Varicella (chickenpox), the primary infection with the varicella zoster virus (VZV), is mainly a childhood illness, usually with an uncomplicated course of disease.1 However, complications resulting in hospitalization are known to occur in 2–6 per 100,000 population, and in 13–28 per 100,000 children.1,2 As a neurotropic virus, VZV infection may result in neurologic complications in the course of varicella or secondary herpes zoster disease.3–6 VZV is considered one of the most common viruses potentially causing severe diseases of the central nervous system (CNS), such as encephalitis, meningitis, cerebellitis, myelitis, cerebrovascular disease, cerebral nerve palsy and convulsion.3,5–8According to a systematic review, roughly 14%–20% of all pediatric varicella-associated hospitalizations may be due to neurologic complications.4
Before the introduction of universal varicella vaccination in Germany, an annual incidence of 2.4 per 100,000 children <17 years of age was reported for varicella-associated neurologic complications, corresponding to about 330 hospitalized children in Germany each year.3Acute cerebellar ataxia, febrile convulsion, encephalitis or meningitis and cerebral convulsion were the most frequent neurologic complications.3 Interestingly, patients with neurologic complications were significantly older (median 4 vs. 3 years) and required a longer hospital stay (median 6 vs. 5 days) compared with children with other varicella-associated complications.3
Germany’s Standing Committee on Vaccination (STIKO) recommended universal, health insurance-financed varicella vaccination for all children in July 2004, with 1 dose at 11–14 months of age.9 In July 2009, a 2-dose schedule was recommended, with a second dose to be applied at 15–23 months of age.10 The introduction of universal varicella vaccination in Germany resulted in an overall decline of varicella-associated complications recorded by practice-based sentinel surveillance11and of the overall rate of varicella-associated hospitalizations.12
In this study, we assessed the type and incidence of varicella-associated neurologic complications in children during the first 7 years following the STIKO 2004 recommendation.
MATERIALS AND METHODS
A pediatric hospital surveillance study was conducted in Bavaria (one of the largest Federal States of Germany) from January 2005 to December 2011, within the framework of the “Bavarian Varicella Surveillance Project.”13 The pediatric hospitals (37 in 2005, 36 since 2006) covered an annual study population of on average 2,069,000 children <17 years of age in Bavaria (2005–2011), representing approximately 16% of this age group in Germany.14During the study period, a total number of between 135,800 and 143,100 pediatric patients per year were admitted to these hospitals. All hospitals were invited to participate in annual, standardized data queries on hospitalized varicella patients based on discharge diagnoses from hospital databases, coded according to the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10).
Participating hospitals provided anonymized basic demographic data, month and year of hospital admission, duration of hospital stay, all ICD-10 codes and procedural codes for each patient fulfilling the following inclusion criteria: at least one ICD-10 code for varicella (B01.0–B01.9) as main diagnosis or as any secondary diagnosis at discharge; child <17 years of age at hospital admission; hospital stay within the time period 2005 to 2011; duration of hospital stay at least 1 day.13 All children with an ICD-10 code for varicella meningitis (B01.0) or varicella encephalitis (B01.1), or for any neurologic complication or symptom in combination with any other code indicating varicella disease (B01.2, “varicella pneumonia”; B01.8, “varicella with other complications”; B01.9, “varicella not otherwise specified”), were included in the analysis as patients with varicella-associated neurologic complications (eg, patients with a code for ataxia in combination with code B01.9). Unspecified codes for encephalitis/meningitis in combination with a code for varicella were considered as varicella-associated encephalitis/meningitis, unless there was an additional code for encephalitis/meningitis caused by a different pathogen (eg, B00.4, “encephalitis due to herpes simplex virus”). Patients were allocated to predefined categories of neurologic complications.3 If several neurologic complications were reported for a single patient, the patient was allocated to a category in the following hierarchical order: cerebral vasculitis/ischemic infarction > encephalitis or meningitis > cerebral (afebrile) convulsion > febrile convulsion > syncope > other neurologic complication (including ataxia/ataxic gait, suggesting underlying cerebellitis); patients with facial nerve palsy as the only neurologic complication were listed as a separate category.3
