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Universal varicella vaccination might reduce opportunities for varicella-zoster virus (VZV) exposure and protective immunological boosting, thus increasing herpes zoster incidence in latently infected adults. We assessed humoral and cell-mediated immunity (CMI), as markers of VZV exposure, in adults aged ≥50 years.We repurposed data from placebo recipients in a large multinational clinical trial (ZOE-50). Countries were clustered based on their varicella vaccination program characteristics, as having high, moderate, or low VZV circulation. Anti-VZV antibody geometric mean concentrations, median frequencies of VZV-specific CD4 T cells, and percentages of individuals with increases in VZV-specific CD4 T-cell frequencies were compared across countries and clusters. Sensitivity analyses using a variable number of time points and different thresholds were performed for CMI data.VZV-specific humoral immunity from 17 countries (12 high, 2 moderate, 3 low circulation) varied significantly between countries (P .0001) but not by VZV circulation. No significant differences were identified in VZV-specific CMI between participants from 2 high versus 1 low circulation country. In 3/5 sensitivity analyses, increases in CMI were more frequent in high VZV circulation countries (.03 ≤ P .05).We found no consistent evidence of reduced VZV exposure among older adults in countries with universal varicella vaccination.NCT01165177.

Background Infants exposed to varicella zoster virus (VZV) in utero ≤5 days before or ≤48 hours after delivery and preterm infants are at high risk for varicella complications. An expanded-access program assessed varicella outcomes after administration of varicella zoster immune globulin (human) (VARIZIG) in a real-world setting. Methods In this open-label, expanded-access program, high-risk infants received ≤125 IU/10 kg of VARIZIG (NCT00338442). VZV outcomes and safety were assessed. Results There were 43 newborns exposed to VZV in utero and 80 preterm infants exposed to VZV; >80% received VARIZIG within 96 hours of reported exposure. When varicella outcomes were available, varicella occurred in 7 of 38 (18%) in utero–exposed newborns and zero of 65 preterm infants. Varicella-related complications were reported in 3 in utero–exposed newborns (3 with >100 lesions, 1 each with encephalitis and pneumonia). Adverse events were reported for 16% of in utero–exposed newborns and 25% of preterm infants, but few were considered related to VARIZIG. There were no deaths attributable to varicella or VARIZIG. Conclusions Varicella incidence and morbidity were low in in utero–exposed infants and zero in preterm infants who received prophylactic VARIZIG. There were few VARIZIG-related safety concerns., Infants born prematurely or to women who develop varicella zoster virus ≤5 days before or ≤48 hours after delivery and who were treated with varicella zoster immune globulin (VARIZIG) had a low incidence of varicella and varicella-related morbidity, regardless of administration

Background Routine vaccination with varicella-zoster (VZV) vaccine has resulted in significant declines in the incidence of VZV cases, hospitalizations, and deaths across pediatric age. This vaccine is safe and effective and adverse events are monitored closely. Methods We describe a case of vOka meningoencephalitis in a twelve-year-old vaccinated boy who presented with altered mental status and a vesicular facial rash. Results A twelve-year-old healthy, fully-vaccinated boy presented to urgent care clnic with left-sided frontotemporal headache, left-sided eye pain, and photosensitivity. Over several days, a left-sided facial rash progressed to include papular and vesicular lesions over the cheek, as well as over the left side of the chin and at the midline of the lower lip. He was somnolent, sleeping 18- 20 hours a day. The child was evaluated by a pediatric neurologist who noted a left-sided ptosis and left lateral rectus palsy; he was admitted for further workup. Cerebrospinal fluid (CSF) analysis showed WBC of 33 cells/ml3 with 92% lymphocytes; glucose of 44mg/dL (serum glucose 84mg/dL), and protein of 50mg/dL (range: 15-45). Nasopharyngeal multiplex polymerase chain reaction (PCR) (BioFire Diagnostics, Salt Lake City, Utah) was positive for rhinovirus/enterovirus. Testing of facial vesicles for varicella-zoster virus (VZV) and herpes simplex virus (HSV) was negative by DFA and culture, and enteroviral throat and rectal PCRs were negative. However, CSF PCR for VZV was found to be positive. In light of this finding, the viral isolate was sent to Dr. Anne Gershon’s research lab at Columbia University Medical Center for typing and was determined to be vOka. Quantitative and functional immune studies were performed, and were normal. The patient initially received 7 days of intravenous acyclovir, during which time his rash resolved and mental status returned to baseline. He completed a total of 14 days of acyclovir and has had no recurrences. Conclusion This case represents only the tenth case of Oka-strain meningitis in an immunocompetent child reported to date, and one of very few cases in immunocompetent adolescents. While rare, vOka meningitis is an entity of which primary care pediatricians and infectious diseases specialists should be aware, even in older children. Disclosures All Authors: No reported disclosures

