimen of Oka/Merck varicella vaccine in approximately 2000 healthy children 12 months to 12 years of age. METHODOLOGY: Subjects with a negative history of varicella were randomized to receive either one or two injections of the vaccine given 3 months apart and were followed for clinical reactions and serologic response (glycoprotein-based enzyme-linked immunosorbent assay). RESULTS: Both one- and two-dose vaccine regimens were generally well-tolerated. The incidences of varicelliform rash and fever were less frequent after the second injection. However, a slight increase in the incidence of injection site reactions was noted after the second injection; these were generally mild. Seroconversion rates by glycoprotein-based enzyme-linked immunosorbent assay were 98.2% (1700 of 1731) after one injection and 99.9% (717 of 718) after two injections. A significant (P < 0.001) boost in geometric mean titers was observed in children who received a second injection of vaccine 3 months after the first injection. Of the children who seroconverted at 6 weeks postregimen (one or two doses as assigned), 99.8% (528 of 529) of the one-dose group and 99.8% (473 of 474) of the two-dose group maintained antibody to varicella at 1 year with geometric mean titers of 19.5 and 31.2, respectively. CONCLUSIONS: Administration of a one- or two-dose regimen of the live Oka/Merck varicella vaccine (VARIVAX) is immunogenic and is generally well-tolerated in healthy children 1 to 12 years old. Antibody to varicella persists in > 99% of vaccinees 1 year after vaccination regardless of a one- or two-dose regimen. Long-term follow-up studies of this cohort of children may determine whether a two-dose regimen offers superior protection against chickenpox.

Analysis of immune responses to varicella zoster viral proteins induced by DNA vaccination.

In this study we sought to examine the mechanism by which immune responses were induced following intramuscular injection of mice with DNA expression vectors encoding genes of varicella zoster virus (VZV). Both VZV-specific antibody and T cell proliferative responses were induced by immunization with DNA sequences for the immediate early 62 (IE62) and glycoprotein E (gE). The viral proteins were shown to be expressed in non-regenerating, rather than regenerating muscle cells. After primary immunization, muscle cells did not express major histocompatibility complex (MHC) class II transcripts and little inflammatory response was detected at the site of inoculation. Histochemical staining and non-isotopic in situ hybridization demonstrated that a second injection of IE62 plasmid DNA was again associated with protein synthesis in non-regenerating muscle cells but that a marked inflammatory infiltrate was induced in muscle tissue. These cells, but not muscle cells, expressed MHC class II transcripts. Significantly, PCR analyses demonstrated that IE62 DNA localized specifically to local draining lymph nodes following primary DNA immunization by intramuscular inoculation. These experiments indicate that transport of plasmid DNA to sites of antigen presentation in regional lymphoid tissue may play an important role in the initial generation of immune responses and that enhancement by secondary inoculation is mediated by immune cells that traffic to the site of viral protein synthesis in muscle cells.

The synthesis and immunogenicity of varicella-zoster virus glycoprotein E and immediate-early protein (IE62) expressed in recombinant herpes simplex virus-1.

In order to evaluate the conditions for optimal expression and immunogenicity of varicella-zoster virus (VZV) proteins in a herpes simplex virus-1 (HSV-1) vector, we selected the VZV glycoprotein E (gE), encoded by ORF 68 and the VZV product of ORF 62, an immediate-early major tegument protein (IE62). Three HSV/VZV recombinants were generated: (1) VZV gE protein coding sequences along with the promoter region were inserted into the thymidine kinase (TK) gene of HSV-1 strain KOS; (2) VZV gE expressed from the HSV-1 ICP4 promoter was inserted into the glycoprotein C (gC) gene of HSV-1 strain F; and (3) VZV IE62 protein coding sequences under the control of the HSV-1 ICP4 promoter were inserted into the gC gene of HSV-1 strain F. Immunoblot analysis and immunoperoxidase staining of infected cell monolayers demonstrated vector expression of VZV proteins. Following intracranial inoculation in mice, both VZV gE-HSV (TK) and VZV IE62-HSV (gC) induced an IgG response against VZV gE or VZV IE62. When tested in cytotoxicity assays using T-lymphocytes from VZV immune human donors, the range of precursor frequencies for T-lymphocytes that recognized VZV gE or VZV IE62 was similar whether these proteins were expressed by HSV-1 or a vaccinia vector. These experiments demonstrate that HSV-1 is a competent vector for expression of these VZV proteins and support the feasibility of engineering a combined vaccine for these closely related alpha-herpesviruses.

Immune responses to varicella-zoster virus.

The host response to VZV is critical to the outcome of primary VZV infection. The maintenance of immune memory to the virus is required to prevent symptomatic re-infection on exogenous re-exposure to VZV and to prevent symptomatic reactivation of endogenous virus. Immunization with live varicella (Oka) vaccine elicits primary and memory immunity to VZV. Humoral and cell-mediated host responses induced by the wild-type virus and by the vaccine strain are comparable, which is consistent with the clinical observation that varicella vaccine protects against or significantly reduces the clinical symptoms caused by primary VZV infection. Widespread use of the varicella vaccine in healthy children will yield further knowledge about host-virus interactions, such as the role of exogenous re-exposure in maintaining persistent immunity, which will be relevant to vaccine strategies to prevent other human herpesvirus infections.

Fusarium brain abscess. Case report.

The common soil fungus, Fusarium, is rarely pathogenic in man but occasionally causes serious disease, particularly in immunocompromised hosts. A case is reported of Fusarium brain abscess and meningitis occurring in a patient with chronic infectious mononucleosis syndrome and immunodeficiency. The patient died despite aspiration of the abscess and treatment with amphotericin B. This case demonstrates the importance of identifying the offending pathological organism through abscess aspiration in immunocompromised patients.

Intravenous ribavirin therapy for adenovirus pneumonia.

We report on the effectiveness of intravenous ribavirin for severe adenoviral pneumonia in a 10-month-old male following orthotopic liver transplantation. On day 20 post-transplantation, he developed high fever, marked respiratory compromise, and hypoxemia. The chest radiograph showed bilateral pulmonary infiltrates. Samples of bronchoalveolar lavage fluid grew adenovirus, serotype 1. Marked clinical and radiological improvement was noted after intravenous ribavirin therapy. A prospective clinical trial is needed to determine the efficacy of ribavirin therapy for severe adenovirus disease.

Management of varicella-zoster virus infections in children.

The introduction of varicella vaccine for immunization of healthy children is expected to have a gradual impact on the incidence of VZV infections in the population but antiviral therapy remains an important intervention in clinical practice. The efficacy of aciclovir for treatment of primary and recurrent VZV infections in children has reduced the morbidity and mortality of these illnesses in immunocompromised children dramatically. Oral aciclovir is an effective and useful for the management of varicella in healthy children and adolescents.