Statistical Analyses and Incidence Estimates
Data were submitted by the hospitals as Microsoft Excel files and transferred into SPSS version 23.0 (SPSS Inc., Chicago, IL) for statistical analysis. In view of the annual variation in the number of participating hospitals, the numbers of patients and the numbers of neurologic complications are presented as averages per hospital and year; additionally, annual averages per 100 hospital beds were calculated to correct for potential differences in hospital size. All other data are reported as numbers and percentages or as median with interquartile range (IQR). Patient characteristics were compared between subgroups using Pearson’s χ2 test or Fisher’s exact test for categoric data, and the Mann–Whitney U test for continuous data, with a level of significance of 0.05 (2-sided). Annual incidence estimates (for neurologic complications, for encephalitis or meningitis and for varicella-associated hospitalizations overall) were calculated by extrapolating the number of varicella patients observed per hospital bed in the subgroup of participating hospitals to the total number of pediatric hospital beds in the study area.15 The resulting numbers of cases were related to the respective annual populations of children in Bavaria, and 95% confidence intervals were calculated. To assess the trend across years for significance, Poisson regression models with a linear time trend and with the logarithm of the number of pediatric beds in participating hospitals as offset were fitted to the absolute number of cases reported per year (analyses performed in R for Windows 3.2.216). In addition, a sensitivity analysis based on the subgroup of hospitals participating in all 7 years was carried out to examine whether the patterns seen in the annual averages per hospital were affected by potential differences in characteristics of participating hospitals between study years.
Ethical Considerations and Data Protection
Only anonymized data were collected. The study was approved by the Bavarian Data Protection Office (Munich, Germany) and the Ethics Committees of the Medical Faculties at the University of Munich and the University of Würzburg.
Participating Hospitals and Characteristics of Children With Neurologic Varicella-associated Hospitalizations
Between 22 and 29 pediatric hospitals (61%–78% of all 36–37 eligible hospitals) participated per study year, representing a total of 1738 to 2640 pediatric hospital beds. From January 2005 to December 2011, the participating hospitals reported a total of 1263 hospitalized patients with varicella (median 36, IQR 20–51). Median age at varicella infection was 3 years (IQR 1–5); 55% were male children. Manifestation of at least 1 specific complication was reported for 954 varicella patients (75.5%).
Neurologic complications were reported for a total of 228 (18.1%) of all 1263 varicella-associated hospitalizations. A comparison of the characteristics of hospitalized children with (n = 228) and without (n = 1035) varicella-associated neurologic complications is presented in Table 1. Children with neurologic complications were significantly older than children without these complications (median 4 vs. 3 years), and the proportion of children with chronic comorbidities was lower among patients with neurologic complications (16% vs. 23%). Varicella or a varicella-associated complication or symptom was reported as the main diagnostic code in 97% of patients with neurologic complications; in the remaining 3%, the primary diagnosis was an underlying chronic condition or an unspecific code (eg, “prophylactic isolation”). Duration of hospital stay did not differ significantly between children with or without neurologic complications (median 3 days). There were no fatalities among children with neurologic complications.
Type and Presentation of Varicella-associated Neurologic Complications
The occurrence of specific types of complications overall and the frequency and characteristics of patients for whom the specific complication was the most relevant neurologic diagnosis are summarized in Table 2.
Febrile convulsions were the most relevant diagnosis in 73 children, thus representing approximately one-third (32%) of all 228 patients with neurologic complications. Febrile convulsions were reported as the main diagnostic code in 5 of the 73 patients (7%). Underlying chronic conditions were documented in 7 of the 73 children (10%), including 1 child with an underlying neurologic disorder. The most frequent additional nonneurologic complications were gastrointestinal (in 19%) and upper respiratory tract complications (in 15%).