Background. Varicella zoster virus (VZV) establishes latency in dorsal root, cranial nerve, and enteric ganglia and can reactivate to cause zoster. Serious gastrointestinal dysfunction can result from VZV reactivation in enteric neurons (enteric zoster), but an absence of rash makes diagnosis difficult. We thus determined whether detecting VZV DNA in saliva facilitates identification of enteric zoster. Methods. Nested and real-time polymerase chain reaction were used to validate salivary VZV DNA as a surrogate marker of VZV reactivation and then to determine the utility of that marker for the identification of those individuals within a population defined by abdominal pain that might have enteric zoster. Results. Salivary VZV DNA was detected in 0 of 20 healthy negative controls, 11 of 16 positive controls with zoster or varicella (P < .0001), 2 of 2 patients with zoster sine herpete (P < .01), 6 of 11 patients with unexplained abdominal pain (P < .001), and 0 of 8 patients with unrelated gastrointestinal disorders. Salivary VZV DNA disappeared after recovery in 9 of 9 tested subjects with zoster, 2 of 2 with zoster sine herpete, and 5 of 5 with abdominal pain. One patient with abdominal pain and salivary VZV DNA had perforated gastric ulcers, necessitating a wedge gastrectomy. VZV DNA (vaccine type) was found in the resected stomach; immediate early (ORF63p) and late (gE) VZV proteins were immunocytochemically detected in gastric epithelium. After recovery, VZV DNA and proteins were not detected in gastric biopsies or saliva. Conclusions. Detection of salivary VZV DNA in patients with abdominal pain helps to identify putative enteric zoster for investigation and treatment.

Live attenuated varicella vaccine is recommended for healthy individuals who are susceptible to varicella. Although the vaccine is safe, effective, and used worldwide, serious adverse events have been reported, mainly in immunocompromised patients who subsequently recovered. Here, we describe the fatality of an immunocompromised patient who received the varicella vaccine. His medical history provides a cautionary lens through which to view the decision of when vaccination is appropriate. A middle-aged man with non-Hodgkin lymphoma received chemotherapy and a stem cell transplant. He was vaccinated 4 years post-transplantation, despite diagnosis of a new low-grade lymphoma confined to the lymph nodes. Within 3 months of vaccination, he developed recurrent rashes with fever, malaise, weakness, hepatitis, weight loss, and renal failure. The syndrome was eventually determined to be associated with persistent disseminated zoster caused by the vaccine virus. This case illustrates a circumstance when a live viral vaccine should not be used.

Immunization with the vOka vaccine prevents varicella (chickenpox) in children and susceptible adults. The vOka vaccine strain comprises a mixture of genotypes and, despite attenuation, causes rashes in small numbers of recipients. Like wild-type virus, the vaccine establishes latency in neuronal tissue and can later reactivate to cause Herpes zoster (shingles). Using hybridization-based methodologies, we have purified and sequenced vOka directly from skin lesions. We show that alleles present in the vaccine can be recovered from the lesions and demonstrate the presence of a severe bottleneck between inoculation and lesion formation. Genotypes in any one lesion appear to be descended from one to three vaccine-genotypes with a low frequency of novel mutations. No single vOka haplotype and no novel mutations are consistently present in rashes, indicating that neither new mutations nor recombination with wild type are critical to the evolution of vOka rashes. Instead, alleles arising from attenuation (i.e., not derived from free-living virus) are present at lower frequencies in rash genotypes. We identify 11 loci at which the ancestral allele is selected for in vOka rash formation and show genotypes in rashes that have reactivated from latency cannot be distinguished from rashes occurring immediately after inoculation. We conclude that the vOka vaccine, although heterogeneous, has not evolved to form rashes through positive selection in the mode of a quasispecies, but rather alleles that were essentially neutral during the vaccine production have been selected against in the human subjects, allowing us to identify key loci for rash formation.

