Surveillance of varicella-associated paediatric hospitalisations and complications in Switzerland from 2021 to 2023

DOI: https://doi.org/https://doi.org/10.57187/s.3872

Introduction

Varicella zoster virus (VZV) infection is a well-known and highly infectious childhood disease. Primary infection causes chickenpox, clinically presenting as a characteristic pruritic rash with macular, papular, vesicular and crusted skin lesions which may appear simultaneously. After primary infection, VZV persists lifelong in sensory nerve ganglia and when reactivated presents as shingles, with a characteristic dermatomal distribution, also known as herpes zoster [1]. Most people think of varicella as a benign childhood disease. However, worldwide, numerous studies have demonstrated a relevant amount of morbidity including bacterial and neurological complications leading to hospitalisation in children with or without underlying chronic conditions [2–5].

In Switzerland, the last prospective surveillance study on VZV-associated hospitalisations of children was conducted during a 3-year period from 2000 to 2003 and included 335 cases and a hospitalisation rate of 13 per 10,000. The median age of patients was 3.5 years. Secondary bacterial infections, central nervous system involvement and pneumonitis were the most common complications. Overall, 319 complications were recorded. Intensive care unit (ICU) treatment was documented in 11 (3%) patients, 12 (4%) experienced sequelae and 3 died [6].

Since January 2023, the Federal Office of Public Health (FOPH) has recommended universal varicella vaccination (UVV) for infants. The preferred immunisation is a quadrivalent measles, mumps, rubella and varicella (MMRV) vaccine with the first dose administered at 9 months and the second dose at 12 months of age. The FOPH also recommend a catch-up vaccination for all individuals 1–40 years of age who have not had varicella or two varicella vaccinations yet [7]. In addition, the FOPH and the Federal Commission for Vaccination (EKIF) have recommended vaccination against herpes zoster with the adjuvanted subunit vaccine Shingrix^® since 2021. This is for healthy people aged ≥65 years, patients with immunodeficiency aged ≥50 years and patients with severe immunodeficiency aged ≥18 years [8].

The aim of this study was to assess the burden of VZV-associated hospitalisations and complications in children (0–16 years) over a 2-year period from 2021 to 2023 in Switzerland. This will allow future evaluation of the impact of universal varicella vaccination in Switzerland.

Methods

Study design

We are conducting an observational, prospective surveillance study, which started in July 2021 and is planned to continue until June 2027, on reported VZV hospitalisations in children by use of the Swiss Paediatric Surveillance Unit (SPSU) in Switzerland to assess VZV-associated disease burden in hospitalised children aged 0–16 years prior to the introduction of universal varicella vaccination in Switzerland. All 29 Swiss paediatric clinics are members of the Swiss Paediatric Surveillance Unit, participate in the study and report their cases monthly to the Swiss Paediatric Surveillance Unit [9]. This current analysis refers to the initial 2-year period (July 2021 to June 2023) without a follow-up.

The study protocol was prepared by authors MB and UH and approved by the Ethics Committee Northwestern and Central Switzerland (EKNZ) (project number: 2021-00211). It can be accessed by contacting the corresponding author (MB). According to article 34 a of the HFG (swissethics.ch), the need for individual consent was waived by the Ethics Committee.

Case definition

Hospitalised children and adolescents aged ≤16 years (in the text described as “children”) with clinical manifestations of VZV infection (ICD-10: B01.-), i.e. varicella or herpes zoster.

Study population

All children who meet the case definition regardless of underlying chronic conditions or other comorbidities are eligible for reporting. Patients with VZV infection who were primarily hospitalised for a different diagnosis were also included. After reporting a case to the Swiss Paediatric Surveillance Unit, the centres receive an anonymised questionnaire (Supplementary 1. Appendix Questionnaire). Questionnaire data are collected in a central database (secuTrial^®), set up by the clinical trial unit (CTU) of Cantonal Hospital Lucerne. MB, UH and the database managers are the only individuals who had access. Data cleaning was performed by MB and NS. Missing data were correctly addressed and considered as missing or unknown.