Of 66 (29% of 228) patients with varicella-associated encephalitis or meningitis, 41 patients (62% of 66) were diagnosed with encephalitis, 22 (33%) with meningitis and 3 with both encephalitis and meningitis (5%). Underlying chronic conditions were reported for 12 of these patients (18%), including 5 with neurologic disorders. The most frequent neurologic symptoms in patients with encephalitis or meningitis were ataxia/coordination difficulties (17%) and febrile convulsions (8%); facial nerve palsy was documented for 1 patient (2%). For 2 patients with varicella meningitis, herpes zoster without complications was reported as additional diagnosis (3%). The most frequent nonneurologic diagnoses in children with encephalitis or meningitis were dehydration/feeding difficulties (18%) and gastroenteritis (8%). Three patients (5%) additionally showed systemic bacterial infection. Two children (3%) with additional nonneurologic complications (sepsis and acute respiratory insufficiency, respectively) received complex intensive care treatment.
Thirty patients were diagnosed with syncope (13% of 228). This complication was the main diagnostic code in 20 children (67% of 30). Median age was 7 years and, thus, higher than in the majority of children with other neurologic complications. Two patients (7%) had a chronic comorbidity. The proportion of patients with additional nonneurologic complications was lowest in this group (23%); the most frequent nonneurologic complications were dehydration/feeding difficulties. Median hospital stay (2 days) was shorter than among patients with other neurologic complications.
Twenty-five (11% of 228) patients showed cerebral convulsions as the most relevant neurologic diagnosis. These convulsions were the main diagnostic code in 56% of the 25 patients. For a relevant proportion (28%) of these children, an underlying chronic condition was reported, including 5 children with neurologic disorders. One patient (4%) with underlying neurologic and other disorders received complex intensive care treatment. The most frequent nonneurologic complications were dehydration/feeding difficulties (in 20%) and lower respiratory tract complications (in 12%).
Facial nerve palsy was reported as the only neurologic complication in 6 (3% of 228) patients, and was the main diagnostic code in 5 (83%) of these 6 children. Patients with facial nerve palsy had the highest median age (9.5 years); none had a chronic underlying condition. Additional, nonneurologic complications were frequent (in 67%) and included gastrointestinal complications, coinfections and bronchitis. Children with facial nerve palsy typically showed a longer hospital stay (median 8 days) than children with other types of neurologic complications.
Cerebral vasculitis or ischemic infarction was reported for 4 (2% of 228) varicella patients, aged 1–4 years. This subgroup of patients exhibited the longest hospital stay; none of these 4 patients had underlying chronic conditions. Two of these children were admitted because of cerebral infarction; one was diagnosed with cerebral convulsion, facial nerve palsy and monoplegia of an upper extremity, and the other child with hemiplegia. The other 2 patients in this subgroup were diagnosed with intracranial phlebitis/thrombophlebitis. One of these children was admitted primarily because of acute orbit inflammation, with dehydration and feeding problems as further diagnoses. The other child had varicella encephalitis as primary diagnosis, in addition to status epilepticus and bacterial pneumonia.
Other complications were reported for 24 patients (11% of 228). They included 7 (3% of 228) patients for whom ataxia was the most relevant neurologic complication (14 patients with ataxia overall), with a median age of 5 years (IQR 3–7). One ataxia patient additionally suffered from a cerebellar malignancy. Neurologic complications in the other patients included coordination disturbance/vertigo (4), neuropathy (3), encephalitis or meningitis caused by coinfecting pathogens (2; Streptococcus pneumoniae, tick-borne encephalitis virus) and cerebral edema (2) as the most frequent.
Change in Neurologic Complications and Overall Varicella Hospitalizations Over Time
The monthly distribution of neurologic complications showed a typical seasonal pattern for varicella with a peak in winter/spring from 2005 to 2010, but no longer in 2011 (Fig. 1). The occurrence of varicella-associated neurologic complications in children <17 years of age decreased significantly between 2005 and 2011 (P < 0.001),with a continuous decline from a maximal annual average of 2.0 patients per 100 hospital beds in 2005 to a minimum of 0.8 in 2011, a decrease by roughly 59% (Table 3). In the subgroup of children up to 7 years of age, varicella-associated neurologic complications per 100 hospital beds decreased from an average of 1.9 in 2005 to 0.4 in 2011 (P < 0.001; Fig. 2). In contrast, the annual number of older children varied between 0.1 and 0.4 patients per 100 hospital beds, with no clear trend over time. Overall, between 2005 and 2011, the incidence estimates per 100,000 children <17 years of age showed a decrease of neurologic complications from 2.8 to 1.2 (in children 0–7 years of age from 6.0 to 1.4; Table 4). The median age of children with neurologic complications increased from 3 years (IQR 1–5) in 2005 to 7.5 (IQR 6–10.5) in 2011 (P < 0.001).
