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Abstract
Introduction In September 2015, the UK became the first country in the world to introduce the 4-component meningococcal B vaccine(4CMenB) into the routine vaccine schedule for infants. 4CMenB is known to cause fever in infants. Infants presenting with fever, particularly those under 3 months, have a significant risk of serious bacterial infection(SBI).
Method Between September 2015 and January 2016, we performed a prospective audit of management of infants between 30 and 180 days attending the regional paediatric emergency department(ED) in Northern Ireland, within 4 days of receiving 4CMenB.
Results 35 ED attendances in infants aged 30–180 days were due to symptoms occurring after primary vaccinations including 4CMenB, representing an estimated 0.8% of the vaccinated population in the catchment area. 86% of infants presented after the first vaccine and parents reported giving paracetamol to 94% of infants. 80% of infants presented with fever. Blood tests were performed in 62% of infants and leucocytosis was present in 73%. All cultures taken were negative and 51% were admitted to hospital. 100% of final diagnoses were vaccine related (diagnosis made by exclusion).
Discussion In this study, an estimated 0.8% of the vaccinated population in the catchment area attended ED with symptoms occurring after primary vaccinations including 4CMenB. Infants with fever have a higher risk of SBI, but infants with fever in the post-vaccination period may not have the same risk. Further data are essential to inform national guidelines on investigation and management of fever in infants following vaccination with 4CMenB, possibly incorporating a less-invasive approach.
- accident & emergency
- infectious diseases
- immunisation
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What is already known on this topic?
The 4-component meningococcal B (4CMenB) vaccination is associated with fever in infants.
Fever in infants, particularly those under 3 months, is associated with an increased risk of serious bacterial infections.
What this study adds?
Infants may present to the emergency department after 4CMenB vaccination despite appropriate parental advice and paracetamol administration.
Leucocytosis is common post-4CMenB vaccination with routine primary vaccines.
National guidelines do not take infants with post-vaccination fever into account.
Introduction and aims
Invasive meningococcal disease (IMD) is an important cause of morbidity and mortality, especially in infants. The incidence of IMD in the UK is 2 per 100 000 population and Neisseria meningitidis group B (Men B) accounts for 87% of cases.1 Northern Ireland has a population of 1.8 million and in 2014, Men B accounted for 79% of the 29 cases of IMD.2
In September 2015, the UK became the first country in the world to introduce the 4-component meningococcal B vaccine (4CMenB or Bexsero) into the national vaccination schedule.3
Three doses of 4CMenB are administered with the first dose at 8 weeks with other primary immunisations.3 It is estimated to protect against 88% of MenB strains4 and has some effect against group W meningococci, whose increasing incidence in England is causing concern.5
4CMenB is reported to cause fever when administered to infants, especially when given with other infant vaccines.6 Prophylactic paracetamol, with the first dose ideally administered at the time of vaccination and two further doses, reduces episodes of fever.7
To help reduce unscheduled medical attendances following vaccination, UK recommendations are that paracetamol is administered with 4CMenB vaccine and parents are provided with information on the vaccine.5
Infants presenting with fever, particularly those under 3 months, have a significant risk of serious bacterial infection (SBI). It is recommended in national guidelines to undertake investigations in all infants <90 days presenting with fever and to give empiric antimicrobial treatment in many cases. The escalation of investigations to include cerebrospinal fluid (CSF) testing is recommended in the presence of specific findings including leucocytosis and appearing unwell.8
Our aim was to audit the investigation, management and clinical outcomes of infants attending the emergency department (ED) following 4CMenB vaccination and look at the possible impact on healthcare resources.
Methods
The Royal Belfast Hospital for Sick Children is the regional children’s hospital for Northern Ireland, which has 35 000 ED attendances per year of children under 14 years. We performed a prospective audit of management of infants between 30 and 180 days of age attending the ED post-primary vaccinations including 4CMenB. We included all infants from 30 to 180 days of age in order to capture those who received 4CMenB including those who received it early or late. We looked at clinical course, adherence to National Institute for Health and Care Excellence (NICE) guidelines on fever in the under 5s: assessment and initial management (CG160) and to Public Health England guidance on advice to parents and administration of antipyretics in infants given 4CMenB. We included those presenting within 4 days of 4CMenB vaccination, between 1 September 2015 and 31 January 2016.