With regards to VZV-associated stroke cases, reports via Swiss Paediatric Surveillance Unit were supplemented by a second source of information, the Swiss Neuropaediatric Stroke Registry (SNSR) (https://snpsr.neuropaediatrie.ch/). To record and describe the epidemiological situation in Switzerland, place of residence (Switzerland or Not-Switzerland) was recorded, not patient’s race or ethnicity. Analyses were performed for three subgroups, primary healthy patients, immunocompromised patients and patients with underlying disease other than immunodeficiency. The quantitative variable age was assigned to four age categories. The categories were chosen by analogy with similar studies from other countries to ensure comparability [3–6, 10–23]. Other quantitative variables were not further categorised.

Statistical analysis

Statistical analysis was performed with IBM SPSS Statistics 29.0.1.0 (171). We used data editor functions, prepared and cleaned data and performed data transformation with arithmetic and statistical functions (mean, median, range). The functions are described in chapters 5, 7 and 8 of “IBM SPSS Statistics 29 Core System User’s Guide” [24]. For the incidence calculation, population data were adopted from the Federal Office of Statistics [25]. We extracted age-specific numbers of inhabitants from population figures for 2021 and 2022 in Switzerland for the calculation of mean age. For the estimated number of varicella cases per year, we used varicella incidence numbers from a systematic review on estimated age-specific seroprevalence and annual varicella incidence per 100,000 in Switzerland and extrapolated this data to the mean inhabitants stated above [16]. This resulted in an estimated number of 85,398 varicella cases per year. We calculated an annual hospitalisation incidence per 100,000 inhabitants by using the calculation path (# hospitalised patients / # inhabitants) × 100,000 where # hospitalised patients was the mean age-specific number of hospitalised varicella patients with a residence in Switzerland during the 2-year study period, yielding a figure of (108 / 1,493,157) × 100,000 = 7.2 per 100,000. The calculation of the annual hospitalisation rate per 10,000 varicella patients was (# hospitalised patients / estimated # varicella cases per year) × 10,000 or (108 / 85,398) × 10,000 = 12.6 per 10,000 varicella patients. The definition for # hospitalised patients remained the same. The varicella hospitalisation incidence refers to Swiss residents aged 0 to 16 years while the annual hospitalisation rate refers to the estimated varicella cases per year. For further illustration, see table 1. 

Tools

ChatGPT 3.5 (Version 10.01.2024) was used to improve scientific English in the discussion section. We used the prompt Please improve the text in respect to the scientific language but keep the contents. The text output was revised and corrected by the authors regarding the accuracy of content. We used the STROBE cohort reporting checklist guidelines before paper submission [26].

Results

During the 2-year study period, 239 hospitalised patients were reported (237 only to the Swiss Paediatric Surveillance Unit, 1 only to the Swiss Neuropaediatric Stroke Registry and 1 to both surveillance systems). Varicella was the primary admission reason for more than two thirds of all varicella patients. For only a few patients, a different diagnosis was the primary reason for their hospital admission: pneumopathy (n = 6), epilepsy (n = 2), neuroblastoma (n = 1), perforated appendicitis (n = 1), renal failure (n = 1), syndrome of inappropriate antidiuretic hormone secretion (SIADH) (n = 1) and a new diagnosis of dilated cardiomyopathy (n = 1). All herpes zoster patients were hospitalised due to their clinical herpes zoster presentation.

Immunocompromised patients were defined as patients with primary immunodeficiency or under immunosuppressive therapy and possible other chronic disease. Underlying chronic diseases were skin disorders, cancer or leukaemia, genetic syndromes, cardiovascular diseases, HIV, inflammatory bowel disease, congenital neurological disorder, lung disorder, nephrotic syndrome, epilepsy, vasculitis, sickle cell disease and haemolytic anaemia. Skin disorders, cancer or leukaemia, genetic syndromes and cardiovascular diseases were most common over the 2-year study period. There were no significant differences between the two years of observation in the distribution of the underlying chronic diseases. Figure 1 shows that less than one fifth (40/239) of all hospitalised patients had any underlying chronic disease including immunodeficiency. Only 5 (2%) of all immunocompromised patients had no underlying chronic disease other than their immunodeficiency.

