Severe chickenpox disease and seroprevalence in Sweden – implications for general vaccination

Open AccessPublished:August 08, 2021DOI:https://doi.org/10.1016/j.ijid.2021.08.012

      Highlights

      • The majority of hospitalized chickenpox patients had complications.
      • Half of all chickenpox complications was seen in previously healthy children.
      • Adult migrants had an increased risk of chickenpox hospitalization.
      • The varicella zoster IgG seroprevalence was 66.7% at 5 years and 91.5% at 12 years.

      Abstract

      Objectives: To describe the current panorama of severe chickenpox disease and seroprevalence in Sweden, as a basis for the approaching decision on universal vaccination.
      Methods: Patients discharged with an International Classification
      of Diseases 10th revision-code for chickenpox (B01-B01.9) in eight pediatric and infectious diseases departments in Stockholm and Gothenburg in 2012-2014 were included in the study and their medical charts were reviewed. Further, residual serum samples collected from 11 laboratories across Sweden were analyzed for varicella zoster IgG-antibodies to investigate age-specific seroprevalence.
      Results: A total of 218 children and 46 adults were included in this hospital-based study; 87.2% of children and 63.0% of adults had complications. An underlying condition was not associated with an increased risk of complication. Dehydration (31.7%), bacterial skin infections (29.8%) and neurological involvement (20.6%) were the most frequent complications in children. Among adult cases, 63% were born abroad. The seroepidemiological analysis included 957 patient samples. Seroprevalence was 66.7% at 5 years and 91.5% at 12 years. Infants and adolescents/adults were overrepresented among admitted patients compared to seroprevalence data.
      Conclusions: Half of all complications in hospitalized chickenpox cases were seen in previously healthy children, which supports universal childhood vaccination. Adult migrants was a risk group for chickenpox hospitalization. Age-specific seroprevalence was similar to neighboring countries.

      Keywords

      Background

      Chickenpox is the clinical manifestation of primary infection with varicella zoster virus (VZV) and a mild disease in the vast majority of cases. However, complications do occur, primarily bacterial infections of vesicles, sometimes with deeper infection and sepsis, as well as neurological complications (e.g. encephalitis, meningitis, or classically acute cerebellitis with ataxia). Rare complications such as pneumonitis, hepatitis and haemorrhagic complications may occur (
      • Gershon A
      • Marin M
      • Seward JF.
      Varicella Vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines.
      ). There is even an increased risk of stroke in the 6-month time period after a chickenpox episode (
      • Thomas SL
      • Minassian C
      • Ganesan V
      • Langan SM
      • Smeeth L.
      Chickenpox and risk of stroke: a self-controlled case series analysis.
      ). After primary infection, the virus establishes latency in nerve ganglia and can reactivate as shingles and/or neurological engagement (
      • Gershon A
      • Marin M
      • Seward JF.
      Varicella Vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines.
      ).
      Many countries worldwide, including 13 EU-countries (
      European Centre for Disease Prevention and Control
      Vaccine Schedules in the European Union.
      ,
      European Centre for Disease Prevention and Control
      ), have implemented universal chickenpox vaccination with a live attenuated vaccine. So far, Sweden has not. The epidemiology of chickenpox varies around the world (
      World Health Organization
      Varicella and herpes zoster vaccines: WHO position paper, June 2014.
      ). In countries without vaccination programs, the age of infection is dependent on social-mixing patterns in the youngest age groups (
      • Nardone A
      • de Ory F
      • Carton M
      • Cohen D
      • van Damme P
      • Davidkin I
      • et al.
      The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region.
      ). Before deciding on a national vaccination program, each country needs to assess it's own disease burden (European Centre for Disease Prevention and Control, 2014,
      World Health Organization
      Varicella and herpes zoster vaccines: WHO position paper, June 2014.
      ). Chickenpox hospitalization rates have previously been investigated using register data and were found to be relatively low in Sweden at 3.6/100,000 person-years (
      • Widgren K
      • Giesecke J
      • Lindquist L
      • Tegnell A.
      The burden of chickenpox disease in Sweden.
      ).
      This study aimed to increase the understanding of the current nature of severe chickenpox disease in Sweden. It examined the severity of symptoms, complications and underlying conditions of hospitalized chickenpox cases, from reviewing their medical charts. In addition, a seroepidemiological analysis was performed to assess the age of infection, and to put the extent and age distribution of severe disease into context. The entire study was carried out to inform the decision on a national vaccination program.