Regarding specific neurologic complications (Table 3), febrile convulsions occurred only in children 0–7 years of age; the frequency of patients with this complication decreased from a maximum of 0.8 patients per 100 hospital beds in 2005 and in 2006 to the lowest numbers in 2010 (0.05) and 2011 (0.12), corresponding to a decrease by 84%–94%. For varicella encephalitis or meningitis, a maximum of 0.6 patients per 100 hospital beds was reported in 2005 and a minimum of 0.2 in 2011; during the intervening years, the frequency fluctuated on an intermediate level. The overall decline was observed only in encephalitis or meningitis patients 0–7 years of age (from an annual average of 0.5 patients per 100 hospital beds in 2005 to 0.06 in 2011), whereas in older children there was no clear trend. Within this diagnosis group, encephalitis was the predominant diagnosis in 2005 to 2009 (67%–80% of all annually 9–15 encephalitis or meningitis patients), whereas encephalitis and meningitis occurred in equal proportions in 2010 (4 patients each), and only 1 patient (25%) was reported with encephalitis compared with 3 (75%) with meningitis in 2011. For cerebral convulsions, syncope, facial nerve palsy, cerebral vasculitis/infarction and other neurologic complications, no clear trend was apparent in the data.
Similarly, the frequency (Table 3) and incidence (Table 4) of varicella-associated hospitalizations overall (including patients with neurologic complications, patients with nonneurologic complications and patients without specific complications) decreased between 2005 and 2011. The age of patients with varicella-associated hospitalization increased from a median of 3 years (IQR 1–5) in 2005 to 5 years (IQR 3–8) in 2011 (P < 0.001).
Sensitivity analyses restricted to the 14 hospitals participating in all 7 study years confirmed the observed patterns of decrease.
Germany was the first country in Europe where nationwide, universal varicella vaccination for children was introduced to reduce the burden of disease and varicella-associated complications.17 Following the recommendation in 2004, regional and nationwide vaccination coverage in the target group reached levels of about 70%–80% by 2011, and was associated with a marked decline in varicella-associated hospitalizations particularly among children.12,13
Our study also detected a decline in the overall number of varicella-associated hospitalizations. This is in accordance with German Statistical Office Hospital Statistics on Bavaria, which shows a comparable decrease of pediatric hospitalizations with varicella (B01) as primary ICD-10 diagnosis between 2005 and 201118,while pediatric hospital admissions overall remained at a stable level during this period. Contrary to the case of children, these hospital statistics show no consistent trend for varicella-associated hospitalizations in adults: among adults, absolute numbers remained at a similar level between 2005 and 2011.18
The overall decline in pediatric varicella-associated hospitalizations was paralleled in our study by a decline in the number of hospitalized children with varicella-associated neurologic complications during these first 7 years following the recommendation, particularly among children up to 7 years of age, who were increasingly covered by universal vaccination (Fig. 2). To our knowledge, this is the first study in Europe investigating the impact of vaccination on varicella-associated neurologic complications in children at a population level. The observed decline in neurologic complications was mainly due to a decrease in the number of children hospitalized with febrile convulsions, and with encephalitis or meningitis. Extrapolating our results from Bavaria to Germany, they would correspond to an estimate of 380 children hospitalized nationwide with varicella-associated neurologic complications in 2005 compared with 148 in 2011, and to an estimate of 108 children with varicella-associated encephalitis or meningitis in 2005 compared with 49 in 2011.
