Immunity to varicella zoster virus among young adults: a decline prior to widespread uptake of varicella vaccines.

BACKGROUND: The epidemiology of chickenpox in Israel is changing, mainly due to the increasing - but not universal - uptake of varicella vaccine. PATIENTS AND METHODS: We conducted a seroprevalence study of varicella zoster virus (VZV) antibodies among 536 Israeli military recruits 18 years of age, on the basis of a representative sample of sera collected in 2003. RESULTS: The overall seroprevalence rate was 94.6%, which was significantly lower than that observed in a similar population in 1992 (98.4%, p < 0.001). The rate was lower among subjects whose fathers had less than 12 years of schooling (89.8%, p = 0.033). No statistically significant differences were observed when data were stratified by sex, subject's level of education, or origin. CONCLUSION: This decline in the level of immunity must be considered when determining pre- and post-exposure vaccination policy among young adults in crowded environments.

The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region.

The European sero-epidemiology network (ESEN2) aims to standardise serological surveillance of varicella zoster virus (VZV) in 11 participant countries. In each country, serum banks were collected between 1996 and 2003 and tested for VZV antibodies. Assay results were standardised so that international comparisons could be made. Age-specific forces of infection were calculated for three age groups (<5, 5-9 and >or=10 years of age) and used to estimate the base reproduction number (R(0)) and the herd immunity threshold (H). Most VZV infection occurred in childhood, but there was a wide variation in transmissibility, with R(0) ranging from 16.9 in the Netherlands to 3.3 in Italy. Herd immunity thresholds varied from 70% in Italy to 94% in the Netherlands. There are substantial differences in VZV sero-epidemiology within the European region, which will need to be taken into account in designing national policies regarding VZV vaccination.

Seroepidemiology of Varicella zoster in Israel prior to large-scale use of varicella vaccines.

OBJECTIVES: This large-scale study provides up-to-date estimates of Varicella zoster virus (VZV) age-specific seroprevalence and characteristics of VZV transmission in a representative sample of the Israeli population. METHODS: In 2000-2001, 1,642 sera collected from an agestratified general population sample were tested for VZV antibodies using an indirect IgG ELISA system. RESULTS: The age-weighted VZV overall estimate was 90.2%. Seropositivity increased rapidly with age, from 68.9% at age 4 to 94.4% at age 7 and 96.6% at age 12 years. The highest force of infection was in the 4-5 years age group (0.548 per susceptible year) followed by the 6-9 years age group. Multivariate analysis revealed that VZV seroprevalence estimates were significantly associated with age and place of origin. The highest seroprevalence estimate was found among subjects of Eastern origin. CONCLUSIONS: The seroepidemiology of VZV in Israel shows a pattern corresponding to that described for developed European countries. This study indicates that the highest force of infection is in pre-school children. Knowledge of pre-vaccination seroepidemiology is important to evaluate the effect of vaccination programs on the epidemiology of the disease.

Reported exposure to chickenpox: a predictor of positive anti-varicella-zoster antibodies in parturient women.

OBJECTIVE: To determine the positive and negative predictive values of recalled exposure to chickenpox for identifying anti-varicella-zoster virus (VZV) seropositive parturient women. METHODS: Blood samples were taken from laboring women during February 1998: All women completed questionnaires concerning a history of chickenpox in themselves and their children. Anti-VZV antibodies were determined by the immunofluorescent antibodies to membrane antigen (IFAMA) technique. RESULTS: Three hundred and twenty-seven women formed the study population; 239 women (73.1%) recalled chickenpox in themselves or their children, of which 229 (95.8%) were seropositive for anti-VZV antibodies. Of the 88 women who gave a negative/uncertain history of chickenpox 82 (93.2%) were seropositive and 6 (6.8%) were seronegative. All 87 mothers who were certain their children had had chickenpox were seropositive, including all 16 mothers who had a negative personal history. Thus, a woman with a history of chickenpox had a positive predictive value of 95.8%, and a woman with a lack of history had a negative predictive value of 6.8% (sensitivity 73.6%, specificity 37.5%), while a positive history of chickenpox in a child had a positive predictive value of 100%. CONCLUSIONS: Most women with no known history of VZV infection have evidence of prior exposure by serologic testing. Moreover, 100% of women with a negative history who were exposed to VZV in their children were protected from the disease. Therefore, mothers exposed to VZV during pregnancy can be reassured that most likely they are protected. However, the practice of testing all pregnant women exposed to the disease should be continued.

Placental transfer and decay of varicella-zoster virus antibodies in preterm infants.