      Material and methods

       Chart reviews

       Study population and inclusion criteria

      During the acute stage, chickenpox is highly contagious and hospitalized patients need an isolation room. Thus, in the covered regions of Stockholm and Gothenburg (population 2.16 and 0.96 million, respectively) all admitted chickenpox cases had to be cared for in either of the following departments. In Stockholm: the Departments for Infectious Diseases at Karolinska University Hospital, Danderyd Hospital, Capio St Göran's Hospital, Södersjukhuset or the Pediatric Departments at Astrid Lindgren Children's Hospital and Sachs’ Children's Hospital. In Gothenburg: the Department for Infectious Diseases or the Pediatric Department at Queen Silvia Children's Hospital, both at Sahlgrenska University Hospital.
      This study included all patients with chickenpox admitted to any of the departments between 1 January 2012 and 31 December 2014. The hospital records of included patients were retrospectively identified by the International Statistical Classification of Diseases and Related Health Problems, 10th Revision-code (ICD-10 code) B01 Varicella, B01.0 Varicella meningitis, B01.1 Varicella encephalitis, B01.2 Varicella pneumonia, B01.8 Varicella with other specified complications, B01.9 Varicella without complication, either as the primary or secondary discharge diagnosis. The ICD-10 diagnosis was confirmed by reviewing the medical charts, and consistency was checked for with a primary VZV infection (i.e. description of a present or recent generalized rash). Patients with shingles, described as a local rash, were excluded. Cases aged >50 years without a rash but with VZV-related neurological complications were also excluded, as symptoms were assumed to be caused by virus reactivation. Ambiguous cases, as to whether the symptoms were due to primary infections or reactivations were excluded from the main analyses, but are described in the results section. These were patients either aged <50 years and without a rash or aged >50 years and with a generalized rash. Several of the hospitals received referrals of severely ill patients from other regions, and cases who were not resident in the catchment areas were also excluded in order not to skew results.

       Data collection

      A member of the study team (KW, LPB) manually examined each medical chart and collected relevant data in an EpiData questionnaire (EpiData Association, Odense, Denmark). Any ambiguity was discussed between team members to ensure similar procedures and coding. Data were collected on demography, medical history, epidemiology, outcome and complications. Neurological complications were classified as cranial nerve affection, encephalitis, aseptic meningitis, encephalopathy and cerebrovascular disease, according to previously published criteria (
      • Persson A
      • Bergstrom T
      • Lindh M
      • Namvar L
      • Studahl M.
      Varicella-zoster virus CNS disease–viral load, clinical manifestations and sequels.
      ), with widening of the encephalitis category to meningoencephalitis for those fulfilling both meningitis and encephalitis criteria. Dehydration was defined as a documented need of parenteral rehydration. There were duplicate records for patients who were moved between departments or admitted on several occasions during the same course of illness. One record was created for each patient, containing information on all relevant admissions; length of hospital stay was counted as total inpatient days.
      The case records in the database were matched to the Total population register at Statistics Sweden, using the cases’ personal identity number, and information on country of birth and municipality were added to the records. The complete database was subsequently anonymized and no personal identifiers were left when the statistical analyses were carried out.

       Data analysis

      A descriptive analysis of characteristics, complications and outcome was performed; stratified for children and adults defined as <18 years and ≥18 years, respectively. Continuous data were described in medians and ranges, as data were skewed, and compared where applicable with Wilcoxon/Mann-Whitney test, whereas categorical data were compared using χ²-test. Statistical analyses were carried out in Stata Statistical Software, Release 13 (StataCorp LP, TX, USA).

       Serology

      Over recent years, the Public Health Agency of Sweden has collected anonymized residual blood serum and plasma samples from clinical chemistry laboratories for influenza surveillance purposes (
      • Morner A
      • Brave A
      • Kling AM
      • Kuhlmann-Berenzon S
      • Krook K
      • Hedenskog M
      • et al.
      Pandemic influenza A(H1N1)pdm09 seroprevalence in Sweden before and after the pandemic and the vaccination campaign in 2009.
      ). Samples collected in 2011-2013 were post-hoc analyzed for varicella zoster-specific IgG antibodies using ELISA Enzygnost® Anti-VZV/IgG. Samples were obtained from eleven sites in nine regions across the country, primarily from primary care patients. Lower and upper cut-off values for the anti-VZV IgG were defined as 50 and 100 mIU/ml by the manufacturer, results in between were classified as equivocal and were recorded as positive, as suggested by deOry et al. (
      • de Ory F
      • Echevarria JM
      • Kafatos G
      • Anastassopoulou C
      • Andrews N
      • Backhouse J
      • et al.
      European seroepidemiology network 2: Standardisation of assays for seroepidemiology of varicella zoster virus.
      ).
      Based on seroepidemiological studies from other European countries (
      • Nardone A
      • de Ory F
      • Carton M
      • Cohen D
      • van Damme P
      • Davidkin I
      • et al.
      The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region.
      ) and a previous register-based study (
      • Widgren K
      • Giesecke J
      • Lindquist L
      • Tegnell A.
      The burden of chickenpox disease in Sweden.
      ), the peak incidence of chickenpox in Sweden was assumed to be at daycare age. Thus, samples from patients aged 0-5 years were selected. Samples from 12-13 year-olds were also analyzed, to compare with the few previous VZV serology studies in Sweden, showing the very high seroprevalence of 98% at this age (
      • Parment PA
      • Svahn A
      • Ruden U
      • Brakenhielm G
      • Storsaeter J
      • Akesson L
      • et al.
      Immunogenicity and reactogenicity of a single dose of live attenuated varicella vaccine and a booster dose of measles-mumps-rubella vaccine given concomitantly at 12 years of age.
      ,
      • Svahn A
      • Berggren J
      • Parke A
      • Storsaeter J
      • Thorstensson R
      • Linde A
      Changes in seroprevalence to four herpesviruses over 30 years in Swedish children aged 9-12 years.
      ). For each 1-year age group there were 99-137 residual samples; a comparable sample size was also used by the European Seroepidemiology Network (ESEN2) and considered adequate to assess age-specific seroprevalence (
      • Nardone A
      • de Ory F
      • Carton M
      • Cohen D
      • van Damme P
      • Davidkin I
      • et al.
      The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region.
      ). The mean seroprevalence was estimated with 95% confidence intervals by 1-year age groups.