Background. Because of ongoing outbreaks of varicella, a second dose of varicella vaccine was added to the routine immunization schedule for children in June 2006 by the Centers for Disease Control and Prevention. Methods. We assessed the effectiveness of 2 doses of varicella vaccine in a case-control study by identifying children ≥4 years of age with varicella confirmed by polymerase chain reaction assay and up to 2 controls matched by age and pediatric practice. Effectiveness was calculated using exact conditional logistic regression. Results. From July 2006 to January 2010, of the 71 case subjects and 140 matched controls enrolled, no cases (0%) vs 22 controls (15.7%) had received 2 doses of varicella vaccine, 66 cases (93.0%) vs 117 controls (83.6%) had received 1 dose, and 5 cases (7.0%) vs 1 control (0.7%) did not receive varicella vaccine (P

Although varicella vaccine is given to clinically stable human immunodeficiency virus (HIV)-infected children, its effectiveness is unknown. We assessed its effectiveness by reviewing the medical records of closely monitored HIV-infected children, including those receiving highly active antiretroviral therapy (HAART) between 1989 and 2007. Varicella immunization and development of varicella or herpes zoster were noted. Effectiveness was calculated by subtracting from 1 the rate ratios for the incidence rates of varicella or herpes zoster in vaccinated versus unvaccinated children. The effectiveness of the vaccine was 82% (95% confidence interval [CI], 24%-99%; P = .01) against varicella and was 100% (95% CI, 67%-100%; P.001) against herpes zoster. When the analysis was controlled for receipt of HAART, vaccination remained highly protective against herpes zoster.

Varicella-zoster virus (VZV)–specific cell-mediated immunity responses are essential for recovery from primary (varicella) or reactivation (herpes zoster) infection with VZV [1-4]. Patients who lack adequate VZV-specific cell-mediated immunity often have severe and prolonged infections with VZV, some of which are fatal [3-5]. Thus, VZV-specific cell-mediated immunity is a marker for protection against primary VZV infection, and the presence and magnitude of this response correlates with recovery from varicella and with the incidence and severity of reactivation as manifested by herpes zoster. VZV-specific cell-mediated immunity is also a component of primary responses to varicella vaccine administered to susceptible children and adults and has been used to evaluate candidate vaccines to prevent herpes zoster in immunocompromised and elderly individuals [6-9]. In this report, we present a regression model of VZV-specific memory CD4 responses as a function of age, from early childhood to advanced adulthood among healthy individuals with prior VZV wild-type infectionas a reference against which responses of other select groups of individuals are compared. Comparisons are made to elderly recipients of a zoster vaccine and to human immunodeficiency virus (HIV)–infected children and adults. We demonstrate that VZV-specific cell-mediated immunity is determined by the nature of primary immunization (natural infection vs VZV vaccination) and the age and immune status of the subject tested.

Because human primary afferent neurons are not readily obtained, we sought to develop a model in which the lytic, latent, and reactivating phases of varicella-zoster virus (VZV) infection were recapitulated in neurons from an animal source. Enteric neurons were obtained from the small intestine of adult guinea pigs and from the bowel of fetal mice. Latency was established when these neurons were infected by cell-free VZV in the absence of fibroblasts or other cells of mesodermal origin. In contrast, lytic infection ensued when fibroblasts were present or when the enteric neurons were infected by cell-associated VZV. Latency was associated with the expression of a limited subset of viral genes, the products of which were restricted to the cytoplasm. Lysis was associated with the expression of viral glycoproteins, nuclear translocation of latency-associated gene products, and rapid cell death. Reactivation was accomplished by expressing VZV open reading frame (ORF) 61p or herpes simplex virus ICP0 in latently infected neurons. Isolated enteric neurons from guinea pigs and mice recapitulate latent gene expression in human cranial nerve and dorsal root ganglia. Expression of latency-associated VZV gene products was detected in 88% of samples of adult human intestine, suggesting that VZV not only infects enteric neurons but also is latent in the human enteric nervous system. This in vitro model should facilitate further understanding of latency and reactivation of VZV.