OBJECTIVES: To compare the placental transfer of maternal varicella-zoster (VZV) antibodies to preterm and term infants and to investigate antibody decay during the first 6 months of life in the preterm infants. STUDY DESIGN: Maternal and umbilical cord blood samples were taken from 113 healthy mother-newborn pairs: 64 term (gestational age > or =37 weeks) and 49 preterm (gestational age < or =35 weeks). Premature infants were further tested at 1, 2, and 6 months. Anti-VZV antibody to membrane antigen was measured with the immunofluorescent technique. RESULTS: Preterm infants of gestational age < or =28 weeks had positive cord antibody and a geometric mean titer significantly lower than those in preterm infants of gestational age 29 to 35 weeks and term infants (25% vs 95% and 95%, respectively, P <.001 for each, and 2.5 +/- 2.2 vs 10.5 +/- 2.4 and 12.6 +/- 2.4, respectively, P <.001 for each). There was no difference between the preterm 29 to 35 weeks of gestation and term groups. Fetal-maternal ratios for both preterm groups were <1 and were significantly less than the fetal-maternal ratio in the term infants. The transfer of maternal antibodies to term infants was significantly greater than to the 29- to 35-week preterm infants (P =.01). At 2 months of age, 25% of 29- to 35-week preterm infants and no preterm infant < or =28 weeks had a positive titer. At 6 months of age, all preterm infants were seronegative, and the geometric mean titer in both groups declined to undetectable levels. CONCLUSION: Transplacental transfer of maternal VZV antibodies is diminished in preterm infants. VZV antibody levels are significantly lower in preterm infants born at < or =28 weeks' gestational age compared with those in preterm infants 29 to 35 weeks' gestational age and term infants. Anti-VZV titers decrease to undetectable levels in preterm infants by 6 months of age or earlier; thus these infants appear to be susceptible to chickenpox before the scheduled 12-month vaccination.

The natural history of primary herpes simplex type 1 gingivostomatitis in children.

Herpetic gingivostomatitis is the most common specific clinical manifestation of primary herpes simplex infection in childhood. The aim of the present study was to describe the clinical signs, symptoms, viral shedding, serologic findings, and complications in community-acquired gingivostomatitis. We prospectively followed children with herpes simplex type 1 gingivostomatitis lasting less than 72 hours. Clinical examination and viral culture were repeated every 2 to 3 days as long as symptoms or signs persisted. Thirty-six children (ages 12-77 months) were included in the study. Mean duration of oral lesions was 12.0+/-3.4 days; extraoral lesions (in 26 children), 12.0 +/-3.9 days; fever, 4.4+/-2.4 days; and eating/drinking difficulties, 9.1+/-3.0 and 7.1+/-3.1 days, respectively. In all children, viral cultures of the oral lesions were positive for herpes simplex virus (HSV) type 1; viral shedding persisted for a mean of 7.1+/-2.5 days (range 2-12 days). The main complications were dehydration, with three children hospitalized for intravenous rehydration, and one case of secondary bacteremia. Herpetic gingivostomatitis is a relatively severe manifestation of primary HSV type 1 infection in young children.

Herpes simplex virus proteins are damaged following photodynamic inactivation with phthalocyanines.

The photodynamic inactivation of herpes simplex virus type 1 (HSV-1) by two phthalocyanines (Pcs), the cationic dye HOSi-PcOSi(CH3)2(CH2)3N+(CH3)3I-(Pc5) and the amphiphilic dye aluminum dibenzodisulfophthalocyanine hydroxide (AlN2SB2POH), has been compared with that by the anionic dye, Merocyanine 540 (Mc540). Both Pc derivatives demonstrate a remarkable virucidal activity upon light activation even 3 h after the onset of HSV-1 adsorption, while Mc540 is effective for only 30 min after adsorption. Since fusion and virus penetration are promoted by membrane glycoproteins, we have studied the damage to viral proteins following photodynamic treatment (PDT) of HSV-1 and its relation to inactivation. The effect of AlN2SB2POH PDT is assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Major changes are found in the protein profile of PDT-treated HSV-1. A reduced ability of specific antibodies to react with HSV-1 major envelope proteins is detected by employing the Western blot assay. In particular, we demonstrate the related changes of glycoprotein D (gD), a structural protein of the HSV envelope. Since the envelope proteins participate in viral entry into the host cell, these alterations to viral envelope proteins may impair their ability to participate in early events of viral entry, leading to reduced infectivity of HSV-1. In contrast, no significant changes in the proteins' electrophoretic mobility could be seen after PDT with Mc540 or with Pc5. When HSV-1 purified proteins are subjected to combined electrophoretic and electro osmotic forces on cellulose acetate, there is a shift in their cathode mobility, which may indicate changes in the protein mass and protein net charges following AlN2SB2POH photosensitization. There are only minor changes in the virus proteins, assayed as above, when HSV-1 is treated with Pc5.

Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study.

OBJECTIVES: To examine the efficacy of aciclovir suspension for treating herpetic gingivostomatitis in young children. DESIGN: Randomised double blind placebo controlled study. SETTING: Day care unit of a tertiary paediatric hospital. SUBJECTS: 72 children aged 1-6 years with clinical manifestations of gingivostomatitis lasting less than 72 hours; 61 children with cultures positive for herpes simplex virus finished the study. MAIN OUTCOME MEASURES: Duration of oral lesions, fever, eating and drinking difficulties, and viral shedding. INTERVENTION: Aciclovir suspension 15 mg/kg five times a day for seven days, or placebo. RESULTS: Children receiving aciclovir had oral lesions for a shorter period than children receiving placebo (median 4 v 10 days (difference 6 days, 95% confidence interval 4.0 to 8.0)) and earlier disappearance of the following signs and symptoms: fever (1 v 3 days (2 days, 0.8 to 3.2)); extraoral lesions (lesions around the mouth but outside the oral cavity) (0 v 5.5 days (5.5 days, 1.3 to 4.7)); eating difficulties (4 v 7 days (3 days, 1.31 to 4.69)); and drinking difficulties (3 v 6 days (3 days, 1.1 to 4.9)). Viral shedding was significantly shorter in the group treated with aciclovir (1 v 5 days (4 days, 2.9 to 5.1)). CONCLUSIONS: Oral aciclovir treatment for herpetic gingivostomatitis, started within the first three days of onset, shortens the duration of all clinical manifestations and the infectivity of affected children. Further studies are needed to evaluate the ideal dose and length of treatment.

Treatment of viral infections with 5-aminolevulinic acid and light.

BACKGROUND AND OBJECTIVE: When 5-aminolevulinic acid (ALA) is exogenously supplied, protoporphyrin IX (PpIX) is accumulated in various cells and makes them light sensitive. The possibility of using such an approach for the treatment of viral infections was studied in this work. STUDY DESIGN/MATERIALS AND METHODS: ALA was added to cultured cells infected with human immunodeficiency virus (HIV). Accumulation of PpIX in the cells as well as virus infectivity after photodynamic treatment (PDT) were assessed. For in vivo studies, guinea pigs were infected with herpes simplex virus (HSV) and then administered ALA at intervals after infection. The animals were exposed to PDT at the site of infection 3 hours after ALA administration. Clinical observations and virus titration were made daily. For clinical studies, two patients with Molluscum contagiosum and Verrucae vulgares were treated with ALA fortified with an iron chelating agent and dimethylsulfoxide, followed 4 hours later by PDT. RESULTS: Cells that are infected with HIV accumulated PpIX upon addition of ALA in vitro. This accumulation was enhanced approximately two-fold in the presence of an iron chelator. Subsequent exposure to red light PDT drastically reduced the virus titer (> 99% for U1 cells latently infected with HIV). In guinea pigs infected with HSV, subsequent administration of ALA and exposure of the lesions to red light shortened the duration of vesicles' appearance from more than a week to a few days and reduced HSV titer in the lesions by > or = 5 log10. ALA-PDT treated AIDS patient suffering from Molluscum contagiosum or a kidney transplant patient with Verrucae vulgares showed greatly improved clinical symptoms one month after treatment. CONCLUSION: It is concluded that ALA-PDT could be effective in treating certain viral infections, particularly those resulting in warts.

Detection of adeno-associated virus type 2 sequences in the human genital tract.

Adeno-associated virus (AAV) is a defective parvovirus with unknown pathogenicity. It requires helper functions for its normal replication in human tissue and therefore is not readily isolated from clinical specimens. We have used the PCR method to examine the following clinical samples for the presence of AAV sequences: (i) 15 nasopharyngeal aspirates from symptomatic patients, (ii) 7 swab or fluid specimens from vesicles of patients suspected of having varicella-zoster virus infections, (iii) 21 human papilloma virus-positive genital biopsy specimens, (iv) 61 genital swab specimens from women suspected of having herpes simplex virus (HSV) infection examined either directly or following propagation in tissue culture, (v) 62 samples of first-trimester aborted material, including 38 samples from spontaneous abortions and 24 samples from induced abortions, (vi) 11 samples of chorionic villi taken from women undergoing genetic prenatal diagnosis, and (vii) three lots of cultured human embryonic cells. AAV sequences were detected only in samples taken from the genital tracts of women suspected of having HSV infection and not in any of the other types of samples. Samples from 11 patients were positive for AAV: for 4 patients the original swab sample was positive, for 4 patients the cultured swab sample was positive, and for 3 patients both the original swab samples and the cultures were positive. Five of the 11 patients were infected with HSV. Our study demonstrates the presence of AAV in the female genital tract. However, in contrast to a previous report (E. Tobiasch, M. Rabreau, K. Geletneky, S. Larue-Charlus, F. Severin, N. Becker, and J. R. Schlehofer, J. Med. Virol. 44:215-222, 1994), we did not find solid evidence of its replication in maternal or embryonal tissues from the first trimester of pregnancy. The questions of a potential pathogenic etiology of AAV and the interaction with HSV remain open.