       Ethical considerations

      For the chart reviews, permission was obtained from the Heads of Departments and Ethical approval from the Stockholm Regional Ethical Review Board Dnr 2015/588-31/4 and Dnr 2015/1119-32. A separate Ethical approval was obtained for the serological study, Dnr 2016/1050-32.

      Results

       Chart reviews

      A total of 362 records of 314 unique patients admitted to the selected departments with a chickenpox diagnosis during the study period were identified. After excluding cases who were exposed but without disease (n=2), given the wrong ICD-10 code (n=2), not residing in Sweden (n=6), explicitly described as shingles (n=12) or assumed reactivations (n=3), 289 cases remained for further analysis. Their records were matched to the register at Statistics Sweden; three patients could not be matched and 12 cases were from other regions, and excluded. Five cases had a generalized rash and were aged >50 years and five cases had no rash and were <50 years; these were judged as ambiguous and subsequently excluded from the main analyses, but will be described below. A total of 264 (84%) of the cases were included in the main analysis.

       Characteristics of cases and source of infection

      The median age of patients was 3.6 years (range: 0-49.5 years). There were 218 children (<18 years) and 46 adults (≥18 years). There was a male predominance among children, but not among adults. Basic demographic data are presented in Table 1. The vast majority of children were born in Sweden (98.2%), whereas 37.0% of adults were (n=17). The adult foreign-born cases were primarily from the Middle-East, Asia and Africa.
      Table 1Baseline characteristics and outcome of hospitalized chickenpox cases (n=274) in Stockholm and Gothenburg, Sweden, 2012-2014, for children, adults and ambiguous cases (as to whether they had primary or reactivated varicella zoster disease).
      Children, <18 yearsAdults, ≥18 yearsAmbiguous cases
      Baseline characteristics or outcomen=218 (%)n=46 (%)n=10 (%)
      Age groups, years
      0 years45 (20.6)
      1-4 years122 (56.0)
      5-12 years44 (20.2)
      13-17 years7 (3.2)1(10.0)
      ≥18 years46 (100.0)9 (90.0)
      Female91 (41.7)24 (52.2)6 (60.0)
      Birth country
      Sweden214 (98.2)17 (37.0)9 (90.0)
      Europe, not Sweden2 (0.9)5 (10.9)1 (10.0)
      Middle East1 (0.5)9 (19.5)
      Asia9 (19.5)
      South America1 (0.5)1 (2.2)
      Africa1 (0.5)5 (10.9)
      Underlying illness94 (43.1)27 (58.7)8 (80.0)
      Immunosuppressive treatment
      High-dose corticosteroids, current/previous chemotherapy, immunosuppressants.
      14 (6.4)4 (8.7)6 (60.0)
      Length of hospital stay, median days (range)3 (0-45)2 (0-13)5.5 (2-85)
      ≤1 day45 (20.6)16 (34.8)
      2-5 days116 (53.2)22 (47.8)5 (50.0)
      >5 days57 (26.2)8 (17.4)5 (50.0)
      Time from disease onset to admission, median days (range)4 (-6-21)2.5 (-1-33)4 (0-8)
      Any complication190 (87.2)29 (63.0)10 (100.0)
      Time from complication to admission, median days (range)0 (-3-12) n=1820 (-4-4) n=260.5 (-6-5)
      Intensive care treatment7 (3.2)1 (2.2)1 (10.0)
      Antiviral treatment65 (29.8)42 (91.3)10 (100.0)
      Lumbar puncture32 (14.7)5 (10.9)5 (50.0)
      ≥5 cells11 (34.4)1 (20.0)5 (100)
      VZV DNA-PCR positive6 (19.4) n=310 (0)5 (100)
      low asterisk High-dose corticosteroids, current/previous chemotherapy, immunosuppressants.
      Underlying illness was reported in 43.1% of children and 58.7% of adults, and six patients (25% of adult women) were pregnant. Asthma, neurological disease and allergies/eczema were most prevalent among both children and adults. A reported 6.8% were on medical treatment affecting the immune system (Table 2). Twenty-one records held information on vaccination status; two reported previous chickenpox vaccination. Data on smoking were collected, but information was missing in about half of adult case charts and was not analyzed further.
      Table 2Underlying conditions among hospitalized child and adult chickenpox cases (n=264) in Stockholm and Gothenburg, Sweden, 2012-2014.
      Children, <18 yearsAdults, ≥18 years
      Underlying conditionn=218 (%)n=46 (%)
      Any underlying condition (incl. pregnancy)94 (43.1)31 (67.4)
      Any underlying illness94 (43.1)27 (58.7)
      Asthma/obstructiveness36 (16.5)5 (10.9)
      Other respiratory disease3 (1.4)4 (8.7)
      Allergy and eczema17 (7.8)4 (8.7)
      Neurological disease17 (7.8)4 (8.7)
      Mb Down/chromosomal variations4 (1.8)2 (4.4)
      ADHD/autism2 (0.9)2 (4.4)
      Cardiac disease or hypertension7 (3.2)2 (4.4)
      Rheumatological disease4 (1.8)3 (6.5)
      Other autoimmune disease, including hypothyroidism5 (2.3)3 (6.5)
      Hematological malignancy (current or previous)5 (2.3)0 (0)
      Tumour (current)1 (0.5)1 (2.2)
      Allogen/autologous stem cell transplant1 (0.5)0 (0)
      Organ transplant2 (0.9)1 (2.2)
      Immune deficiency (treatment or disease)0 (0)1 (2.2)
      Metabolic disease4 (1.8)0 (0)
      Diabetes type 1 or 22 (0.9)2 (4.4)
      Ongoing pregnancy (% of females)0 (0)6 (25.0)
      Other17 (7.8)7 (15.2)
      In 153 case records, there was information on any recent exposure to another case of VZV disease: there was a household contact in 57.5% of these and 86 of 88 contacts had chickenpox. In addition, 26.1% had a close VZV contact outside the household (i.e. in the same daycare), 39 of 40 were a chickenpox case.

