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A 2-month-old infant is brought into the emergency department with a 24 h history of fever. He was born at term and had an uneventful neonatal period with no risk factors for sepsis. Clinical examination was unremarkable apart from a temperature of 38.5°C. Upon further questioning, his mother revealed that the infant had received his routine vaccinations the previous day. She had been advised to give prophylactic paracetamol at the time of vaccination but had refrained from doing so because, 2 years previously, the same practice nurse had told her to give paracetamol to her older child only if he developed fever after vaccination. You are not aware of current national recommendations or the evidence for prophylactic paracetamol with vaccination.
Structured clinical question
In infants receiving their routine primary immunisations (population), does prophylactic paracetamol given around the time of vaccination (intervention) compared with no prophylactic paracetamol (comparison) reduce the risk of fever post vaccination (outcome)?
Search strategy and outcome
MEDLINE, EMBASE and PubMed (1 January 2000 to 30 June 2015). Used terms (prophyla*) AND (vaccine* OR immuni*) AND (antipyretics OR paracetamol OR ibuprofen OR acetaminophen). The search was then limited to randomised controlled trials (RCTs) and systematic reviews with no language limitations. The search retrieved 22 articles including one systematic review,1 which included all the relevant articles identified by the search as well as hand-searching through reference lists and clinical trials databases, apart from an as-yet unpublished RCT reported on http://www.clinicaltrials.gov 2 and a more recent RCT assessing the effect of prophylactic paracetamol on adverse reactions (including fever) and vaccine responses in infants receiving a MenB vaccine with their routine vaccinations (table 1).3
From 1 September 2015, infants in the UK are offered a novel multicomponent protein-based MenB vaccine (Bexsero; GSK biologicals) alongside their routine vaccinations at 2, 4 and 12 months (https://www.gov.uk/government/collections/immunisation). Neisseria meningitidis (the meningococcus) remains a major global cause of meningitis and septicaemia and is associated with significant long-term morbidity and mortality.4 Meningococci are classified according to their polysaccharide capsule into 12 main capsular groups, including 5 that are responsible for the majority of invasive meningococcal disease (IMD) worldwide: A, B, C, W and Y. In the UK, meningococcal group C disease is rare since the introduction of routine vaccination in 1999.5 Consequently, meningococcal group B (MenB) has been the most important capsular group causing IMD across all age groups, being responsible for >90% of cases in infants and toddlers.6 The recently licensed MenB vaccine is highly immunogenic and is estimated to protect against 73–88% of MenB strains causing invasive disease in England and Wales.7
Concomitant administration of Bexsero with routine infant vaccinations, however, is associated with higher rates of some reactions, especially fever. In a phase IIb, multicentre, open-label, parallel group, randomised controlled study of 1885 infants enrolled from August 2008 to July 2010 in Europe, fever was reported in 51–61% when 4CMenB was coadministered with routine vaccines compared with 26–41% of infants receiving 4CMenB alone and 23–36% after routine vaccines alone at a 2–3–4 or 2–4–6 month schedule.8 Coadministration of vaccines was also associated with increased rates of severe local pain after a dose of Bexsero (12–16%) compared with 1–3% after Diphtheria, Tetanus, acellular Pertussis, Hepatitis B, Polio and Haemophilus influenzae type b (DTaP-HBV-IPV/Hib) or pneumococcal conjugate vaccine (PCV)7 in the control groups. Post-vaccination fever typically peaks at 6 h and declines by 24 h, being very uncommon after 48 h.3 Notably, though, febrile seizure was reported in only one of the 1885 infants, 2 days after the second 4CMenB dose.
Other post-vaccination reactions are typically mild to moderate and of limited duration, without significant medical consequences. However, parental concern may lead to unnecessary general practitioner (GP) surgery and emergency department attendances, with subsequent increases in healthcare costs, and potentially put off parents from attending subsequent vaccination visits. To reduce the risk and intensity of fever after Bexsero vaccination, parents have been advised to give their infant three doses of oral paracetamol suspension at 4–6 h intervals, with the first dose given around the time of vaccination or as soon as possible after (https://www.gov.uk/government/collections/meningococcal-b-menb-vaccination-programme).
This advice is contrary to previous recommendations against the use of prophylactic antipyretics around the time of vaccination because a study published in 2009 reported lower immune responses to some of the vaccine antigens in infants receiving prophylactic paracetamol compared with infants who did not receive prophylactic paracetamol.9 In this randomised, controlled, open-label vaccination trial, 459 infants were enrolled from 10 centres in the Czech Republic and randomly assigned to receive three prophylactic paracetamol doses every 6–8 h (n=226) or no prophylactic paracetamol (n=233) after each vaccination with a ten-valent PCV coadministered with DTaP-HBV-IPV/Hib and oral human rotavirus vaccine. In the prophylactic paracetamol group, fever ≥38°C was reported in 42% and 36% after primary and booster vaccinations compared with 66% and 58% in the control group. However, antibody concentrations were significantly lower for all 10 pneumococcal vaccine serotypes, as well as for Hib, diphtheria, tetanus and the pertussis antigen, pertactin. After boosting, too, lower antibody concentrations persisted in the prophylactic paracetamol group for tetanus and all but one pneumococcal serotype. In a follow-up study, however, the authors found that, regardless of whether previous vaccination was given with or without paracetamol prophylaxis, induction of immunological memory following vaccination and persistence of the PCV's impact on carriage reduction was seen until at least 28 months post-booster vaccination.10
Subsequently, a systematic review published in 2014 assessed the effect of prophylactic antipyretic administration on post-vaccination adverse reactions in children.1 The authors retrieved 2579 citations until March 2014 and included 13 RCTs with 5077 children in the final analysis. A range of different formulations, doses and schedules for paracetamol and ibuprofen were used in the different clinical trials. Most trials used paracetamol (oral suspension and suppositories) at 10–15 mg/kg and ibuprofen at 6.6–10 mg/kg, with the first dose given at any time between 0 and 30 min before vaccination and up to 1 h after vaccination. Post vaccination, paracetamol (3–4 doses) and ibuprofen (3 doses) were given at 4–8 h intervals in the different trials.