In Germany, data on neurologic complications and other varicella-associated hospitalizations from the prevaccination period are available from a nationwide study conducted by us in 2003 and 2004, using a different surveillance system but similar criteria for patient categorization.3,15 Demographic and clinical characteristics of all varicella-associated hospitalizations were comparable in 2003–2004 (prevaccination)15 and 2005–2011 (postvaccination). The overall proportion of children with neurologic varicella complications was somewhat lower (18%) in the postvaccination period compared with the prevaccination period (25%),3 but was still within the range reported by other studies.4Similar to the prevaccination period and to other investigations, varicella patients with neurologic complications were significantly older than children without such complications.3,4,19 Additionally, the results of our 2005–2011 study presented here confirm previous observations that patients with neurologic complications are less frequently reported to be suffering from immunocompromising and other chronic conditions.3,20,21 It cannot be ruled out that high risk patients may be more likely to receive treatment with antiviral medication or to receive this treatment at an earlier disease stage after diagnosis of varicella. A detailed evaluation of this question was not possible as the procedural codes available for analysis did not include the necessary information. Information on the use of immunoglobulin treatment, however, was available and showed that patients with and without neurologic complications did not differ with respect to treatment with immunoglobulin.
Patients with neurologic complications showed very similar demographic characteristics before3 and after introduction of universal varicella vaccination in Germany, as well as similar proportions and characteristics of most specific neurologic complications (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C542). However, it is likely that acute cerebellar ataxia, the most frequent neurologic diagnosis reported in our previous study3 and other studies,4,21,22 was underrepresented in the present ICD-10-based investigation (11% vs. previously 31%), as no specific ICD-10 code is available for this diagnosis. In both German studies, median age was highest in children with syncope or facial nerve palsy, and low in children with febrile convulsions.3 The overall length of hospital stay of neurologic patients was shorter in our present study (median 3 vs. previously 6 days), with a markedly shorter length of stay in children with varicella encephalitis or meningitis (median 7 vs. previously 13 days). This suggests that the previous, physician-based surveillance study may have preferentially captured more severe cases of varicella encephalitis or meningitis and, thus, may have underestimated the overall occurrence of these complications. Apart from the differences stated above, the demographic and clinical characteristics of children with neurologic complications were largely consistent with studies from other countries.4,19,21–23
The prevaccination annual incidence of neurologic complications in 2003/2004 was similar (2.4/100,000 children <17 years of age3) to the incidence estimates in 2005 to 2007, when vaccination coverage for the target population in the study area was still below or around 50%.13 However, as higher coverage levels in the population were reached in Bavaria between 2008 and 2011,13 incidences decreased, particularly in the age group covered by universal varicella vaccination. For older children, no consistent trend over the years was observable, with the lowest incidences in this age group in 2005 and 2008 and the highest in 2007 and 2011. It has been speculated that with increasing coverage among younger children, an increase in the number of older children with varicella-associated complications might be expected, because of delayed contact with the wild-type virus. This was not observed in our study, though the age of children with neurologic complications increased from a median of 3 years in 2005 to 7.5 years in 2011. Similarly to the incidence of neurologic complications, the incidences of varicella-associated hospitalizations overall decreased in younger children between 2008 and 2011.
Only few other studies have thus far investigated the impact of varicella vaccination on neurologic complications. Some recent population-based investigations detected a decreasing rate of pediatric varicella encephalitis in Australia with increasing vaccination coverage,24 but showed no reduction in pediatric strokes in the United States despite a strong overall decline of varicella-associated hospitalizations during the postvaccination period.25 A decline in the number of varicella-associated CNS complications after introduction or funding of varicella vaccination was also reported for individual hospitals in Canada and Taiwan,21,26 and in the number of various specific neurologic complications for 12 tertiary care hospitals in Canada.27 A study on clinical and laboratory features of VZV-associated CNS disease in a small cohort of varicella and herpes zoster patients from the United States conducted during the postvaccine era suggested a shift from pediatric encephalitis to meningitis as the now most frequent VZV-associated CNS complication in children.28 In our study, the highest number of pediatric varicella patients with encephalitis or meningitis was observed in 2005, with numbers at an intermediate level from 2006 to 2010, and the lowest number of cases in 2011 (50% of the frequency in 2005). Interestingly, within this patient group, varicella encephalitis was more frequent than meningitis during the first years of observation, but no longer during the last 2 years, possibly indicating a similar proportional shift from encephalitis to meningitis.