       Complications, antiviral treatment and sequelae

      Complications are presented in Table 3. Dehydration was most common, mainly due to the mucosa of the mouth being heavily affected by vesicles. Neurological complications affected 49 cases (18.6%), 26 of them had lumbar punctures: 11 (42.3%) with pleocytosis in the cerebrospinal fluid (CSF). Of 25 VZV DNA-PCR analyses performed on CSF samples, six (24.0%) were positive; two in patients without pleocytosis. An additional 11 patients, either critically ill or with mainly headache and/or irritability but not fulfilling criteria for encephalopathy or meningitis, also had a lumbar puncture: one with pleocytosis, but none with positive VZV DNA-PCR in CSF. All patients (n=15) with meningitis, meningoencephalitis, encephalopathy or cranial nerve paralysis, and all patients aged >35 years received antiviral therapy.
      Table 3Complications among hospitalized child and adult chickenpox cases (n=264) in Stockholm and Gothenburg, 2012-2014. Some patients suffered from more than one complication and were included in more than one group.
      ChildrenAdults
      Complicationn=218 (%)n=46 (%)
      Any complication190 (87.2)29 (63.0)
      Any complication, excl dehydration alone180 (82.6)24 (52.2)
      Septicemia5 (2.3)1 (2.2)
      Skin65 (29.8)5 (10.9)
      Skin infection54 (24.8)5 (10.9)
      Cellulitis24 (11.0)0 (0)
      Neurological45 (20.6)4 (8.7)
      Encephalopathy4 (1.8)2 (4.4)
      Meningitis2 (0.9)0 (0)
      Meningoencephalitis6 (2.8)0 (0)
      Cerebellitis15 (6.9)1 (2.2)
      Cranial nerve affection1 (0.5)0 (0)
      Febrile seizures22 (10.1)0 (0)
      Seizures without fever2 (0.9)0 (0)
      Cerebrovascular disease1 (0.5)1 (2.2)
      Respiratory30 (13.8)5 (10.9)
      Pneumonia (bacterial)17 (7.8)2 (4.4)
      Pneumonitis (viral)5 (2.3)4 (8.7)
      Bronchitis10 (4.6)1 (2.2)
      Gastrointestinal (GI)28 (12.8)6 (13.0)
      Gastroenteritis/GI-symptoms26 (11.9)3 (6.5)
      Hepatitis, including elevated transaminases3 (1.4)3 (6.5)
      Coagulopathy11 (5.1)0 (0)
      Eye involvement6 (2.8)1 (2.2)
      Otitis8 (3.7)0 (0)
      Dehydration69 (31.7)9 (19.6)
      Other56 (25.7)11 (23.9)
      Sixty-seven cases had symptoms grouped as other complications: these were primarily localized bacterial infections such as tonsillitis and lymphadenitis, or vague or transient neurological symptoms that did not fulfill the criteria for any of the specified neurological complications.
      There were no deaths among cases in the main analysis during inpatient care. Eight (3.0%) of the patients were admitted to an intensive care unit (ICU). Five previously healthy children were in ICU due to organ failure related to sepsis, four recovered, while one was left with severe sequelae and subsequently diagnosed with a critical immunodeficiency. Two children with underlying neurological disease and previous seizures were in ICU for observation, and recovered. One adult patient with underlying autoimmune disease was also treated in ICU. Additionally, four cases who were hospitalized during the acute stage of the disease with complicated but not severe illness suffered sequelae with unknown correlation to the infection: two children had delayed motor or psychosocial development, one case suffered a subdural hematoma 3 months after infection, and one developed an attention and hyperactivity disorder.

       Risk factors for complications

      Children had more complications than adults (87.2% and 63.0%, p<0.001) (Figure 1). There was no significant difference as to whether children with or without underlying conditions developed complications (84.0% and 89.5%, p=0.23). In fact, 58.4% of pediatric complications were seen in previously healthy children. For adults, complications were seen in 61.3% of cases with an underlying condition and 66.7% without (p=0.72). The risk of complications was not higher in pregnant women compared to other admitted adult cases (33.3% and 67.5%, p=0.11). There was no significant difference in the length of hospital stay between those with and without underlying conditions, but between those with and without complications (median 3 and 2 days, respectively, p=0.02). It was found that 56.1% of patients had either an underlying condition or a complication, 37.1% had both and 6.8% had neither.
      Figure 1
      Figure 1Percentage of hospitalized chickenpox cases in Stockholm and Gothenburg in 2012-2014 (n=264) with an underlying illness or pregnancy, any complication, and complication excluding dehydration alone, according to age.