Figure 1Study flow chart of varicella zoster virus (VZV)-associated hospitalisations. Underlying chronic disease: excluding immunocompromised host who are presented separately in the figure. Group 1: no complications. Group 2: with complications. Other diagnosis: varicella was not primary reason for hospitalisation. All patients hospitalised due to another diagnosis had concomitant varicella.

Table 2 shows the general characteristics of primary healthy patients and those with underlying chronic illnesses including immunodeficiency. For immunocompromised patients and patients with an underlying chronic disease other than immunodeficiency, median age was higher. Patients’ residence was for nearly all patients in Switzerland. No patient had received vaccination prior to hospitalisation. VZV exposure was mostly unknown or via contact with family members regardless of patients’ immune status and other chronic comorbidities. Almost half of all hospitalisations occurred in children aged 9 months to 4 years old. Four primary healthy patients were hospitalised with varicella due to their young age which the treating physicians considered a risk factor for a complicated course of chickenpox. Of these, two were neonates and two were 2 months old. However, none of them experienced a complication and they were discharged within five days. The mean interval between the onset of rash and hospitalisation was 4.95 days(median 4, range −1–61) and the mean duration of all varicella hospitalisations was 5.7 days (median 4, range 0–33). Patients with herpes zoster, if not primary healthy, stayed longer in hospital than patients with varicella. In general, immunocompromised patients stayed longer in hospital than primary healthy patients. In contrast to herpes zoster, varicella patients with underlying chronic disease other than immunodeficiency were hospitalised for a shorter period than primary healthy varicella patients.

Figure 2 shows that few varicella cases were reported during study year 1 with a nationwide outbreak during study year 2 from December 2022 to May 2023. Cantons with the highest number of varicella hospitalisations in their children’s hospitals and clinics were Zurich (n = 49), Vaud (n = 29), Lucerne (n = 24), Basel (n = 22) and Bern (n = 20).

Figure 2Seasonality of varicella hospitalisations. Varicella as primary reason for hospitalisation: study year one n = 45; study year two: n = 179.

Table 3 demonstrates complications from varicella for the total study period. Complications secondary to varicella were the most common reason for hospitalisation in the majority of patients, most frequently skin disorders. From April 2022 to July 2023, invasive infections with group A Streptococcus were reported in 52 varicella cases. Musculoskeletal complications were the second most common and neurological complications the third. Several patients experienced more than one complication. Over 90% of primary healthy children experienced complications compared to less than a third of immunocompromised patients and three quarters of patients with an underlying chronic disease other than immunodeficiency. Severe complications with admission to the ICU appeared only in primary healthy children. Typical were skin infections, focal purulent collection, musculoskeletal and neurological disorders and lung involvement with pneumonia or pneumonitis. And fulminant varicella with multiorgan failure, sepsis or death only occurred in primary healthy children as well. Two patients had a varicella-associated ischaemic stroke. Two deaths occurred. One 2-year-old patient with varicella and a fulminant pneumococcal sepsis already died on day of admission in the emergency department. The other fatal case was also two years old, admitted with varicella in septic shock, who also died in the emergency unit shortly after arrival. Clinical circumstances and microbiology revealed Streptococcus pyogenes as the cause of the lethal sepsis.

Among the 15 patients with herpes zoster, 13 (87%) had an underlying chronic disease. Seven patients (47%) developed complications of whom five were not primary healthy. Three patients had complications that involved the central nervous system (meningitis n = 2, encephalitis n = 1). Two patients had skin complications, namely cellulitis (n = 1) and invasive group A streptococcal infection (n = 1). One patient had elevated liver enzyme values (AST/ALT) in the laboratory and in one patient pneumonia was detected on X-ray.