When investigating the frequency of neurologic complications in the postvaccine era, it should be kept in mind that factors other than vaccination may also influence the occurrence of neurologic complications in varicella patients. An increase in CNS complications has been observed during the last decades in countries without universal varicella vaccination, where varicella vaccination rates were low. In a study in Tuscany, Italy, from 1997 to 2004, the incidence in varicella CNS complications increased from previously between 1.0 and 1.7 per 100,000 children to levels of about 3.1 to 3.5, possibly because of the emergence of a particularly neurotropic VZV strain.29 In England, varicella meningitis increased more or less continuously from 0.2 per million population in 2001/2002 to 0.6 in 2010/2011, whereas varicella encephalitis and other varicella-associated complications showed annual fluctuations but without a clear trend.30 The reason for the increase in varicella meningitis in England is unclear. A shift from a risk-group-based varicella vaccination strategy to universal childhood vaccination in these countries might offer the potential to counteract such trends. However, if varicella CNS complications continue to increase in unvaccinated children in these areas, the overall decrease of such complications with increasing vaccination coverage might initially be less pronounced than that observed in our study.
In our ICD-10-based study, data on patient vaccination status was not available; nevertheless, it may be assumed that most reported patients were unvaccinated. With increasing numbers of vaccinated children, however, future surveillance of VZV-associated CNS disease should also include information on patient vaccination status and VZV strain to be able to assess the frequency and type of neurologic complications associated with breakthrough varicella due to the wild-type virus on the one hand, and those associated with the vaccine strain on the other hand. In a recent study from Turkey, neurologic complications were identified as the cause of hospitalization in about one-third of children hospitalized with breakthrough varicella.31 Neurologic complications of VZV disease caused by the vaccine strain have thus far been detected extremely rarely in varicella-vaccinated children,28,32 but this might be partly due to the fact that the virus type is currently only rarely analyzed in such patients. Such additional data will be needed to evaluate the long-term impact of varicella vaccination.
Analysis of ICD-10-based routine data from hospital databases has various limitations.15 Although ICD-10 coding is mandatory for hospital reimbursement in Germany and has been so since 2004, the coding might have been wrong or incomplete in some patients. Data protection restrictions meant that only anonymous data could be obtained from the hospitals. Thus, neither potential multiple admissions per patient or transfer of a patient to another hospital could be identified, nor was it possible to confirm the ICD-10-reported diagnosis by medical chart review. It cannot be ruled out that a neurologic diagnostic code was, in rare cases, (conservatively) classified as comorbidity though it might more likely have been a sequela of varicella disease (eg, epilepsy). Furthermore, postinfectious neurologic complications occurring weeks or months after varicella disease6,23 may not have been coded as being varicella-associated. Hence, our study may still underestimate the overall frequency of neurologic varicella-associated complications. Nevertheless, the comparison of our results with the incidence estimates from the prevaccination period and the trend observed in our data from 7 consecutive postvaccination years provide confirmation of a significant decline of varicella-associated neurologic complications in Germany.