       Data quality

      At discharge, 35.2% of cases had an ICD-10 code for chickenpox with complication (B01.0-B01.8). Compared to the information in the medical charts, an ICD-10 diagnosis of complicated chickenpox had a sensitivity of 41.1% and a specificity of 93.3%. An additional ICD-10 code was given in 67.4% of all charts, either representing a complication or underlying condition. This coding was not consistent with the information in the medical charts.

       Ambiguous cases

      Five patients aged ≥50 years had a generalized varicella rash; all had an autoimmune disease and/or were on immunosuppressants. All were born in Sweden or high-endemic European countries (Table 1). Five patients aged <50 years (range: 17-43 years) had no rash and presented with neurological symptoms with pleocytosis and positive VZV DNA-PCR in CSF; all were born in Sweden, two were immunosuppressed and three were previously healthy (Table 1). Contrary to adolescents/adults included in the main analysis with a generalized rash and neurological symptoms, they had no recent VZV exposure. These ten patients were classified as ambiguous as to whether they suffered primary infection or reactivations, according to the definition above.

       Serology

      A total of 957 samples collected during 2011-2013 were analyzed. Figure 2 presents the seroprevalence per 1-year age group in children aged 0-5 and 12-13 years. In the first months of life, seroprevalence was almost 100% due to circulating maternal antibodies, which waned to a nadir at the age of 6-9 months. This gave a mean seroprevalence of 45% for 0 year-olds. Among 5-year-olds, the seroprevalence had reached 66.7% and by the age of 12 years, it was 91.5%. The seroprevalence was overall higher for girls than for boys (OR 1.6, 95% CI 1.26-2.11) but this difference decreased after adjustment for age, year of sampling and region (OR 1.38, 95% CI 1.01-1.88).
      Figure 2
      Figure 2Varicella zoster virus seroprevalence by 1-year age groups in children aged 0-5 and 12-13 years. Residual samples (n=957) from clinical chemistry laboratories were analyzed for Varicella zoster virus IgG-antibodies (ELISA Enzygnost®) in Sweden, 2011-2013.

       Comparison of seroprevalence and hospitalizations

      The seroepidemiological results suggest a median age for acquisition of antibodies of around 4 years, which corresponds well with the median age of admission at 3.6 years. Of the sampled 1-year-olds, 16.1% were seropositive, whereas 17.2% of the admitted cases were 0 years and 15.2% were 1 year. By the age of 12 years, 8.5% of sampled children were still seronegative, but 20.1% of the admitted cases were above this age.

