This study confirms that severe complications of varicella, including death, continue to occur in the UK and Ireland.
By using active surveillance among all consultant paediatricians, we should have captured the overwhelming majority of severe varicella cases meeting the case definition among hospitalised children. The use of follow‐up questionnaires meant we were able to categorise cases better as severe and capture more information than was previously available through routine records. Nevertheless, the figures obtained are minimum estimates as there may still have been under‐ascertainment to an unknown degree, despite an extremely high response rate for cards (92.3%) and questionnaires (92.5%).
This study could not have included data on all varicella hospitalisations, as this would have been unmanageable with the methodology used, for which the BPSU specifies a limit of around 300 cases per year. It was therefore necessary to restrict ascertainment to severe cases. Initially, we considered achieving this limit by restricting the study to ICU/HDU admissions. However, it was decided that, as ICU/HDU admission criteria vary by location and bed availability, this might end up being a marker of management practice rather than severity, and capture only some cases. Indeed, only 27 (24%) of ascertained cases were admitted to ICU/HDU. We therefore decided to specify which clinical presentations would be considered as severe complications. This gave clear inclusion criteria but may have excluded other presentations considered just as severe. Indeed, 28 of the initial reports (15%), while reporting true varicella complications, did not meet the case definition. These included presentations of cellulitis, abscess or osteomyelitis in the absence of bacteraemia, cerebral infarct, acute renal failure, orchitis, idiopathic thrombocytopenic purpura, stroke and ataxia not requiring hospitalisation. It is worth emphasising that most children admitted to hospital in the UK and Ireland as a result of varicella will not have met our case definition. Such children often appear to have secondary bacterial infection of skin lesions, manifest by fever and cellulitis, yet infrequently have positive blood cultures or meet criteria for toxic shock syndrome or necrotising fasciitis.
This was the first active prospective epidemiological study for varicella in either the UK or Ireland. Previous studies in the UK have used retrospective analysis of routine hospital records. The most recent study found overall hospitalisation rates of 16.17 per 100
000 children aged 0–14 years,3
with highest rates among 0–4 year olds (38.7/100
000), decreasing almost 10‐fold for children aged 5–14 years (4.6/100
000). This compares with an overall rate of 0.82/100
000 for severe complications in our study for children aged 0–15 years, highlighting the fact that most hospitalisations for varicella would not be captured by our case definition, mainly because they were less severe. UK varicella deaths have been reported previously, from routine statistics, to be an average of 4 (1991–2000),3
or 8.5 (1967–1985)8
deaths per year for children aged 0–14 years. Our figure of six deaths, including one intrauterine death, is within this range. The lower figures are for more recent years, which may reflect the wider use of prophylaxis in high‐risk contacts and/or earlier treatment of high‐risk cases. Immunosuppression was cited for 23% of the childhood deaths in the early study,8
compared to one (20%) of our post‐natal deaths.
Internationally, there have been two recent active, prospective studies using methods similar to ours. A study by the German Paediatric Surveillance Unit found an equivalent rate for severe complications (0.85/100
although the case definition was different as it considered only neurological, bacterial superinfection and haematological complications above certain threshold criteria and excluded immunocompromised children. Strikingly, this study recorded no deaths, despite three fatalities being reported through routine statistics in Germany that year.9
However, these deaths may not have met the study case definition. The authors also reported a much lower rate of sequelae on discharge (4%), but again this may be due to differences in definitions. A similar study was also conducted by the Swiss Paediatric Surveillance Unit and estimated overall varicella hospitalisation as 5.9/100
000 in children aged 0–16 years. However, it was not possible to determine rates of specific complications and deaths, as varicella and herpes zoster figures were not separated.10
In addition to the above, there are many other, primarily retrospective, studies that report varicella complications, chiefly for all hospitalised cases, regardless of severity. The results of our study are generally concordant with these reports, although, as for the above, direct comparison is often difficult due to differing case ascertainment, case definitions, inclusion and exclusion criteria, classification of complication types, and the lack of population rates. However, a literature review shows that our median age of 3 years is within the reported median range of 2.8–4.3 years.11,12,13,14,15,16,17,18