We thank Karin Seeger for her contributions to the statistical analyses and comments on the manuscript, and Sabrina Hanke and Christina Bungartz for their support in data management. The following hospitals participated in the study: Kreisklinik Altötting, Zentrum für Kinder- und Jugendmedizin (Altötting); Klinikum St. Marien Amberg, Klinik für Kinder und Jugendliche (Amberg); Klinikum Aschaffenburg, Klinik für Kinder- und Jugendmedizin (Aschaffenburg); Klinikum Augsburg, Klinik für Kinder und Jugendliche (Augsburg); Klinik Josefinum, Kinderkrankenhaus (Augsburg); Klinikum Sozialstiftung Bamberg, Kinderklinik (Bamberg); Klinikum Bayreuth GmbH, Kinderklinik (Bayreuth); Regiomed-Kliniken gGmbH, Klinik für Kinder- und Jugendmedizin (Coburg); DONAUISAR Klinikum Deggendorf, Kinder- und Jugendmedizin (Deggendorf); Universitätsklinikum Erlangen, Kinder- und Jugendklinik (Erlangen); Klinikum Fürth, Klinik für Kinder und Jugendliche (Fürth); Klinikum Garmisch-Partenkirchen GmbH, Fachabteilung Kinder- und Jugendmedizin (Garmisch-Partenkirchen); Sana Klinikum Hof GmbH, Kinderklinik (Hof); Klinikum Kaufbeuren, Abteilung Pädiatrie (Kaufbeuren); Klinikum Kempten-Oberallgäu, Kinderklinik (Kempten); Klinikum Landsberg am Lech, Abteilung für Kinder- und Jugendmedizin (Landsberg); Kinderkrankenhaus St. Marien, Abteilung für Kinder- und Jugendmedizin (Landshut); Städtisches Klinikum München GmbH, Klinikum Harlaching, Klinik für Kinder- und Jugendmedizin (München); Ludwig-Maximilians-Universität München, Dr. von Haunersches Kinderspital (München); Städtisches Klinikum München GmbH, Klinikum Schwabing, Klinik für Kinder- und Jugendmedizin (München); Klinikum Dritter Orden, Klinik für Kinder- und Jugendmedizin (München); Kliniken St. Elisabeth, Abteilung für Kinder- und Jugendmedizin (Neuburg a.d. Donau); Klinik Hallerwiese, Cnopf’sche Kinderklinik (Nürnberg); Klinikum Nürnberg, Klinik für Neugeborene, Kinder und Jugendliche (Nürnberg); Kinderklinik Dritter Orden (Passau); Krankenhaus Barmherzige Brüder Regensburg, Klinik für Kinder- und Jugendmedizin (Regensburg); RoMed Klinikum Rosenheim GmbH, Kinderklinik (Rosenheim); Leopoldina-Krankenhaus der Stadt Schweinfurt GmbH, Klinik für Kinder und Jugendliche (Schweinfurt); Klinikum Starnberg, Klinik für Kinder- und Jugendmedizin (Starnberg); Kliniken Südostbayern AG, Klinikum Traunstein, Klinik für Kinder- und Jugendmedizin (Traunstein); Kliniken Nordoberpfalz AG, Klinikum Weiden, Klinik für Kinderheilkunde und Jugendmedizin (Weiden); Universitätsklinikum Würzburg, Kinderklinik und Poliklinik (Würzburg); Missionsärztliche Klinik gGmbH, Kinderklinik (Würzburg).
1. Heininger U, Seward JF. Varicella. Lancet. 2006;368:1365–1376.
2. Papaloukas O, Giannouli G, Papaevangelou V. Successes and challenges in varicella vaccine. Ther Adv Vaccines. 2014;2:39–55.
3. Rack AL, Grote V, Streng A, et al. Neurologic varicella complications before routine immunization in Germany. Pediatr Neurol. 2010;42:40–48.
4. Bozzola E, Tozzi AS, Bozzola M, et al. Neurological complications of varicella in childhood: case series and a systematic review of the literature. Vaccine. 2012;30:5785–5790.
5. Gilden D, Nagel MA, Cohrs RJ, et al. The variegate neurological manifestations of varicella zoster virus
infection. Curr Neurol Neurosci Rep. 2013;13:374.
6. Grahn A, Studahl M. Varicella-zoster virus infections of the central nervous system – Prognosis, diagnostics and treatment. J Infect. 2015;71:281–293.
7. Persson A, Bergström T, Lindh M, et al. Varicella-zoster virus CNS disease–viral load, clinical manifestations and sequels. J Clin Virol. 2009;46:249–253.
8. Amlie-Lefond C, Jubelt B. Neurologic manifestations of varicella zoster virus
infections. Curr Neurol Neurosci Rep. 2009;9:430–434.
9. Robert Koch-Institut. Empfehlungen der Ständigen Impfkommission (STIKO) am Robert Koch Institut/Stand: Juli 2004. Epidemiologisches Bulletin. 2004;30:235–250.
10. Robert Koch-Institut. Empfehlungen der Ständigen Impfkommission (STIKO) am Robert Koch Institut/Stand: Juli 2009. Epidemiologisches Bulletin. 2009;30:279–298.