      Discussion

      This study described complications and underlying conditions of children and adults hospitalized with chickenpox in 2012-2014 in Stockholm and Gothenburg, Sweden, a country without routine chickenpox vaccination. No deaths among the 264 hospitalized cases were found but a few cases were either critically ill during the acute illness or developed severe sequelae. Half of all complications were seen in previously healthy children. The serology analysis showed a steep rise in VZV seroprevalence with increasing age during daycare years. Infants and adolescents/adults were overrepresented among admitted cases compared to seroprevalence data.
      In-depth clinical information on all hospitalized cases were available and could be compared to the ICD-10 coding, which was both a major strength and limitation of this study. When collecting information on underlying risk factors and complications, it became evident that the coding of these were lacking in detail. Nonetheless, the coding of disease category seemed fair. All cases with an ICD-10 code for chickenpox (B01-B01.9) at the time of discharge as either the primary or secondary diagnosis were included. Fourteen records (4.5%) had to be removed as they were evidently given the wrong ICD-10 code: 12 should have been given a shingles ICD-10 code (B02). However, the sensitivity and to what extent primary varicella infections and its complications failed to be included were not assessed. It was assumed that some patients with late-onset complications and a few patients who were deemed non-contagious and cared for in other departments were missed.
      It cannot be ruled out that there was some cross-reactivity against Herpes simplex virus glycoprotein B in the serological analyses (
      • Bernstein DI
      • Frenkel LM
      • Bryson YJ
      • Myers MG.
      Antibody response to herpes simplex virus glycoproteins gB and gD.
      ,
      • Edson CM
      • Hosler BA
      • Respess RA
      • Waters DJ
      • Thorley-Lawson DA.
      Cross-reactivity between herpes simplex virus glycoprotein B and a 63,000-dalton varicella-zoster virus envelope glycoprotein.
      ,
      • Kitamura K
      • Namazue J
      • Campo-Vera H
      • Ogino T
      • Yamanishi K.
      Induction of neutralizing antibody against varicella-zoster virus (VZV) by VZV gp3 and cross-reactivity between VZV gp3 and herpes simplex viruses gB.
      ). However, a widely accepted commercial assay with high specificity and sensitivity was used (
      • Sauerbrei A
      • Schafler A
      • Hofmann J
      • Schacke M
      • Gruhn B
      • Wutzler P.
      Evaluation of three commercial varicella-zoster virus IgG enzyme-linked immunosorbent assays in comparison to the fluorescent-antibody-to-membrane-antigen test.
      ) and the results of this study were compared against data from sero-surveys where the same limitations applied (
      • Nardone A
      • de Ory F
      • Carton M
      • Cohen D
      • van Damme P
      • Davidkin I
      • et al.
      The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region.
      ). HSV1 seroprevalence reached >20% in the first few years of life (
      • Tunback P
      • Bergstrom T
      • Andersson AS
      • Nordin P
      • Krantz I
      • Lowhagen GB.
      Prevalence of herpes simplex virus antibodies in childhood and adolescence: a cross-sectional study.
      ,
      • Tunback P
      • Bergstrom T
      • Claesson BA
      • Carlsson RM
      • Lowhagen GB.
      Early acquisition of herpes simplex virus type 1 antibodies in children–a longitudinal serological study.
      ) and 37-38% by early teenage years (
      • Svahn A
      • Berggren J
      • Parke A
      • Storsaeter J
      • Thorstensson R
      • Linde A
      Changes in seroprevalence to four herpesviruses over 30 years in Swedish children aged 9-12 years.
      ,
      • Tunback P
      • Bergstrom T
      • Andersson AS
      • Nordin P
      • Krantz I
      • Lowhagen GB.
      Prevalence of herpes simplex virus antibodies in childhood and adolescence: a cross-sectional study.
      ) in previous Swedish studies. The majority of cases had varicella-related complications and half of the cases had underlying conditions. However, there was no correlation between underlying conditions and complications in either children or adults. This could partly be due to early antiviral treatment of at-risk patients successfully preventing complications. This could also be an artefact due to a lower threshold for children with underlying conditions seeking medical attention and for them being admitted out of concern for complicated disease. Presumably, the same is true for adult cases in general and those with underlying conditions in particular. In fact, the majority of complications in children were seen in previously healthy individuals, as described in other studies ((
      • Helmuth IG
      • Poulsen A
      • Molbak K.
      A national register-based study of paediatric varicella hospitalizations in Denmark 2010-2016.
      ), ,
      • Liese JG
      • Grote V
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      • Fischer R
      • Belohradsky BH
      • v Kries R
      • et al.
      The burden of varicella complications before the introduction of routine varicella vaccination in Germany.
      ), supporting the introduction of general chickenpox vaccination in childhood.
      The later onset of disease in tropical countries leads to a larger seronegative proportion among adult populations than in countries with temperate climates. As the risk of severe disease is higher with infection later in life, migration from a low-endemic country is a potential risk factor for severe disease. Nearly two-thirds of adult cases were born outside of Sweden; the corresponding figure for the entire Stockholm and Gothenburg adult population was 23% in 2013, meaning that adult migrants were heavily overrepresented in this study. In particular, cases with African and South-East Asian descent were overrepresented, which is compatible with the epidemiology in these regions (
      • Al-Turab M
      • Chehadeh W.
      Varicella infection in the Middle East: Prevalence, complications, and vaccination.
      ,
      • Arlant LHF
      • Garcia MCP
      • Avila Aguero ML
      • Cashat M
      • Parellada CI
      • Wolfson LJ
      Burden of varicella in Latin America and the Caribbean: findings from a systematic literature review.
      ,
      • Goh AEN
      • Choi EH
      • Chokephaibulkit K
      • Choudhury J
      • Kuter B
      • Lee PI
      • et al.
      Burden of varicella in the Asia-Pacific region: a systematic literature review.
      ,
      • Hussey H
      • Abdullahi L
      • Collins J
      • Muloiwa R
      • Hussey G
      • Kagina B.
      Varicella zoster virus-associated morbidity and mortality in Africa - a systematic review.
      ) and findings from other studies covering migrants in Europe (
      • Toikkanen SE
      • Baillot A
      • Dreesman J
      • Mertens E.
      Seroprevalence of Antibodies against Measles, Rubella and Varicella among Asylum Seekers Arriving in Lower Saxony, Germany, November 2014-October 2015.
      ,
      • van Rijckevorsel GG
      • Damen M
      • Sonder GJ
      • van der Loeff MF
      • van den Hoek A.
      Seroprevalence of varicella-zoster virus and predictors for seronegativity in the Amsterdam adult population.
      ).
      The proportion of cases with a complication described with a varicella ICD-10 code was comparable to other register-based studies (
      • Bernal JL
      • Hobbelen P
      • Amirthalingam G.
      Burden of varicella complications in secondary care, England, 2004 to 2017.
      ,
      • Mirinaviciute G
      • Kristensen E
      • Nakstad B
      • Flem E
      Varicella-related Primary Health-care Visits, Hospitalizations and Mortality in Norway, 2008-2014.
      ), whereas the proportion of cases with a documented complication in the medical chart was considerably higher, in parity with other hospital-based studies (
      • Blumental S
      • Sabbe M
      • Lepage P
      Belgian Group for V. Varicella paediatric hospitalisations in Belgium: a 1-year national survey.
      ,
      • Glode Helmuth I
      • Broccia MD
      • Glenthoj JP
      • Harder K
      • Jensen L
      • von Linstow ML
      • et al.
      Children Hospitalized With Varicella in Denmark: Sensitivity of the National Patient Register.
      , ,
      • Liese JG
      • Grote V
      • Rosenfeld E
      • Fischer R
      • Belohradsky BH
      • v Kries R
      • et al.
      The burden of varicella complications before the introduction of routine varicella vaccination in Germany.
      ,
      • van Lier A
      • van der Maas NA
      • Rodenburg GD
      • Sanders EA
      • de Melker HE.
      Hospitalization due to varicella in the Netherlands.
      ). The range of complications seen in the children in the current study was similar to other hospital-based studies, although comparability was limited due to different study designs, definitions and the fact that many studies were carried out over a decade ago. The most frequently documented complication, and the single complication in a few cases, was dehydration. It was rarely presented or attributed a lower frequency in other studies (