Presence of human papilloma virus in transitional cell carcinoma in Jewish population in Israel.

The possible causal association of human papilloma virus (HPV) with transitional cell carcinoma (TCC) of the urinary bladder in Israeli Jewish patients was assessed. One hundred and ten histopathological TCC sections were examined by peroxidase anti-peroxidase (PAP) method. HPV capsid antigen was demonstrated in 19 out of 110 cases (17.3%). HPV-DNA sequences, determined by in situ DNA-DNA hybridization at high stringency wash were present in 24 cases (21.8%): 16(14.5%) cases proved to be HPV6/11 and 8 (7.3%) were HPV 16/18 positive. Four (3.6%) of the HPV 6/11 positive specimens cross hybridized with HPV 31/33/35 at low stringency conditions. Sixteen samples known to be positive by in situ hybridization were reconfirmed by polymerase chain reaction (PCR). When the PCR was performed on the 43 negative cases, an additional 4(9.3%) HPV positive cases were revealed: two proved to be HPV 6/11 and two HPV 16/18. Comparison of the different methods for HPV detection in 59 TCC histopathological samples, showed good correlation; an overall positivity of 33.9% by PCR, 27.1% by in situ hybridization and 25.4% by PAP was observed. Forty one samples from nontumoral material of the bladder or post mortem specimens served as controls and 4.8% HPV DNA was present in only two cases: one HPV 6/11 and one 16/18. Hence, HPV in TCC of the bladder is detected at a relatively high frequency and might be involved in the pathogenesis of this tumor among Jewish population in Israel.

Effect of topical interferon-beta on recurrence rates in genital herpes: a double-blind, placebo-controlled, randomized study.

The aim of this randomized, double-blind placebo-controlled trial was to evaluate the effect of IFN-beta cream applied at the time of recurrent eruptions of genital herpes during 6 months on the overall rate of recurrence. Therapy was initiated at the clinic for the first treated recurrence, and thereafter by the patient for early treatment of eventual subsequent eruptions. Each recurrence was ascertained at the clinic in all 35 evaluable patients. The mean recurrence rate was significantly lower in the group using IFN-beta cream than in the placebo group (p = 0.03). Complete responders without recurrence for the duration of the trial were 36.4% of all patients and 46% among women versus 15.4 and 16.6% in the placebo groups, respectively. A total of 77.3% of all patients were defined as complete or partial responders, their average recurrences/year decreasing from 11 to 2.2 (p < 0.0001). The topical episodic IFN-beta treatment was well tolerated by patients and without side effects. It is concluded that IFN-beta cream application reduces the overall rate of recurrence of genital herpes.

A seroprevalence study of herpes virus type 2 infection in Israeli women: implications for routine screening.

The aim of the study was to obtain data on the prevalence of herpes simplex virus type 2 (HSV-2) in selected populations of women and to identify groups that might benefit from routine prenatal screening. The prospective seroprevalence study was performed in 1,921 women in Israel during the period 1986-90. Four different population groups of women 17-60 years old were included. Groups 1 and 2 comprised 1,214 healthy female government employees and kibbutz and moshav residents, and Groups 3 and 4 comprised 707 Jewish and non-Jewish women with gynecological complaints. HSV-2 antibody in the sera were studied by the microneutralization method. In the healthy women (groups 1 and 2), the prevalence of antibodies to HSV-2 was 2-3%. Genital HSV-2 asymptomatic shedding was 1%. In the women with gynecological complaints (groups 3 and 4) the prevalence of antibodies to HSV-2 was 10% in Jewish and 16% in non-Jewish women. These data support the conclusion that there is no justification for routine prenatal HSV-2 screening in Israel in a healthy female population.

Selected epidemiological features of herpes genitalis in Israel based on laboratory data.