The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.

Varicella-zoster virus (VZV) causes chickenpox and shingles, and is found in human populations worldwide. The lack of temporal signal in the diversity of VZV makes substitution rate estimates unreliable, which is a barrier to understanding the context of its global spread. Here, we estimate rates of evolution by studying live attenuated vaccines, which evolved in 22 vaccinated patients for known periods of time, sometimes, but not always undergoing latency. We show that the attenuated virus evolves rapidly (∼ 10(-6) substitutions/site/day), but that rates decrease dramatically when the virus undergoes latency. These data are best explained by a model in which viral populations evolve for around 13 days before becoming latent, but then undergo no replication during latency. This implies that rates of viral evolution will depend strongly on transmission patterns. Nevertheless, we show that implausibly long latency periods are required to date the most recent common ancestor of extant VZV to an "out-of-Africa" migration with humans, as has been previously suggested.

BACKGROUND Varicella can be a severe illness in human immunodeficiency virus (HIV)-infected children. The licensed, live attenuated varicella vaccine is safe and immunogenic in HIV-infected children with minimal symptoms and good preservation of CD4(+) T cells (Centers for Disease Control and Prevention immunologic category 1). METHODS To study the safety and immunogenicity of this vaccine in varicella-zoster virus (VZV)-naive, HIV-infected children with moderate symptoms and/or more pronounced past or current decreases in CD4(+) T cell counts, such children (age, 1-8 years) received 2 doses of vaccine 3 months apart. The children were observed in a structured fashion for adverse events. Blood was tested for VZV antibody and VZV-specific cell-mediated immunity (CMI) at baseline, 8 weeks after each dose, and annually for 3 years. Subjects who had no evidence of immunity 1 year after vaccination received a third dose and were retested. RESULTS The vaccine was well tolerated; there were no vaccine-related, serious adverse events. Regardless of immunologic category, at least 79% of HIV-infected vaccine recipients developed VZV-specific antibody and/or CMI 2 months after 2 doses of vaccine, and 83% were responders 1 year after vaccination. CONCLUSIONS HIV-infected children with a CD4(+) T cell percentage of > or =15% and a CD4(+) T cell count of > or =200 cells/ microL are likely to benefit from receiving varicella vaccine.

It was long assumed, before recent developments proved otherwise, that the presence of an infection with varicella zoster virus (VZV) was inevitably associated with a rash. We now know, due to the use of polymerase chain reaction (PCR) and other methods that have improved diagnosis, that patients can harbor infections with VZV even in the absence of cutaneous manifestations Such “occult” VZV infections often affect the nervous and gastrointestinal systems. Central nervous system (CNS) VZV infections without rash were initially identified at autopsy [1] and subsequently in patients with meningitis through the PCR detection of VZV DNA in cerebrospinal fluid (CSF) [2]. Although there appears to be a relationship between VZV infection and arterial ischemic stroke (AIS) [3], these patients also do not display a rash when they develop symptoms involving the CNS. In the current issue of Clinical Infectious Diseases, Thomas et al describe the connection between varicella and subsequent AIS in children. They used 4 large databases and a self-controlled case series, analyzing data from strokes in the varicella cases. Data were analyzed 0–6 months after an episode of varicella and again at a later time. This method avoids confounding factors and is efficient at relating a rare condition, such as stroke in childhood, to a common infection, varicella, although it does not provide information on the absolute risk of postvaricella stroke. Thomas et al’s study revealed that in the 6 months following varicella, the incidence of childhood stroke is increased by a factor of approximately 4. There was no significant increase in strokes in adults after varicella, nor was there any increase in strokes 7– 12 months after varicella in children. The pathogenesis of postvaricella stroke is not known, but VZV can infect cerebral arteries, which provokes inflammatory responses that damage the infected arteries and may lead to aneurysms [4–6]. Because the interval between an episode of varicella and a stroke can be as long as 6 months, reactivation of latent VZV acquired during varicella, rather than a smoldering persistent infection in arteries, seems more likely to cause AIS, although either possibility remains plausible. The VZV that infects arteries could be delivered from sensory neurons in which VZV reactivates or as a result of a viremia. It may well be that most strokes following varicella are, in reality, strokes following zoster without rash. When one such stroke develops, there may be recurrences [7]. Strokes may also follow classic zoster, particularly when the ophthalmic branch of the trigeminal nerve is involved. It is conceivable that AIS after varicella in children is a manifestation of a rare defect in innate immunity described in certain severe alpha herpesvirus infections [8–12]. One mystery is why VZV would be at increased risk for reactivation soon after varicella. This timing may reflect the putative immunologic predisposition. Clearly, additional knowledge of the state of VZV prior to infection of cerebral arteries, as well as the immunologic status of the host who has experienced a VZV-induced stroke, is needed. A relationship between zoster and stroke was appreciated before postvaricella stroke was recognized. At first termed giant cell arteritis, it now appears that this vasculitis syndrome is similar to what is termed VZV vasculopathy [13]. VZV vasculopathy may be a subset of giant cell arteritis. It was recognized historically that in the months following zoster, patients (usually adults) might manifest symptoms of stroke ipsilateral to the side of the body where zoster occurred. Because strokes in children are unusual or rare, this increase in CNS disease from varicella, albeit serious to individuals, is not a major public health problem. The morbidity (which may be long-lasting) Received 16 September 2013; accepted 18 September 2013; electronically published 2 October 2013. Correspondence: Anne A. Gershon, MD, Department of Pediatrics, Columbia University College of Physicians and Surgeons, 622 W 168th St, PH 19-110, New York, NY 10032 (aag1@columbia.edu). Clinical Infectious Diseases 2014;58(1):69–71 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit663