      • Blumental S
      • Sabbe M
      • Lepage P
      Belgian Group for V. Varicella paediatric hospitalisations in Belgium: a 1-year national survey.
      ,
      • van Lier A
      • van der Maas NA
      • Rodenburg GD
      • Sanders EA
      • de Melker HE.
      Hospitalization due to varicella in the Netherlands.
      ). After dehydration, secondary bacterial skin infections were the most common complications among children (29.3%). A review of varicella disease from 2015 showed this to be the most common complication of admitted children with chickenpox in Europe (
      • Helmuth IG
      • Poulsen A
      • Suppli CH
      • Molbak K.
      Varicella in Europe-A review of the epidemiology and experience with vaccination.
      ). The frequency varies across studies; the current level is on the lower end of the spectrum (
      • Blumental S
      • Sabbe M
      • Lepage P
      Belgian Group for V. Varicella paediatric hospitalisations in Belgium: a 1-year national survey.
      ,
      • Bonhoeffer J
      • Baer G
      • Muehleisen B
      • Aebi C
      • Nadal D
      • Schaad UB
      • et al.
      Prospective surveillance of hospitalisations associated with varicella-zoster virus infections in children and adolescents.
      ,
      • Dubos F
      • Grandbastien B
      • Hue V
      Hospital Network for Evaluating Management of Common Childhood D, Martinot A. Epidemiology of hospital admissions for paediatric varicella infections: a one-year prospective survey in the pre-vaccine era.
      ,
      • Glode Helmuth I
      • Broccia MD
      • Glenthoj JP
      • Harder K
      • Jensen L
      • von Linstow ML
      • et al.
      Children Hospitalized With Varicella in Denmark: Sensitivity of the National Patient Register.
      ), previously explained by good availability to primary care (
      • Glode Helmuth I
      • Broccia MD
      • Glenthoj JP
      • Harder K
      • Jensen L
      • von Linstow ML
      • et al.
      Children Hospitalized With Varicella in Denmark: Sensitivity of the National Patient Register.
      ,
      • Liese JG
      • Grote V
      • Rosenfeld E
      • Fischer R
      • Belohradsky BH
      • v Kries R
      • et al.
      The burden of varicella complications before the introduction of routine varicella vaccination in Germany.
      ). Neurological complications, mainly cerebellitis and febrile seizures, were seen in a fifth of admitted children, consistent with other European studies (
      • Helmuth IG
      • Poulsen A
      • Suppli CH
      • Molbak K.
      Varicella in Europe-A review of the epidemiology and experience with vaccination.
      ). A quarter of patients presenting with neurological complications exhibited PCR positivity in CSF; others have found similarly low frequencies of PCR positivity among chickenpox cases with neurological complications (
      • Koskiniemi M
      • Piiparinen H
      • Rantalaiho T
      • Eranko P
      • Farkkila M
      • Raiha K
      • et al.
      Acute central nervous system complications in varicella zoster virus infections.
      ,
      • Science M
      • MacGregor D
      • Richardson SE
      • Mahant S
      • Tran D
      • Bitnun A.
      Central nervous system complications of varicella-zoster virus.
      ).
      The complications of adult primary varicella infection are less well-described in the literature and often presented with reactivated disease (
      • Bernal JL
      • Hobbelen P
      • Amirthalingam G.
      Burden of varicella complications in secondary care, England, 2004 to 2017.
      ). As shown in this study, the distinction is not always evident. The current adult cases had less frequent complications than the children. However, it should be born in mind that they represented a larger proportion of all incident adult cases, that is: the proportion with complication was likely to be high compared with that in children.
      This study made a-priori definitions for how to identify ambiguous cases, as to whether they had primary infection or reactivation. The suspicion that they suffered from reactivated disease was corroborated by their risk factors (i.e. they were largely born in high-endemic countries, had no recent VZV exposure and were immunosuppressed); thus, it is believed that these restrictions were fair. There will be differences in risk factors and complications between primary VZV infections and reactivations. This study attempted to disentangle them, to give a better representation of primary disease for the assessment of a possible impact of chickenpox vaccination. However, in the long-term, reactivations will also be prevented by chickenpox vaccine, since the live attenuated vaccine strain appears less prone to reactivations than wild-type virus (
      • Breuer J.
      Molecular Genetic Insights Into Varicella Zoster Virus (VZV), the vOka Vaccine Strain, and the Pathogenesis of Latency and Reactivation.
      ,
      • Civen R
      • Marin M
      • Zhang J
      • Abraham A
      • Harpaz R
      • Mascola L
      • et al.
      Update on Incidence of Herpes Zoster Among Children and Adolescents After Implementation of Varicella Vaccination, Antelope Valley, CA, 2000 to 2010.
      ,
      • Weinmann S
      • Chun C
      • Schmid DS
      • Roberts M
      • Vandermeer M
      • Riedlinger K
      • et al.
      Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005-2009.
      ).
      The second part of this study concerned varicella seroprevalence, which has not been studied in Sweden for two decades. During 2011-2013, age-specific seroprevalence was found to be comparable to those of other northern European countries, mainly Finland and Norway (
      • Del Fava E
      • Rimseliene G
      • Flem E
      • Freiesleben de Blasio B
      • Scalia Tomba G
      • Manfredi P
      Estimating Age-Specific Immunity and Force of Infection of Varicella Zoster Virus in Norway Using Mixture Models.
      ,
      • Nardone A
      • de Ory F
      • Carton M
      • Cohen D
      • van Damme P
      • Davidkin I
      • et al.
      The comparative sero-epidemiology of varicella zoster virus in 11 countries in the European region.
      ), with similar daycare habits and social-mixing patterns as Sweden. During the first years of life, when children are exposed to the virus through other children, a steep rise in seropositivity was seen and two-thirds of the children had contracted the disease by 5 years. By twelve years, the seroprevalence was 91.5%, which was slightly lower than the 98% reported in previous Swedish studies from the late 1990s (
      • Parment PA
      • Svahn A
      • Ruden U
      • Brakenhielm G
      • Storsaeter J
      • Akesson L
      • et al.
      Immunogenicity and reactogenicity of a single dose of live attenuated varicella vaccine and a booster dose of measles-mumps-rubella vaccine given concomitantly at 12 years of age.
      ,
      • Svahn A
      • Berggren J
      • Parke A
      • Storsaeter J
      • Thorstensson R
      • Linde A
      Changes in seroprevalence to four herpesviruses over 30 years in Swedish children aged 9-12 years.
      ). Reasons for this decrease in seroprevalence could be chance or migration from low-endemic areas. It is not believed that this could be explained by vaccination and subsequent delayed age of infection for unvaccinated individuals, as the chickenpox vaccination at own-cost was increasing but still quite low in 2010-2014 in Sweden. Although, the median ages for seroconversion and admission were similar, the proportion of admissions among incident cases was higher for infants, adolescents and adults. These are indeed well-known risk groups for severe disease (
      • Gershon A
      • Marin M
      • Seward JF.
      Varicella Vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines.
      ).
      A small gender difference in seroprevalence was found, with lower levels for boys than girls. Such gender difference in VZV seroprevalence has also been described from the Netherlands (
      • de Melker H
      • Berbers G
      • Hahne S
      • Rumke H
      • van den Hof S
      • de Wit A
      • et al.
      The epidemiology of varicella and herpes zoster in The Netherlands: implications for varicella zoster virus vaccination.
      ) and France (
      • Khoshnood B
      • Debruyne M
      • Lancon F
      • Emery C
      • Fagnani F
      • Durand I
      • et al.
      Seroprevalence of varicella in the French population.
      ), but has not been found in other European countries (
      • Gabutti G
      • Rota MC
      • Guido M
      • De Donno A
      • Bella A
      • Ciofi degli Atti ML
      • et al.
      The epidemiology of Varicella Zoster Virus infection in Italy.
      ,
      • Manikkavasagan G
      • Dezateux C
      • Wade A
      • Bedford H.
      The epidemiology of chickenpox in UK 5-year olds: an analysis to inform vaccine policy.
      ). Females tend to have stronger innate and adaptive immune responses against both infections and vaccines (
      • Ghosh S
      • Klein RS.
      Sex Drives Dimorphic Immune Responses to Viral Infections.
      ,
      • Klein SL
      • Flanagan KL.
      Sex differences in immune responses.
      ,
      • Poland GA
      • Ovsyannikova IG
      • Kennedy RB.
      Personalized vaccinology: A review.
      ).