ICU treatment was necessary for 33 (14%) patients, 32 (14%) with varicella and 1 (7%) with herpes zoster. For varicella and herpes zoster patients, the mean length of stay in the ICU was 3.5 days (median 2, range 0–14). The herpes zoster patient stayed in the ICU for 6 days and improved status after infection. For varicella patients, the mean length of stay was 3.4 days (median 2, range 0–14). Skin complications like cellulitis and soft tissue abscess and musculoskeletal complications were the most common reason for ICU admission (n = 10). Most varicella patients in the ICU (91%) did not experience sequelae or die.

In total, 214 varicella patients had a favourable outcome, i.e. had recovered (n = 117) or improved when discharged (n = 97). Only 8 patients experienced sequelae, mainly remaining skin defects (n = 5), residual loss of the vestibulocochlear nerve (n = 1), pain (n = 1) or ataxia (n = 1). With regards to herpes zoster, 13 of 15 patients had a favourable outcome. Six patients recovered and seven had improved status when discharged; only two had sequelae, one a right peripheral facial nerve palsy and the other pain.

During hospitalisation, cerebrospinal fluid was obtained from 22 (9%) patients. They were 2 times positive with varicella zoster virus evidence. Table 4 shows the number and type of pathogens from blood cultures and other site cultures for varicella patients. In total, 56 Streptococcus pyogenes, 15 Staphylococcus aureus and 16 other bacteria were reported. None of the 15 herpes zoster patients had a positive blood culture. 

Table 5 lists therapies for varicella and herpes zoster patients. Varicella patients were prescribed more antibiotic therapy while herpes zoster patients received more antiviral therapy. All immunocompromised patients received intravenous antiviral therapy. Antifungal therapy was only prescribed once for an immunocompromised herpes zoster patient.

With data from a systematic review on varicella prevalence in European countries before universal childhood vaccination, population data from Switzerland and the Swiss Paediatric Surveillance Unit reports, we estimated the number of varicella cases per year and calculated the annual hospitalisation incidence per 100,000 inhabitants and the annual hospitalisation rate per 10,000 varicella patients by age groups and present them in table 1 [16, 25]. Only children with varicella and resident in Switzerland were included in these calculations (n = 216). The calculated annual varicella hospitalisation incidence for our 2-year study period was 7.2 per 100,000 and the estimated annual hospitalisation rate 12.6 per 10,000.

Discussion

This observational prospective 2-year surveillance study, encompassing reports from all Swiss children’s hospitals within the Swiss Paediatric Surveillance Unit, elucidates the morbidity rate of varicella, particularly manifesting in previously healthy (>80%) children. The study shows a comprehensive portrayal of hospitalisations and associated complications of varicella in Switzerland, prior to the implementation of universal varicella vaccination recommendations. Furthermore, it illustrates the seasonal and yearly variations in varicella epidemiology with a nationwide outbreak during the second study year from December 2022 to May 2023. Paediatric varicella hospitalisation frequencies increased 4- to 7-fold in these months compared to the first study year. The seasonal distribution of varicella hospitalisations adhered to its well-established pattern, with a peak incidence during the winter and spring months [2, 11, 12, 14, 17, 18]. Since 2005, there have been no descriptive national epidemiological studies pertaining to varicella-related hospitalisations. Hereby we give an up-to-date epidemiological investigation on varicella morbidity and mortality in children in Switzerland.

The annual hospitalisation rate of 13 per 10,000 remains consistent with the findings of the preceding prospective surveillance study conducted in Switzerland in 2005. Looking at European studies and a study from New Zealand, characterised by either the absence of universal varicella vaccination or low vaccination coverage, the annual varicella hospitalisation incidence ranges from 0.82 to 29.5 per 100,000 [2–5, 11, 13, 14, 19]. Our calculated annual varicella hospitalisation incidence, quantified at 7.2 per 100,000, falls within this broader range. This incidence closely aligns with figures reported in the Netherlands (6.8 per 100,000) and New Zealand (8.6 per 100,000) and underscores the idea of comparability of varicella-related hospitalisation rates across nations with analogous demographic and infrastructural characteristics [3, 19].