A standard proforma was available in the ED, and ED staff were educated at the start of the study and encouraged to obtain complete immunisation history particularly focusing on recent immunisations. All infants who presented post-routine vaccinations plus 4CMenB in the last 4 days were included. Clinicians were encouraged to complete the forms and ED consultants reviewed all ED charts allowing for missed cases to be identified. An electronic database was searched at the end of the period to ensure all cases were identified. All proformas were reviewed by a single auditor, and missing data were collected from parents.
Results
There were 1413 infants aged 30–180 days who presented to the ED during the 5-month audit period. Thirty-five of these infants presented following routine vaccinations including 4CMenB. Based on the birth cohort and vaccination coverage (92.6%)9 in our area applicable to the 5-month period studied, we estimate that this represents 0.8% of those vaccinated in our catchment area.
The median age was 2 months (range, 2–5 months). Ten (29%) infants were referred to ED by their general practitioner (GP), with 25 self-referrals. Thirty (86%) infants presented after the first dose of 4CMenB vaccine and five (14%) after their second dose of the vaccine. Parents of 33 (94%) infants reported administering paracetamol and administration was within 1 hour of vaccination in 30 (86%). Parents received information on the new vaccine and the possibility of fever in 29 (83%) infants, with no information given to 2 (6%) and unknown status in 4 (11%). The median timing of presentation to ED post-vaccine was 10 hours 30 min (range, 5.5–81 hours) with four infants presenting more than 48 hours after vaccination. These four infants all had symptoms since the day of their vaccine. Of those who presented after 48 hours, two were febrile, both of which commenced within 12 hours of vaccine and resolved by 72 hours, one presented with reduced feeding and irritability and one with diarrhoea.
Twenty-eight (80%) infants presented with fever, 25 (71%) with irritability and 20 (57%) with fever and irritability. Of those presenting with fever, further data were available for 26, of which 11 had no fever recorded in hospital, with 7 recorded by thermometer by carers or in primary care prior to presentation and 4 brought to ED described as ‘feeling hot’. Fifteen infants had a documented fever in the ED. The median time of fever post-vaccination was 7 hours. Other features are shown in table 1.
Presenting symptoms in 35 infants attending emergency department within 4 days of 4CMenB vaccination
Blood tests were performed in 22 (62%) infants. Leucocytosis >15×109/L was present in 16 (73%) of these infants. The C-reactive protein was under 10 mg/L in 80% (16) (median 3.9 and IQR 1.2–6.1).
Of the 35 infants who presented with fever post-vaccination, 19 (54%) had blood cultures and 6 (17%) had CSF samples taken (none had CSF pleocytosis); all were culture negative. Twenty-eight (80%) had urine specimens checked, with two positive for Escherichia coli, neither of which were felt to be significant by the treating medical team. Eleven (31%) received broad-spectrum antibiotics. Eighteen (51%) were admitted, with a median length of stay of 16.5 hours (range, 11–64 hours). Table 2 shows a summary of the management of the infants presenting with symptoms or initial investigations that are highlighted in NICE fever guidelines as significant. All final diagnoses were vaccine-related reactions assigned by the treating team.
Management of infants presenting with symptoms and initial investigations highlighted in NICE fever guidelines as significant and triggers for further investigation and management
Discussion
In this study, 35 ED attendances in infants aged 30–180 days were due to symptoms occurring after primary vaccinations including 4CMenB, representing an estimated 0.8% of the vaccinated population in the catchment area. Investigations were performed in over 60% of infants and leucocytosis was common, in some cases leading to escalation in management, in accordance with national guidance on management of fever in infants. Fifty-one per cent of infants were admitted to hospital. All of those attending had a discharge diagnosis of vaccine-related symptoms. Attendance at the ED was a relatively infrequent occurrence in the vaccinated population in our area, in keeping with previously published data.6 10 However, our data indicate that when infants attend, they are likely to undergo investigations, receive antibiotics and are often admitted to hospital.
