After implementation of routine universal varicella vaccination in early childhood in the United States, CNS disease caused by VZV still occurs and, albeit rarely, can result from the reactivation of vaccine virus. However, the epidemiology of CNS VZV disease appears to be changing. Studies performed in different regions of the world prior to licensure of the varicella vaccine found VZV to be a leading cause of childhood encephalitis [24
]. Encephalitis was infrequently seen among our pediatric cohort (2 pediatric cases among the 17 without genotyping data presented with encephalitis). Even though acute cerebellar ataxia is the most common complication of VZV infection in children [28
], no cases were reported in this cohort, most likely due to referral bias. All children with specimens genotyped in this study (n
= 7) presented with meningitis. In contrast, VZV is now recognized as one of the leading causes of adult encephalitis. Indeed, in 2 recent encephalitis studies, VZV was the second most common etiology identified, second only to HSV [29
]. All patients older than 60 years (n
= 9) with specimens genotyped in this study presented with encephalitis. Among our cases, VZV CNS disease frequently presented without the characteristic HZ rash. The clinical implications are important because VZV may not be considered in the differential diagnosis of a patient presenting without a rash with CNS disease as routinely as HSV, and antiviral medications thus may be prematurely discontinued once HSV is ruled out. In fact, VZV CNS disease can resemble HSV encephalitis clinically and on neuroimaging as illustrated by 2 of our patients who had temporal lobe abnormalities, a characteristic finding of HSV but not usually associated with VZV [31
VZV isolates are classified based on their geographic distribution as European Group (Clade 1, Clade 3), Asian (Clade 2), and Mosaic Group (Clade 4, Clade 5, Clade VI, and Clade VII). There are currently at least 5 and possibly as many as 7 distinctive genotypes identified: Clades 1–5, and provisional genotypes Clade VI and Clade VII [18
]. The vaccine strain belongs to Clade 2 and can be differentiated from wild-type VZV by identifying vaccine-associated single base pair polymorphisms as described in our methods. In a global survey of more than 300 VZV isolates, Clade 2 strains were identified only in Japan and Hawaii [17
]. Several more recent studies failed to detect Clade 2 isolates in multiple countries in Europe, but 13% of isolates evaluated in Australia were Clade 2 viruses [17
]. While the overall numbers of isolates evaluated worldwide remains relatively small, it is striking that Clade 2 viruses have never been observed in areas with predominantly European descent that have limited immigration and have not yet been shown to be circulating in the United States. The emerging premise is that countries with a history of European colonization that have received large numbers of Asian immigrants in recent decades are undergoing a shift in the distribution of VZV genotypes, with increasing numbers of Clade 2 strains. The observation of 3 wild-type Clade 2 isolates in this small study may support this notion. Of the 3 cases with wild-type clade 2 cases, all were young (likely reflecting more recent infection trends), one had no recorded ethnicity or travel history, and the other 2 cases, 1 Hispanic and 1 Asian/Pacific Islander, denied any international travel. More detailed information on these cases can be found in . Notably, the Clade 2 strains detected in this study as wild-type using ORF21/ORF22/ORF50 genotyping would have been identified as vaccine genotype using only ORF38/ORF54-based genotyping (BglI+, PstI−), a method that is still in use for the identification of vaccine strain among clinical isolates [34
]. Another important finding was the identification of Clade VI strain, previously not seen in the United States but found in Spain and France [32
]. Sequencing data from the 26 VZV isolates reported here show that all VZV genotypes can be involved in CNS disease.
Only 1 of 26 isolates genotyped in this study was identified as the Oka vaccine strain. Six additional cases of CNS disease associated with VZV vaccine strain have been reported in the literature (), with 2 additional cases of vaccine meningitis confirmed more recently, 1 in Japan (identified in 2008, unpublished data) and 1 in Minnesota (in press). The previously reported cases ranged in age from 15 months to 9 years old. Four children were previously healthy, and 2 were immunocompromised. Length of time from vaccine administration to presentation ranged from 3 months to 8 years. Our case is the oldest reported (12 years old) and had the longest interval to reactivation (11 years). Even though only 7 cases of vaccine-associated CNS diseases are described to date, it is interesting to note that most patients presented with meningitis, and all were preceded by HZ (median time of 4.5 days) prior to CNS symptoms. Based on this very limited number of cases, clinical presentation of vaccine strain reactivation does not appear to differ from wild-type VZV CNS disease, making the diagnosis of vaccine strain reactivation difficult based on clinical presentation alone. The small number of cases reported may also suggest that the vaccine strain is less virulent in the CNS than the wild-type virus. However, the actual number of cases due to VZV vaccine strain reactivation is most likely higher than the number of cases that have been laboratory-confirmed, making any conclusion premature. This highlights the importance of continuing genotyping and strain surveillance studies to distinguish wild-type and vaccine strain infections.
One of the important limitations of this study is that the CEP is not a population-based study. The CEP is more likely biased toward patients that are severely ill and that are diagnostically challenging [14
]. For example, cases that presented with a characteristic rash of VZV and CNS symptoms are likely underrepresented in this sample. Similarly immunocompromised hosts are likely underrepresented since the focus of the project is the immunocompetent host.
In summary, after implementation of routine universal varicella vaccination in the United States, all but 1 case of VZV associated CNS disease observed in this cohort study were due to reactivation of the wild-type virus. Sequencing data from the 26 VZV isolates reported here show that all VZV genotypes can be involved in CNS disease. Our report of a seventh patient with VZV vaccine strain reactivation is similar to cases previously reported, although the time to reactivation, causing HZ and meningitis in an otherwise healthy young girl, was 11 years. In contrast to wild-type VZV CNS illness, which most often causes encephalitis in children, VZV vaccine strain is more often associated with meningitis. This presentation cannot be differentiated from natural VZV CNS disease clinically, emphasizing the importance of sequencing and genotyping.