Rashmi Ranjan Das, Inusha Panigrahi, Sushree Samiksha Naik PLOS ONE- September 2014 Volume 9. Issue 9 Prepared by: Maha al Arrayed Supervised by: Dr Salwa Al Noaimi

 Though routine vaccination is extremely beneficial for children, their adverse effects is a main reason for both child and parental discomfort.  Various side effects in the form of local (skin induration, swelling, rash, pain) and systemic reactions (fever, diarrhea, fainting, seizures) commonly occur.

 Post- vaccination reactions occur hours after vaccination and they are usually mild and self limited.  It is a common practice for many health providers to suggest that an antipyretic be given preventibly at the time of vaccine administration.

 Prophylactic antipyretic administration decreases the post- vaccination adverse reactions.  However, recent studies find that they may also decrease the antibody responses to several vaccine antigens.

 This systemic review aimed to assess the evidence for a relationship between prophylactic antipyretic administration, post- vaccination adverse events, and antibody response in children.

 A systemic search of major databases was carried out till March  Randomized Controlled Trials comparing prophylactic antipyretic treatment versus placebo/ no prophylaxis post-vaccination in children 6 years of age or below were included.  Trials that focused on the therapeutic effects of antipyretics post- vaccination were excluded from the analysis.

 Two reviewers independently applied eligibility criteria, assessed the studies for methodological quality and extracted data.  Methodological quality of the selected trials was done using methodological quality assessment forms based on the criteria outlined in the COCHRANE HANDBOOK FOR SYSTEMIC REVIEWS OF INTERVENTIONS.  Data extraction was done using a data extraction form that was designed and pilot tested.

 Disagreements in extracted data were resolved through discussion with the third author.

Types of participants:  Children of both sex and ≤ 6 years undergoing routine immunization were included.  Children suffering from chronic debilitating diseases, severe malnutrition, and underlying immunodeficiency were excluded.

Types of interventions:  The interventions commenced either before or after the child received any of the routine childhood vaccinations.  It consisted of prophylactic or preventive administration of antipyretics (either paracetamol, ibuprofen or both) or placebo/ no prophylactic antipyretics.  All formulation, dose and schedule of administration of antipyretics were considered.

Types of outcome measures:  Primary outcome measures: 1) Febrile reactions ≥ 38.0 ˚c in the 1 st hrs of primary and booster vaccination 2) Antibody response rate ( measured by Geometric Mean Concentration: GMC) after primary and booster vaccinations.

 Secondary outcome measures: 1) High febrile reactions ≥ 39.0˚c in the 1 st hrs of primary and booster vaccinations. 2) Local symptoms (pain, redness and swelling at injection site) after primary and booster vaccinations. 3) Systemic symptoms (irritability/ fussiness, drowsiness, diarrhea, vomiting and loss of appetite) after primary and booster vaccinations. 4) Nasopharyngeal carriage rate of the organisms Strept. pneumoniae, H. influenza and others.

 The data from various studies were pooled and expressed as odds ratio with 95% confidence interval or mean difference with 95% confidence interval.  A p-value of <0.05 was considered significant.  Assessment of heterogeneity was done using the I-squared statistics.

13 studies included in synthesis 10 trials used paracetamol 1 trial used ibuprofen 2 trials used both

 Primary outcome measures: 1) Febrile reactions ≥ 38.0˚c in the 1 st hours compared to the no prophylactic group:  There was significant reduction in the febrile reactions both after primary and booster vaccinations.

2) Antibody response rate after primary and first booster vaccination:  There was significant difference in the GMC (Geometric Mean Concentration) between the prophylactic paracetamol group and the no prophylactic group of the: 1- anti- pneumococcal IgG antibody for all vaccine serotypes 2- anti-PRP ( H. influenza component) 3- anti- tetanus

 The GMC of anti-PT, anti-FHA (Pertussis component), anti-HBs and anti-polio did not show any significant difference between the prophylactic and no prophylactic groups.

 Though the GMC of all pneumococcal vaccines serotypes and some other vaccines decreased after prophylactic paracetamol, still the level of GMC in the prophylactic group was well above the seroprotection level.

 Secondary outcome measures: Outcomes measuredComment 1- High febrile reactions ≥ 39˚c 2- Pain of moderate- severe grade 3- Local redness 4- Local swelling/ induration 5- Drowsiness 6- Anorexia/ loss of appetite Significant reduction or difference after 1˚ but not booster vaccination compared to placebo/ no prophylaxis

 Secondary outcome measures: Outcomes measuredComment 1- Pain of all grades 2- Persistent cry 3- Irritability/ fussiness Significant reduction after both 1˚ and booster vaccination compared to no prophylactic paracetamol 1- Vomiting 2- Diarrhea 3- Nasopharyngeal carriage rate of the organism No significant difference between prophylactic and no prophylactic groups

 Secondary outcome measures: Outcomes measuredComment 1- Any severe symptomSignificant reduction or difference after booster but not 1˚ vaccination compared to no prophylaxis