Comparative analysis of baseline characteristics among patients revealed that the sex ratio (male:female) was often almost evenly distributed [5, 13, 17, 27]. Our cohort manifested a slight male predominance (58%).

The median age within our cohort, 4.7 years, diverges by 1 to 3 years from the reported median age in other studies [2–4, 11, 13, 14, 19]. The peak frequency of hospitalisations was observed in patients aged 9 months to 4 years. This aligns with findings from several studies, thus illustrating a recognised pattern of elevated varicella hospital admission rates within younger age cohorts. These observations challenge the conventional presumption that severe complications are exclusive to older children, thereby highlighting the vulnerability of younger age groups to varicella-related complications [2–5, 11, 13].

The majority of children requiring hospitalisation due to varicella were primary healthy. Comparative analyses with studies conducted in Germany, the Netherlands, Belgium and Ireland reveal proportions of hospital admissions for primary healthy patients ranging from 61% to 96.3% [2–5, 11]. In our 2-year study period, 83% of all observed hospitalised patients and 88% of the varicella patient subset were healthy. These findings substantiate the assumption that primary healthy children are at risk of severe varicella infections.

Our investigation revealed an augmented occurrence of invasive Group A Streptococcus (iGAS) infections concomitant with varicella compared to pre-COVID-19 years. Specifically, in the second study year, 49 cases of iGAS infections were registered. This noteworthy increase aligns with findings reported in a Dutch study [28]. Other European countries documented an increase of iGAS as well. Cameron et al. documented a notable proportion of infectious complications involving iGAS [11]. McCarthy et al. observed a rise in iGAS infections too [5]. These collective observations underscore the complex interplay between varicella and iGAS infections, emphasising the need for heightened vigilance and surveillance in monitoring such infectious dynamics.

Prevalent underlying chronic diseases in other European studies include congenital anomalies, skin disorders and pneumopathies [2, 3, 11]. We found these categories in our study too; however skin disorders, particularly atopic dermatitis, cancer or leukaemia, genetic syndromes and cardiovascular diseases were the most common. Notably, hospitalisations occurred primarily due to complications from varicella. Varicella complications commonly involve the skin, central nervous system and lungs, with variations in the order and frequency of affected organ systems across studies. Our investigation showed predominant skin infections, followed by musculoskeletal and neurological complications. The observed spectrum of complications in our study aligns with that of comparable studies from other countries [2–5, 11, 13, 14, 17, 19]. During our analysed period, no patient had a history of prior VZV vaccination. All patients admitted to the ICU were primary healthy. The severity of complications concentrating in primary healthy patients has been described in similar studies [4, 11, 19]. Further, the ICU admission rate at 14% for all patients in our study falls within the range observed in European countries and New Zealand (2.5% to 24%) [4, 5, 11, 19].

The fatality rate, observed at 4.5% in 2021–2022 and 0.5% in 2022–2023, closely mirrors the outcomes reported from Switzerland in 2005 and therefore underscores the notion of an unchanged epidemiology of varicella in Switzerland [6]. Fatalities resulting from varicella hospitalisations are documented in various studies [2, 4, 11, 13].

As a limitation, the interpretative scope of our findings is constrained by the abbreviated 2-year study period, marked by fluctuations in the frequency of varicella-related hospitalisations. An extended observation period will provide a more nuanced and accurate description of the epidemiological dynamics. Comparative analyses with other studies are circumscribed by variations in case definitions and methodological approaches. The absence of a follow-up questionnaire or a capture-recapture analysis introduces the potential for underestimating the true burden of disease. Assignment errors may have transpired during the codification process, emphasising the need for cautious interpretation.

Nations that have already instituted universal varicella vaccination strategies have consistently reported a decline in hospitalisations [12, 15, 18, 21–23, 29–31]. Universal varicella vaccination has been proposed and implemented as a measure against severe complications, thereby diminishing the overall burden on healthcare resources and reducing hospitalisation rates [4, 5, 11, 19].