It is difficult to compare the prevalence of risk factors among children with complications, for the reasons stated above, particularly as some studies excluded immunocompromised children. Comparison of specific complication rates is also difficult, as almost every study adopted different classification methods. For example, pneumonia could be classified as either an infectious or respiratory complication. Additionally, some studies reported figures for bacterial, viral and specifically varicella pneumonia separately, while others, like us, did not distinguish these from each other. However, it was possible to compare encephalitis rates directly with those in US retrospective and German prospective studies, for which figures were similar.9,19
Other studies from Turkey and Switzerland reported higher encephalitis rates (0.6/100
000 (95% CI 0.37 to 0.97) and 0.54/100
000 (95% CI 0.29 to 1.0) in children aged less than 16 years, respectively).13,20
We could also compare ataxia rates, which were approximately five to seven times lower in our study compared to those previously reported.13,19,20
This may be because we considered hospitalised cases only, and an exact case definition for ataxia was not specified. Rates for necrotising fasciitis in our study were approximately twice those observed in the recent German prospective study.9
We had a zero rate for Reye's syndrome, consistent with four other recent studies.9,13,16,18,21
This is in contrast to earlier studies for which cases were reported,8,19,20,22,23,24,25,26
and may well reflect the success of public health strategies in preventing aspirin use in children. Our study identified three cases of neonatal varicella (0.40/100
000 live births; 95% CI 0.12 to 1.13). This figure seems very low compared to a recent study by the Australian Paediatric Surveillance Unit (5.8/100
000; 95% CI 4.3 to 7.8). However, that study considered all cases in infants aged less than 1 month, while our study specified perinatal infection. However, even when only babies whose mothers were infected within 1 week before or after birth were considered, the Australian rate remained much higher (3.9/100
000; 95% CI 2.7 to 5.6).27
The reasons for our lower rates are unclear but could include differing epidemiology and climate, clinical practice and reporting patterns.
One of the deaths reported in our study was in a child with HIV. High varicella mortality rates for HIV patients are not typical, with other studies reporting few deaths.28,29
However, fulminant varicella with concomitant cytomegalovirus presented with HIV in this individual.
Our finding of a high proportion of cases having infectious complications is similar to other studies.9,10,11,12,13,16,18,19,20,21,22,23
In particular, there has been recent concern over the relatively high number of invasive Group A Streptococcus infections,30
as found in our study.
What is already known on this topic
- Severe complications of varicella can occur even in previously healthy children.
- Varicella is vaccine preventable, but the UK does not recommend universal immunisation.
What this study adds
- Severe complications of varicella, including death, continue to occur in the UK and Ireland
- There are an estimated minimum of six deaths and 103 cases with severe complications each year in the UK and Ireland.
- Most complications occur in otherwise healthy children and would be preventable only through universal immunisation.
For most of the children in this study, it is unclear why varicella presented so severely. A large majority had no underlying medical conditions. It is possible that strain variation could have played a role, but the study mechanism did not allow for collection of viral material for genetic analysis to test this hypothesis. Studies elsewhere, including in North America, Europe and Australia, have collected, or aim to collect, virological samples to address questions of virus variability and vaccine escape, as related to disease severity.31,32
Most of the cases were potentially preventable by vaccination of the individuals involved, that is, they occurred in immunocompetent children aged over 12 months. Further, studies elsewhere have shown that, even with only partial population uptake of varicella vaccine, substantial herd immunity can be achieved, extending protection to unvaccinated children aged less than 1 year.33
We did not identify any additional high‐risk groups that could be candidates for selective immunisation. Universal vaccination would therefore be the only realistic option to prevent severe complications and deaths, as few, if any, could be identified as potentially preventable under the current UK policy. However, decisions around universal varicella vaccination are complex, and two particular theoretical concerns have been expressed in the UK.34
Firstly, there is concern that the introduction of universal varicella vaccination could cause an epidemiological shift with the age of varicella cases increasing, leading to an overall increased rate of complications. Secondly, as virus transmission in the community would decrease following vaccine introduction, this could cause an increase in herpes zoster in the elderly due to waning levels of immunity. Long‐term data from countries that have already embarked on universal vaccination are awaited to address these concerns. Some preliminary data from one US study indicate a highly significant increase (90%) in zoster following a vaccine‐associated decline in varicella,35
although this is in conflict with another large US study which does not indicate an increase.36
Positive efficacy and safety data on zoster vaccine for the elderly are also emerging.37
Zoster vaccine could potentially ameliorate the above concerns, should they occur, in addition to offering protection against re‐activated varicella zoster infection.