The incidence in Israel of genital infection with herpes simplex virus (HSV) has been increasing steadily over the last two decades. During the years 1973-91, 1,508 patients had an HSV infection confirmed by viral culturing. The yearly incidence of new cases rose from sporadic cases in the seventies to 32.4 cases per 1,000 patients in 1990. The age distribution pattern did not change since 1980 and showed a peak incidence in subjects aged 20-40 years. The increase of HSV type 2 (HSV-2) infection rate in the Israeli population, as judged from specific geometric mean titers (GMT), rose from 15.25 in 1970 to 89.3 in 1991, while the GMT for HSV type 1 (HSV-1) did not increase significantly. The incidence of HSV-2 positive subjects (HSV-2/HSV-1 antibody ratio > or = 1) was low in the Jewish Israeli population, compared to other demographic areas. The predominant type of genital infection was HSV-2, although 21% of genital isolates were HSV-1.

Photodynamic inactivation of herpes viruses with phthalocyanine derivatives.

The antiviral photosensitization capacity of 11 different phthalocyanine (Pc) derivatives was examined using herpes simplex virus-1, herpes simplex virus-2 and varicella zoster virus in the search for the most potent sensitizers for viral decontamination of blood. The kinetics of viral photoinactivation were resolved during the stages of viral adsorption and penetration into the host cells. The capacity of Pc in the photodynamic inactivation of viruses was compared with that of merocyanine 540 (MC540), another widely studied photosensitizer. Sensitivity to photoinactivation decreased progressively with time after addition of viruses to their host cells. The viruses were most sensitive to photodynamic inactivation up to 30 min from the initiation of adsorption. Cell-associated viruses, 45-60 min after the onset of adsorption, are highly resistant to photodynamic treatment by most photosensitizers, with the exception of amphiphilic Pc derivatives. Thus the mixed sulfonated Pc-naphthalocyanine derivatives AlNSB3P and AlN2SB2P demonstrated a remarkable decontamination activity even 60 min after the onset of adsorption. Ultrastructural examination of these photosensitized viruses demonstrated damage to the viral envelope which prevented viral adsorption and/or penetration. The non-enveloped adenovirus was found to be resistant to all the dyes tested.

Varicella-zoster virus immune status in CAPD and chronic hemodialysis patients.

Patients on chronic dialysis who are supposed to disclose an impairment of the immune potential, seldom show clinical viral illnesses. Since severe varicella-zoster virus (VZV) infection develops in immunocompromised patients, we have examined the proliferative activity to VZV in the blood lymphocytes of 16 patients on continuous ambulatory peritoneal dialysis (CAPD) and compared it to healthy matched controls. The cellular in vitro response of these patients to specific VZV antigens was essentially normal. The mean stimulation index for CAPD patients was 7.06, and for matched controls 3.68 (p greater than 0.05). The mean percentage of lymphocytes in CAPD patients as determined by CD3 monoclonal antibodies was 57%, the CD4 helper and CD8 suppressor cells were 41 and 21%, respectively. When those 16 CAPD patients were followed up for the presence of anti-VZV IgA, IgM and IgG immunofluorescent antibody to membrane antigen antibodies during a period of 6 months, the recrudescence of VZV was documented by the appearance of IgA and IgM antibodies and/or fourfold increase in IgG titer in some patients, but no clinical illness was observed. The frequent reactivation of the virus without clinical symptoms in patients undergoing long-term intermittent chronic hemodialysis (HD) or CAPD was strengthened by the presence of increased anti-VZV geometric mean titers (52.68 and 53.00, respectively) in these patients as compared to control subjects (11.75).

[Detection of antigen and antibody in herpes simplex encephalitis].

Laboratory confirmation of herpes simplex (HSV) infection in patients suspected of HSV encephalitis (HSV-E) at the earliest stage of the disease, may contribute greatly to the differential diagnosis and to the initiation of effective antiviral treatment. Our diagnosis of HSV infection was based on: a) detection of viral antigen in CSF cells in the first week of disease by immunofluorescence assay employing monoclonal antibodies against HSV-1 or HSV-2; b) detection of local IgM- and IgG-specific antibodies to HSV in the CSF and in the serum; c) ratio of titers of HSV antibodies in CSF and in serum less than 1:20; d) 4-fold rise in antibody titer to HSV in CSF and/or serum. The incidence of HSV-E was examined through 1987 in 270 patients suspected of viral infection of the central nervous system. In 187 (69.5%) material for laboratory diagnosis was inadequate and in 75 (27.8%) no evidence for infection by HSV was found. HSV infection was confirmed in 8 (2.9%), comprising 9.6% of those with adequate material for laboratory diagnosis. In no case was HSV isolated from the CSF. The importance of adequate material for viral diagnosis by the laboratory is emphasized.