 Primary outcome measures: 1) Febrile reactions ≥ 38.0˚c in the 1 st hrs: There was no significant difference between the prophylactic and no prophylactic ibuprofen groups in the reduction of febrile reactions after 1˚ and booster vaccinations

 Secondary outcome measures: Outcomes measuredComment 1- Pain of all grades 2- Pain of moderate – severe grade 3- Local swelling/ induration 4- Drowsiness Significant increase after 1˚ but not booster vaccination in the no prophylactic group compared to ibuprofen group

 Secondary outcome measures: Outcomes measuredComment 1- High febrile reactions ≥ 39˚c 2- Local redness 3- Prolonged cry 4- Irritability/ fussiness 5- Anorexia/ loss of appetite 6- Vomiting 7- Diarrhea No significant difference between the prophylactic and no prophylactic groups after 1˚ or booster

 Primary outcome measures: Antibody response rate after primary vaccination: Prophylactic paracetamol may interfere with primary series immune response to pneumococcal antigens. Prophylactic ibuprofen did not interfere with pneumococcal responses, but may reduce response to pertussis FHA and tetanus antigens.

 Prophylactic antipyretic (paracetamol) administration significantly reduced the febrile reactions of ≥ 38.0˚c after primary and booster vaccinations.  There were statistically significant differences in the antibody responses between the 2 groups (being lower in the prophylactic paracetamol group).  Yet, the prophylactic group had what would be considered protective levels of antibodies to all of the antigens given after primary and booster vaccinations.

 The RCT that questioned the administration of prophylactic paracetamol during administration of childhood vaccines had concluded that although febrile reactions significantly decreased, prophylactic administration of paracetamol should not be routinely recommended since antibody responses to several vaccine antigens were reduced.

 The present review, however, does not find strong evidence to support the conclusion.  Since the antibody response was not reduced below seroprotection level, it is unlikely that prophylactic paracetamol would have any detrimental effect for individual child concerned (same has been endorsed by AAP in their guidelines).

 Regarding the new trial studying the effect of paracetamol and ibuprofen simultaneously, the results are more complicated, as it found differential effect of the antipyretics on the vaccine antigen responses.  The clinical significance of the findings are still unclear.

 This review finds a benefit in favour of prophylactic antipyretic administration on both local and systemic symptoms post- vaccination.

 The result that favours the benefit of prophylactic antipyretics cannot be accepted without flaws, however. This is due to the following 4 points:

1) There is only a small decrease in the GMC of vaccine antibody titers that may be of a statistically significance but the clinical/ epidemiological relevance is not clear. 2) The follow up study has shown that regardless of administration of prophylactic paracetamol, there was no effect on the nasopharyngeal carriage rate post-booster vaccination. 3) The development of fever or increase in the temperature post- vaccination due to release of endogenous cytokines has been considered as a marker of immune response.

4) The potential interference between different vaccines when co- administered with or without antipyretics should also be taken into consideration. Also, it has been noticed that some vaccines are less immunogenic than others (for example, acellular pertussis vaccine is much less immunogenic than the whole cell). If this is already the case, adding prophylactic paracetamol that could lower the immune response even lower, could be a problem.

Validity of the study:  The clinical question is clearly focused with regard to the population, intervention and outcome measured.  The criteria for selection of studies to be included is in accordance with the specification of the question in regard to population, intervention and results.  The criteria for selection of studies to be included is in accordance with the type of research design that is chosen.

 The literature search method was clearly specified. It is less likely that some relevant studies may have been omitted as articles were cross referenced and trials whose results remained unpublished were identified.  The identified studies were evaluated for methodological quality by more than 1 person independently. The degree of agreement was established by discussion with the third person.

Interpretation of the results:  The data was heterogeneous among different studies. The trials were heterogeneous regarding the dosage schedule, age of enrolled children, type of vaccine used and outcomes measured.

 The risk of bias could not be omitted. All the included trials had moderate to high risk of bias because of the following reasons: open or single blinded nature, small sample size and other sources of bias.  The possibility of publication bias in the analysis cannot be ruled out.

Limitations:  Only 2 trials studied the antibody response (1 trial) and carriage rate (1 trial) as a result the data could not be pooled.  Studies used different doses/ schedules of antipyretic administration resulting in significant heterogeneity of the pooled results.  The age of the participants or timing of administration also markedly differed among studies.

Application in clinical practice:  Given the present review and its results, it is beneficial to give prophylactic antipyretics to reduce the side effects of vaccinations. They are safe and cost-effective.  Not only do the antipyretics reduce the unwanted side effects, there is also no strong evidence to support that they do decrease the immunogenity. The small decrease in antibody response is acceptable thus far and might not affect the individual/ herd immunity.

 More trials correlating the timing, dosage, route of administration of the antipyretics to the antibody response rate and trials correlating the post-vaccine decrease in antibody titers with the natural history of the disease should be done in the future.