Vaccination against chickenpox causes a varicella-like rash in up to 5% of healthy children and 50% of children with leukemia. The vaccine may establish latency and reactivate to cause herpes zoster, albeit more rarely than wild-type virus. All vaccine preparations are composed of a mixture of varicella-zoster virus strains that show genotypic variation at several loci. We have shown, by DNA sequencing of 40 polymorphic loci, that viruses sampled from vesicles in varicella-like and herpes zoster rashes are single clones. This finding suggests that, between the time of inoculation of the vaccine and development of rash, selection of single strains occurs. The results have general implications for the pathogenesis of varicella-zoster virus.

Latent varicella-zoster virus (VZV) was studied in ganglia of rats that had been inoculated subcutaneously with either a high-passaged wild-type, a low-passaged wild-type, or the vaccine strain of virus using in situ hybridization. Nine of 11 rats injected with virus and no control rats developed serum VZV antibodies as demonstrated by fluorescent antibody membrane antigen. Polymerase chain reaction 2 weeks following inoculation did not detect viremia in the rats. VZV was detected by in situ hybridization in ganglia of 10 of the 11 infected rats but not in ganglia of the control rats. The distribution of VZV DNA is identical to that seen in humans; satellite cells and neurons contain VZV DNA. Although all animals received unilateral injections of virus, VZV DNA was in ipsilateral and contralateral ganglia in 6 animals, suggesting that virus replication and viremia had occurred.

Congenital varicella syndrome is a rare complication of varicella-zoster virus (VZV) infection during pregnancy. An infant was exposed to VZV at 18.5 weeks of gestation and had eye and skin abnormalities at birth and persistent feeding difficulties, prompting esophageal biopsies at 12 days and 20 and 20.5 months of age. Esophageal tissues demonstrated specialized intestinal metaplasia (Barrett's esophagus). VZV DNA (in situ hybridization) and proteins (immunohistochemistry and polymerase chain reaction) were found in esophageal epithelial cells adjacent to the Barrett's lesion. Immediate-early 63 protein (IE63) of VZV was demonstrated in the day 12 specimen, and IE62 and the late VZV glycoprotein E (gE) were found in the 20-month specimen. Clinical and endoscopic improvement followed fundoplication and acyclovir therapy, but VZV DNA and IE62 persisted in esophageal tissue. These findings associate VZV with specialized intestinal metaplasia within the esophagus and suggest a novel site for either latent or active VZV infection.

