Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials
Introduction
Fever is part of the normal inflammatory response and frequently occurs in response to infection. This host-defence mechanism has a beneficial effect on many infections and can enhance survival. Fever is also a well described event after vaccination.1, 2, 3, 4 It is produced by endogenous pyrogens, mainly interleukin 1 and tumour necrosis factor α, and is associated with heightened T-cell activity, enhanced antigen recognition, and immune responses.5 Although generally benign and self-limiting,6 fever after vaccination is frequently a concern for parents and health-care professionals, driven by fears of febrile convulsion and by beliefs that it represents a serious pathological change.7, 8 These notions can result in medical visits, unnecessary laboratory investigations, and avoidance or deferral of subsequent vaccinations.
The prophylactic administration of antipyretic drugs has thus become routine practice and is even recommended in some countries for vaccination against diphtheria, tetanus, and whole-cell pertussis (DTPw), combination vaccinations,9, 10 or for children with a history of febrile convulsion.11 Evidence lending support to this approach is scarce; the level of fever is unrelated to the onset of convulsion,12, 13 and antipyretic drugs are ineffective in prevention of benign febrile convulsion in children who are at risk.14
We assessed the effect of the prophylactic administration of paracetamol at the time of vaccination and within the next 24 h on the rate of febrile reactions and vaccine responses in infants after primary vaccination with a ten-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type b vaccine (DTPa-HBV-IPV/Hib) and oral human rotavirus vaccine (HRV), followed by a booster dose of PHiD-CV plus DTPa-HBV-IPV/Hib.
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Study design and participants
Two consecutive (primary and booster vaccination) phase 3, randomised, controlled, open-label studies were undertaken in ten centres in the Czech Republic from Sept 18, 2006, to April 10, 2007 (primary vaccination study), and from July 2, 2007, to April 1, 2008 (data lockpoint for reported analysis, while the study continued for nasopharyngeal carriage endpoints, booster vaccination study).
Study participants were healthy infants aged 9–16 weeks at time of enrolment and 12–15 months at time of
Results
459 participants were enrolled and vaccinated in the primary vaccination study and 414 in the booster study (figure 1). Results from 37 participants from the group not receiving prophylactic paracetamol and who were boosted after the protocol amendment were not included in the reported analyses. One child (no prophylactic paracetamol group) withdrew due to a serious adverse event, encephalitis 27 days after the second vaccine dose, which was not considered by the investigator to be causally
Discussion
This study shows how prophylactic paracetamol reduces febrile reactions after infant primary and booster vaccination. The percentage of children reporting fever of 38°C or greater after each vaccine dose was 40–50% lower when prophylactic paracetamol was administered at the time of vaccination and for the next 24 h. The effect ceased once paracetamol administration ended. However, febrile episodes greater than 39·5°C were uncommon even in the group without prophylactic paracetamol; medical
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