11. Spackova M, Muehlen M, Siedler A. Complications of varicella after implementation of routine childhood varicella vaccination
in Germany. Pediatr Infect Dis J. 2010;29:884–886.
12. Siedler A, Dettmann M. Hospitalization with varicella and shingles before and after introduction of childhood varicella vaccination
in Germany. Hum Vaccin Immunother. 2014;10:3594–3600.
13. Streng A, Grote V, Carr D, et al. Varicella routine vaccination and the effects on varicella epidemiology - results from the Bavarian Varicella Surveillance
Project (BaVariPro), 2006-2011. BMC Infect Dis. 2013;13:303.
15. Liese JG, Grote V, Rosenfeld E, et al.; ESPED Varicella Study Group. The burden of varicella complications before the introduction of routine varicella vaccination
in Germany. Pediatr Infect Dis J. 2008;27:119–124.
16. R Core Team. R: a language and environment for statistical computing. 2015. Vienna, Austria; R Foundation for Statistical Computing. Available at: https://www.R-project.org
.Accessed December 8, 2015.
17. Helmuth IG, Poulsen A, Suppli CH, et al. Varicella in Europe-A review of the epidemiology and experience with vaccination. Vaccine. 2015;33:2406–2413.
19. Gowin E, Wysocki J, Michalak M. Don’t forget how severe varicella can be–complications of varicella in children in a defined Polish population. Int J Infect Dis. 2013;17:e485–e489.
20. Marshall HS, McIntyre P, Richmond P, et al. Changes in patterns of hospitalized children with varicella and of associated varicella genotypes after introduction of varicella vaccine in Australia. Pediatr Infect Dis J. 2013;32:530–537.
21. Science M, MacGregor D, Richardson SE, et al. Central nervous system complications of varicella-zoster virus. J Pediatr. 2014;165:779–785.
22. Bozzola E, Bozzola M, Tozzi AE, et al. Acute cerebellitis in varicella: a ten year case series and systematic review of the literature. Ital J Pediatr. 2014;40:57.
23. Driesen Y, Verweij M, De Maeseneer M, et al. Vascular complications of varicella: description of 4 cases and a review of literature. Pediatr Infect Dis J. 2015;34:1256–1259.
24. Britton PN, Khoury L, Booy R, et al. Encephalitis in Australian children: contemporary trends in hospitalisation. Arch Dis Child. 2016;101:51–56.
25. Leung J, Harpaz R. Impact of the maturing varicella vaccination
program on varicella and related outcomes in the United States: 1994–2012. J Pediatr Infect Dis Soc. 2015. Doi: 10.1093/jpids/piv044.
26. Chi CY, Wang SM, Lin HC, et al. Complications of varicella infection in children in southern Taiwan. J Microbiol Immunol Infect. 2006;39:402–407.
27. Tan B, Bettinger J, McConnell A, et al; Members of the Canadian Immunization Monitoring Program, Active (IMPACT). The effect of funded varicella immunization programs on varicella-related hospitalizations in IMPACT centers, Canada, 2000-2008. Pediatr Infect Dis J. 2012;31:956–963.
28. Pahud BA, Glaser CA, Dekker CL, et al. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine. J Infect Dis. 2011;203:316–323.
29. Frenos S, Galli L, Chiappini E, et al. An increasing incidence of chickenpox central nervous system complications in children: what’s happening in Tuscany? J Clin Virol. 2007;38:358–361.
30. Abdalrahman B, Laverty AA, Beckett G, Majeed A. Trends in hospital admission for varicella and zoster viruses in England, 2001/2002–2010/2011: time trend study. JRSM Open. 2015;6:1–6.
31. Dinleyici EC, Kurugol Z, Kara A, et al; VARICOMP Study Group. Children with breakthrough varicella infection requiring hospitalization in Turkey (VARICOMP Study 2008-2013). Vaccine. 2015;33:3983–3987.
32. Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clin Microbiol Rev. 2013;26:728–743.
varicella zoster virus; surveillance; complication; varicella vaccination
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