Data sharing statement

Anonymised study data can be shared on request by contacting the corresponding author (MB). Apart from software and tools described above in the analysis and tools subheadings, no additional software libraries, frameworks or packages were used in this study.

Acknowledgments

We would like to thank the study nurses involved at the Research Centre of the Children’s Hospital of Central Switzerland (Ms Janine Stritt, Ms Marisa Hostettler and Ms Katja Hrup) in helping with data entry and coordination of CRF’s with the respective centres. We would like to thank all the reporting centres: Paediatric Clinic, Cantonal Hospital, Aarau; Paediatric Clinic, Cantonal Hospital, Baden; University Children’s Hospital Basel, UKBB, Basel; Istituto Pediatrico della Svizzera Italiana, Bellinzona; University Clinic for Paediatrics, Bern; Neonatology, University Clinic for Paediatrics, Bern; Children’s Hospital Wildermeth, Biel; Clinic for Paediatrics and Adolescent Medicine, Cantonal Hospital, Chur; Service de Pédiatrie, Hôpital du Jura, Delémont; Service de Pédiatrie, Hôpital Cantonal, Fribourg; Hôpital des Enfants, HUG, Genève; Service de Pédiatrie, CHUV, Lausanne; Hôpital de l’Enfance, Lausanne; Division de Néonatologie, CHUV, Lausanne; Paediatric Clinic, Cantonal Hospital, Lucerne; Service de Pédiatrie, Hôpital de Zone, Morges; Clinic for Children and Adolescents, Cantonal Hospital, Münsterlingen; Département de Pédiatrie, Hôpital Pourtalès, Neuchâtel; Service de Pédiatrie, Centre hospitalier, Rennaz; Neonatology, Clinic for Obstetrics and Gynecology, St Gallen; Paediatric Clinic, Eastern Switzerland Children’s Hospital, St Gallen; Service de Pédiatrie, CHCVs, Sion; Paediatric Clinic, Spitalzentrum Oberwallis, Visp; Children’s Clinic, Kantonsspital, Winterthur; Service de Pédiatrie, eHnV, Yverdon; Paediatrics/Neonatology, Zollikerberg; University Children’s Hospital, Zurich; Clinic for Children and Adolescents, Triemli Hospital, Zurich; Neonatology, University Women’s Hospital, Zurich for their continuous participation in the study.

We thank the representatives of the paediatric units within the Swiss Paediatric Surveillance Unit: Florence Barbey, François Cachat, Livia Dülli, Simon Fluri, Mathias Gebauer, Silke Grupe, Ulla Jochumsen, Eva Kellner, Ute Kerr, Guido Laube, Bernard Laubscher, Andreas Malzacher, Jane McDougall, Stefan Minocchieri, Vincent Muehlethaler, Anita Niederer, Anne Pittet, Christa Relly, Michel Russo, Fabiola Stollar, Andreas Wörner, Jonas Zeller and all the dedicated physicians for taking care of the patients and helping to complete the questionnaires.

We also thank the Swiss Neuropaediatric Stroke Registry coordinators for reviewing their cases for varicella zoster virus associated stroke cases and reporting a further case.

We would also like to acknowledge the administrative support provided by Daniela Beeli, Mirjam Mäusezahl and Fabien Tschagellar, from the Federal Office of Public Health Switzerland.

Swiss Paediatric Surveillance Unit site coordinators: Florence Barbey, François Cachat, Livia Dülli, Simon Fluri, Mathias Gebauer, Silke Grupe, Ulla Jochumsen, Eva Kellner, Ute Kerr, Guido Laube, Bernard Laubscher, Andreas Malzacher, Jane McDougall, Stefan Minocchieri, Vincent Muehlethaler, Anita Niederer, Anne Pittet, Christa Relly, Michel Russo, Fabiola Stollar, Andreas Wörner, Jonas Zeller and the Swiss Paediatric Surveillance Unit, https://www.spsu.ch/en/home

Disclaimer: The paper represents the views of the authors and not an official position of any institution or funder.

Source of support: Case registration and data provision by the Swiss Paediatric Surveillance Unit.

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