The cautious management of young infants with fever is well established due to the relatively high incidence of SBI and the difficulty distinguishing a SBI from a viral illness. Greenhow et al reported that 13.5% of infants under 3 months of age presenting unwell or with fever had a SBI, and that 92% were urinary tract infections.11 However, this and similar estimates of SBI rates in ED are based on attendances of febrile infants who are clinically unwell for healthcare advice, rather than on infants presenting following immunisation. The prevalence of community-acquired SBI in previously well infants is extremely low. Le Doare et al recently published data on the epidemiology of community-acquired SBI in children, specifically including clinically significant culture-positive bacteraemia or meningitis. Population rates in infants 1 month to 1 year of age were 38.1/100 000 population.12 This estimate may more accurately reflect the risk of SBI in the patient group receiving immunisation.
We observed that leucocytosis was common in our cohort. Leucocytosis post-vaccination has been reported as early as 1924.13 Leucocytosis with neutrophilia has been reported more recently after pertussis vaccination in children.14
Frequency of medically attended visits related to 4CMenB has been quoted as ≤2%.6 Medical attendance with fever in infants was shown to be lower when vaccination administration was not blinded, indicating that parental information may reduce rates of unscheduled medical attendance.6
In a Quebec region, 4CMenB vaccination was offered to individuals under 20 years old and 43 740 individuals received it. Moreover, 6% and 9% of patients sought medical attention or reported absenteeism after the first and second doses, respectively, and two children were hospitalised after vaccination.10 15 Most of our group were appropriately advised and received prophylactic paracetamol, yet parents/carers or primary care physicians were sufficiently concerned to refer them to the ED.
NICE guidelines (CG160) recommend extensive investigation of fever in infants under 3 months and a cautious approach in those aged 3–6 months.8 A low threshold for performing a lumbar puncture and commencing broad-spectrum antimicrobials is suggested, with the presence of leucocytosis identified as a trigger. The prevalence of leucocytosis in this group suggests that strict adherence to NICE fever guidelines is likely to result in unnecessary investigations, hospital admissions and use of broad-spectrum antibiotics in infants with fever after 4CMenB immunisation.
It is notable in our group that few of those with leucocytosis >15×109/L underwent a lumbar puncture (LP). Most, however, were admitted to hospital overnight. It is possible that senior medical review and increased awareness of fever post-4CMenB influenced withholding of LP in favour of a period of observation.
The strengths of our audit include that it is the first study to assess ED attendance post-4CMenB following the implementation of a national immunisation programme. We have provided an estimate of the proportion of infants who received 4CMenB that presented to the ED. This may be an overestimation as the catchment area for the ED may be larger than the trust area. Other limitations include that some cases of post-vaccination fever may have been missed if parents or GPs did not declare vaccinations. We did not collect information on presentations to ED with vaccine-related symptoms before 4CMenB was introduced and consequently cannot provide an estimate of additional attendances related to 4CMenB.
Conclusion
Infants presenting after 4CMenB vaccination pose a diagnostic challenge for paediatricians. The risk of missing an infant with a SBI must be weighed against unnecessary investigations, hospital admission and administration of broad-spectrum antibiotics in a time of increasing antimicrobial resistance. There is a need for education in the ED around vaccine-associated adverse events, which might allow use of clinical judgement and avoidance of investigation. Further research on the epidemiology of febrile infants in the era of 4CMenB may help inform the assessment of risk in this group. National guidelines such as NICE will need to take this group into consideration, once more data are available, as a less-invasive approach may be safe and appropriate.
Footnotes
Contributors Belfast Health and Social Care Trust Audit and Quality Improvement provided help with Excel worksheet development.
Competing interests None declared.
Patient consent No intervention was performed during the audit. Anonymous data were collected on attendance to the emergency department.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This paper has been amended since it was published Online First. Owing to a scripting error, some of the publisher names in the references were replaced with ’BMJ Publishing Group'. This only affected the full text version, not the PDF. We have since corrected these errors and the correct publishers have been inserted into the references.
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