pneumonitis, had not previously been observed in a vaccinated healthy child. Not surprisingly, this girl was eventually found to have an underlying immunodeficiency disease: a novel and rare deficiency in NK T cells. Her immunodeficiency had presented only as recurrent upper-respiratory-tract infections; no mention is made of past measles immunization, and she may not have had difficulties with this vaccine. The other child, reported by Levin et al., was a 1-year-old boy who had a prolonged and dramatic case of zoster after being vaccinated with the Oka strain

TO THE EDITOR—Dr Gilden and his group have proposed that persistent or low-grade productive varicella-zoster virus (VZV) infection occurs in sensory ganglia of patients with postherpetic neuralgia (PHN) [1]. In Nagel’s excellent article [2], an observation that more VZV DNA was present in the saliva of patients with PHN than in saliva from patients without PHN would probably have been interpreted as consistent with this hypothesis, regardless of whether the immune system does or does not control VZV in PHN patients [3]. The fact that the incidence and concentration of prolonged shedding of VZV DNA in saliva was similar in both groups of patients, however, does not support the idea that prolonged replication of VZV causes PHN, although it does not rule it out. We do not know why VZV DNA is present in saliva of patients with herpes zoster and those postinfection [2, 4]. As Dr Gilden and his colleagues note, ganglionitis in PHN has not been directly associated with VZV, possibly, in part, because human ganglia are not readily available for study [1]. Because it is unclear whether the pathogenesis of zoster sine herpete is similar to that of PHN [1], responses to antiviral therapy may not be comparable in each of these conditions. Therefore, because zoster sine herpete responds to antiviral therapy, it does not necessarily follow that PHN will respond in a similar manner. I believe, however, that we can agree that the presence of VZV DNA in saliva and the etiology of PHN remain mysterious and deserve further study [1, 4].