Their findings indicate that prophylactic paracetamol significantly reduced rates of fever (≥38°C), high fever (≥39°C), pain of all grades, local swelling/induration, persistent crying, irritability/fussiness, drowsiness, anorexia/loss of appetite and any severe reaction after infant immunisation, but no differences were observed for local redness, vomiting and diarrhoea.1 The authors also concluded that, although lower antibody concentrations were reported for some of the vaccine antigens in infants receiving prophylactic paracetamol compared with controls who did not receive prophylactic paracetamol, the majority of infants in both groups achieved protective antibody thresholds (ie, the amount of antibody required for protection against invasive disease) after vaccination.
The timing of the paracetamol dose is also important. The unpublished RCT found that three doses (first dose at vaccination, followed by two further doses at 4–6 h intervals) of oral paracetamol was associated with significantly lower rates of post-vaccination fever compared with two doses (first dose at 6 h after vaccination, followed by one further dose after 4–6 h), indicating that the dose given around the time of vaccination is critical (https://clinicaltrials.gov/ct2/show/NCT01392378). 2 This finding was also observed in other RCTs summarised in the systematic review.1
Notably, prophylactic ibuprofen does not appear to have any significant impact on post-vaccination fever rates or any other reaction except for improving pain of all grades (OR 1.52; 95% CI 1.13 to 2.04), swelling/induration (OR 1.44; 95% CI 1.06 to 1.94) and drowsiness (OR 1.36; 95% CI 1.00 to 1.86) after primary immunisations.1 In the unpublished RCT, too, prophylactic paracetamol had a greater impact on reduction in fever after vaccination compared with prophylactic ibuprofen or the control group that did not receive any antipyretics.2
In 2014, an RCT was performed specifically to assess the effect of prophylactic paracetamol in infants receiving Bexsero with their routine vaccinations.10 This RCT found significantly lower rates of fever as well as solicited local and systemic reactions after vaccination in the prophylactic paracetamol, without affecting immune responses to any of the vaccine antigens in the primary immunisation schedule.10 Infants receiving oral infant paracetamol around the time of vaccination followed by two further doses of paracetamol at 4–6 h intervals experienced 51–65% lower rates of fever compared with the control group that did not receive prophylactic paracetamol. Rates of high fever (>39.5°C) were also substantially lower (1.1% vs 3–5%, representing an up to 80% decrease).
Based on the available evidence, therefore, prophylactic paracetamol has been recommended for all infants receiving Bexsero with their routine primary vaccinations at 2 and 4 months of age. Parents have been advised to give three doses of 2.5 mL oral infant paracetamol suspension (120 mg/mL) at 4–6 h intervals with the first dose given at the time of vaccination or as soon as possible after. If the infant is still febrile after the three doses of paracetamol but is otherwise well, parents can continue giving paracetamol at recommended intervals up to 48 h post vaccination. Based on evidence from current literature, prophylactic ibuprofen cannot be recommended for preventing post-vaccination fever in infants. Parents have been advised to contact their GPs or NHS 111 if their child appears unwell or if they are concerned about their child's health at any time. Healthcare professionals should be aware of these recommendations and the evidence base for offering paracetamol prophylaxis to infants receiving Bexsero with their routine vaccinations. Some parents may decide not to give the recommended paracetamol to their infants, while other infants may still develop fever despite being given paracetamol prophylaxis, which could increase medical attendance rates for post-vaccination fever in primary and secondary care. It is, therefore, important that frontline healthcare professionals in GP surgeries and in the emergency department ask about vaccination in the previous 24–48 h to avoid unnecessary referrals and invasive investigations in otherwise well infants presenting with fever.
Clinical bottom line
From 1 September 2015, parents are being advised to give their infants prophylactic paracetamol when they receive the new MenB vaccine, Bexsero, with their routine primary immunisations at 2 and 4 months of age.
The administration of paracetamol, starting around the time of vaccination with two further doses at 4–6 h intervals, significantly reduces the rate and intensity of fever as well as other local and systemic reactions after vaccination in infants.
Clinicians should enquire about recent vaccinations in the previous 48 h when assessing otherwise well infants with fever. At the same time, they need to ensure that infants are appropriately investigated if at all clinically unwell.
Contributors SB and SNL conducted the literature review and wrote the first draft. All authors contributed to the commentary and the clinical bottom line.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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