      Conclusions

      The majority of complications from chickenpox in children were seen in those who were previously healthy, showing that vaccination of at-risk groups or cocoon vaccination around vulnerable children will not prevent the majority of severe chickenpox cases. This strengthens the argument for universal chickenpox vaccination in Sweden. The findings also support vaccination of adolescents without a history of chickenpox and migrants from low-endemic countries, both groups overrepresented among admitted cases. However, the epidemiology of chickenpox is not the only aspect to consider when introducing a vaccination program; a lot is still unknown regarding the duration of protection and the impact on shingles incidence from chickenpox vaccination, with regards to reactivation of vaccine-strain virus and reduction of exogenous boosting. (
      European Centre for Disease Prevention and Control
      ).

      Funding Source

      None.

      Ethical Approval statement

      For the chart reviews, permission was obtained from the Heads of Departments and Ethical approval from the Stockholm Regional Ethical Review Board Dnr 2015/588-31/4 and Dnr 2015/1119-32. A separate Ethical approval was obtained for the serological study, Dnr 2016/1050-32.

      Conflict of Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We would like to thank Eva Hansson-Pilhainen, Teodora Aktas, Lena Wehlin and Margaretha Ljungman, current and former colleagues at the Department for Microbiology at the Public Health Agency of Sweden. We would also like to thank David Björnheden at Queen Silvia Children's Hospital, Sahlgrenska University Hospital for assisting in the screening of medical charts in Gothenburg.

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