(See the article by Nagel et al, on pages 820–4.) The development and deployment of varicella vaccine in the United States has almost eliminated chickenpox [1], but herpes zoster (HZ), which is due to reactivation of latent varicella-zoster virus (VZV), remains very much with us [2]. Since 2006, the live attenuated zoster vaccine, similar to but 14 times stronger than varicella vaccine, has been used to prevent HZ by boosting cellular immunity to VZV in older individuals [3]. The zoster vaccine, however, has not achieved widespread uptake for complex reasons, including problematic availability and high expense [4]. Simultaneously with VZV vaccination programs, molecular virologic techniques have emerged and have proven extremely useful, in particular polymerase chain reaction (PCR), for diagnosis of diseases caused by VZV [5–7]. These diseases include cases of mild varicella, HZ, cranial nerve palsies, VZV encephalitis/meningitis, various ocular diseases, and zoster without rash (zoster sine herpete). PCR may be used not only to diagnose these diseases but also to determine if the VZV in question is the wild type or the Oka vaccine strain [8]. PCR for VZV is mostly performed on specimens from skin rashes or cerebrospinal fluid, but recently PCR has been used to diagnose varicella and HZ using saliva. What is the history of examining saliva for diagnosis of herpesvirus infections? Around the beginning of this century, a transient decrease in normal immune function was demonstrated by scientists at NASA in astronauts following space travel, which was ascribed to stress responses (eg, increased blood cortisol levels) experienced during space flight [9]. Asymptomatic reactivation of Epstein-Barr virus [10, 11] and cytomegalovirus [9] was demonstrated in astronauts, in some instances by examining saliva for viral DNA. Mehta and colleagues then found VZV DNA in saliva in 30% of asymptomatic astronauts, both during and after space flights [12]. This impressive observation led to a study of whether VZV DNA was present in saliva of patients with clinical HZ. In a critical diagnostic study on elderly individuals who were not astronauts, salivary VZV DNA was demonstrated in 54 of 54 patients with HZ [6]. In a follow-up study from the Gilden laboratory, included in this issue of the Journal, an effort was made to determine if postherpetic neuralgia (PHN) complicating and following HZ might be associated with the prolonged presence of VZV DNA in saliva, suggesting chronic ganglionic infection [13]. The saliva of elderly patients with and without a history of PHN after HZ, as well as healthy elderly controls with no history of HZ, was tested for VZV DNA. Among HZ patients, 21 of 32 (67%) had VZV DNA in saliva, compared with 2 of 17 (12%) controls (P = .001). Perhaps unexpectedly, however, the presence of salivary VZV DNA was similar in patients following HZ, whether they had PHN or not. This suggested that prolonged replication of VZV is unlikely to explain PHN, which has therapeutic implications regarding prolonged antiviral therapy for this often-severe illness. Interestingly, this result was not exactly in agreement with the hypotheses of these investigators; earlier studies had suggested prolonged VZV replication in patients with PHN. On the other hand, the current results provide a clue as to how VZV might stimulate long-term immunity to the virus, by subclinical reactivation with resultant stimulation of specific immune responses. Like many successful research investigations, the current study raises a number of additional questions. One is why is VZV DNA present in saliva? This finding is understandable if a zoster rash is on or near the face, but even people with a zoster rash on the extremities have VZV DNA in saliva. Does this indicate that reactivation of VZV occurs in distant dermatomes at the same time? If so, why should VZV frequently reactivate simultaneously in the trigeminal ganglion and in a distant ganglion? Might such a phenomenon be related to the VZV latency burden in ganglia in various locations? Is asymptomatic reactivation of VZV common, and does it produce VZV in saliva? It would be useful to have additional information on larger numbers of healthy individuals, further refining what percentage of varicella-immune individuals shed VZV DNA in saliva over time. Finally, because VZV DNA is present in saliva after vaccination to prevent HZ [14], is this the result of viremia that leads to VZV DNA in saliva, and how is this mechanism related to what occurs in HZ? There has been great interest in an illness that has been termed zoster sine herpete, or HZ without rash, for many years. Clinicians are used to rejecting VZV from the differential diagnosis in patients if no rash is present even though the patient may have other symptoms of VZV infection such as unexplained unilateral pain or cranial nerve paralysis. It is becoming clear, thanks in great part to the use of PCR, that VZV can cause disease without rash. Possibly the first recognition of this phenomenon was in patients infected with human immunodeficiency virus who developed VZV encephalitis without rash [15–17]. In these patients, the diagnosis was made by detecting VZV DNA in cerebrospinal fluid. It was then observed that in significant numbers of patients with facial paralysis without rash, VZV DNA was also demonstrable in their saliva [18]. Now one wonders whether individuals who have dermatomal pain in the absence of facial paralysis and rash, true zoster sine herpete, also may have HZ that can be demonstrated by studying their saliva. Recently, it has been found that VZV DNA is frequently present in saliva and urine in patients with varicella [5]. Interestingly, the time-honored means of identifying VZV disease, measuring antibodies in acute and convalescent serum samples, does not seem to measure up to PCR in either sensitivity or rapidity, and may be simply outdated for diagnosis of disease [5]. Another question remains regarding detection of salivary VZV DNA for diagnosis. What is the best method to collect saliva? A variety of collectors are commercially available, and some investigators have simply used swabs for this purpose. The most sensitive and specific means to identify VZV DNA in saliva deserves further exploration. In addition, more information on the possible infectiousness of VZV in saliva is necessary and could have utility for infection control. At present, however, it is clear that identifying VZV in saliva is becoming a useful, rapid, and noninvasive means for diagnosis of VZV infection. Although it does not seem that there is a causal relationship of the presence of VZV DNA and PHN, the persistence of the viral footprint after clinical disease deserves further exploration to uncover its true meaning.

Eight patients became clinically reinfected with varicella-zoster virus despite the presence of specific antibody in the blood three days to six months before the onset of illness. One patient had had varicella previously; a second had been immunized with live, attenuated varicella vaccine 10 months earlier. While it was suspected that these patients experienced a reactivation of latent virus that caused atypical disseminated zoster rather than varicella, detailed study of the vaccinated child suggests that this was not the case; by restriction-endonuclease techniques, this vaccinee was shown to have been infected with wild-type varicella-zoster virus despite the presence of specific antibody and cellular immunity to the virus. All cases clinically resembled chickenpox. Thus, not only subclinical varicella (manifested by a rise in antibody titer after close exposure) but also clinical reinfection with the virus can occur. Clinical reinfection probably develops more frequently in immunocompromised than in immunocompetent individuals. Reinfections are usually mild.

Live attenuated varicella vaccine was administered to healthy varicella-susceptible adults. Of 187 adults immunized with the Oka strain of vaccine, seroconversion to varicella-zoster virus (VZV) occurred in 82% after one dose and in 94% after two doses. Adverse effects were unusual. After immunization, one subject developed mild zoster caused by wild-type virus. Twelve adults developed a mild breakthrough case of chickenpox after exposure to VZV. Protection after household exposure was observed in nine (56%) of 16; however, the illness in all seven patients with breakthrough illness was modified, with an average of only 24 vesicles. Subjects seropositive at household exposure were unlikely to develop a breakthrough illness. Approximately 25% of vaccinees who seroconverted lost detectable antibodies to VZV after vaccination, but even those who became seronegative were partially protected. Varicella vaccine offered significant protection against severe chickenpox in healthy adults.

Restriction endonuclease analysis of varicella-zoster virus (VZV) DNA has been used in unraveling the complex epidemiology of VZV infections in individuals immunized with a live, attenuated varicella virus vaccine. Early rashes appearing within the first six weeks after vaccination are invariably due to vaccine virus. True breakthrough infections with wild-type VZV also occur in vaccinees. Five cases of zoster have been seen in leukemic children vaccinated while in remission. One case appeared 22 months after vaccination in the same general area as the inoculation. The virus isolated was vaccine derived. A second case of zoster appeared in a dermatome unrelated to the sites of vaccination approximately 19 months after apparently natural varicella. This virus was wild type. Vaccine virus can therefore establish latency and can later reactivate as herpes zoster.

A simple, accurate, and rapid method for laboratory diagnosis of varicella-zoster virus (VZV) infections using countercurrent immunoelectrophoresis (CIE) is described. CIE uses zoster convalescent-phase serum to detect VZV antigen in vesicular fluid. Eighty-six patients were studied, 58 with VZV infections and 28 with vesicular or bullous rashes due to causes other than VZV infection. All patients with documented VZV infection had positive CIE tests for VZV, and the controls were uniformly negative. VZV antigen could be detected up to 15 (varicella) or 16 (zoster) days after the onset of rash. The sensitivity of CIE for detection of VZV antigen was compared with results of viral isolation, immune adherence hemagglutination, and an indirect enzyme-linked immunosorbent assay. The clinical diagnosis of varicella-zoster virus (VZV) infections usually poses little difficulty. However, when a vesicular eruption occurs in an immunocompromised host or in a patient with an underlying skin disorder, or when the rash is atypical, reliance on the laboratory for diagnosis may be crucial. Vesicular eruptions clinically identified as being due to VZV have subsequently been shown to be caused by herpes simplex virus (HSV) [1-3], echoviruses [4, 5], mycoplasma [6], or

A patient with acute lymphocytic leukemia in relapse, who developed severe herpetic gingivostomatitis, was treated with cytosine arabinoside (Ara-C). The titer of herpes simplex virus isolated from the mouth showed a rapid but transient decline following iv administration of Ara-C on two separate occasions. In-vitro studies revealed that the inactivating effect of saliva on herpesvirus was cancelled by antibody to IgA. These observations suggest that the diminution of the amount of herpesvirus isolated from the mouth after treatment was probably the result of inhibition of new viral synthesis by Ara-C coincident with neutralization of preformed virus by secretory IgA. Cytosine arabinoside (Ara-C) inhibited the multiplication of several DNA viruses in mammalian cell cultures [1, 2]. These observations have led to the experimental use of this drug in the treatment of life-threatening viral infections [3-6]. Reports of the efficacy of Ara-C in the treatment of these illnesses, however, have been based mainly on clinical impressions. A patient with acute lymphocytic leukemia in relapse who developed severe herpetic gingivostomatitis provided an opportunity to obtain quantitative data on the effect of Ara-C on synthesis of herpes simplex virus (HSV) in vivo. The inhibition of new viral synthesis by Ara-C provided an opportunity to study the role of secretory IgA in the elimination of HSV.

The need to identify vesicular rashes in patients suspected of having smallpox has led to the development of a variety of laboratory tests. Because of its simplicity, the gel-precipitin test has been widely used to make a presumptive diagnosis of smallpox in such patients. A negative test for smallpox antigen, however, still left the diagnosis in doubt. Therefore, there was a need for methods to identify antigens of other agents that might cause similar diseases.