The Effect of Prophylactic Antipyretic Administration on Post-Vaccination Adverse Reactions and Antibody Response in Children: A Systematic Review

Background Prophylactic antipyretic administration decreases the post-vaccination adverse reactions. Recent study finds that they may also decrease the antibody responses to several vaccine antigens. This systematic review aimed to assess the evidence for a relationship between prophylactic antipyretic administration, post-vaccination adverse events, and antibody response in children. Methods A systematic search of major databases including MEDLINE and EMBASE was carried out till March 2014. Randomized controlled trials (RCTs) comparing prophylactic antipyretic treatment versus placebo post-vaccination in children ≤6 years of age were included. Two reviewers independently applied eligibility criteria, assessed the studies for methodological quality, and extracted data [PROSPERO registration: CRD42014009717]. Results Of 2579 citations retrieved, a total of 13 RCTs including 5077 children were included in the review. Prophylactic antipyretic administration significantly reduced the febrile reactions (≥38.0°C) after primary and booster vaccinations. Though there were statistically significant differences in the antibody responses between the two groups, the prophylactic PCM group had what would be considered protective levels of antibodies to all of the antigens given after the primary and booster vaccinations. No significant difference in the nasopharyngeal carriage rates (short-term and long-term) of H. influenzae or S. pneumoniae serotypes was found between the prophylactic and no prophylactic PCM group. There was a significant reduction in the local and systemic symptoms after primary, but not booster vaccinations. Conclusions Though prophylactic antipyretic administration leads to relief of the local and systemic symptoms after primary vaccinations, there is a reduction in antibody responses to some vaccine antigens without any effect on the nasopharyngeal carriage rates of S. pneumoniae & H. influenza serotypes. Future trials and surveillance programs should also aim at assessing the effectiveness of programs where prophylactic administration of PCM is given. The timing of administration of antipyretics should be discussed with the parents after explaining the benefits & risks.


Introduction
Though routine vaccination is extremely beneficial for children, one of the reasons for non-compliance of children is the adverse effect of the previous vaccination [1,2]. Various side effects in the form of local (skin indurations, swelling, rash, pain, or erythema at injection site) and systemic reactions (fever, joint or muscle pain, vomiting, diarrhea, fainting, seizures, or other central nervous system effects) occur commonly after diphtheria, tetanus toxoids and pertussis (DTP) vaccination [3,4]. Again, these reactions are more common after vaccination with whole cell pertusis component vaccine (DTwP) than with acellular pertusis component vaccine (DTaP). When the reactions occur, they usually occur within 24-48 hours following vaccination, are usually mild and self limited, but can result in discomfort in the child [3,4]. It is a common practice for many health providers to suggest that an antipyretic be given preventively at the time of vaccine administration [5].
If the reactogenicity of these vaccines are decreased in the general population, parental anxiety could be relieved to some extent. But there have been different schools of thought regarding prophylactic antipyretic administration. A systematic review conducted way back in 2007 concluded that parents be counseled to monitor vaccine-related adverse reactions and to treat them if and when they occur [6]. This review summarized the findings pertaining only to DTP vaccination, and not to other childhood vaccinations. Recent clinical trials have found that although febrile reactions were significantly decreased by prophylactic antipyretics, antibody responses to several vaccine antigens were reduced [7,8]. Meanwhile, the American Academy of Pediatrics (AAP) continues to say that either prophylactic or therapeutic use of antipyretics should not be withheld [9]. Therefore, the current systematic review was planned to bridge this gap of information and provide any recommendation on the use of prophylactic antipyretics postvaccination in children based on the available evidence.

Methods
The protocol was registered with PROSPERO (Registration number: CRD42014009717).

Types of studies
Randomized controlled trials (RCTs)

Types of participants
Children of both sex and #6 year age undergoing routine immunization were included. Children suffering from chronic debilitating diseases, severe malnutrition (weight for height , 3SD), and underlying immunodeficiency were excluded because of unpredictability of the antibody response after immunizations.

Types of interventions
The intervention commenced either before, or after the child had received any of the routine childhood vaccinations, and consisted of prophylactic or preventive administration of antipyretics (either paracetamol or ibuprofen or both) or placebo/no prophylactic antipyretics. All formulation, dose and schedule of administration of antipyretics were considered. (2) Local symptoms (pain, redness, and swelling at the injection site) after primary and booster vaccinations (3) Systemic symptoms (temperature, irritability/fussiness, drowsiness, diarrhea, vomiting, and loss of appetite) after primary and booster vaccinations (4) Nasopharyngeal carriage (NPC) rate of the organisms (S. pneumoniae, H. influenzae, and others)

Types of outcome measures
The same temperature cutoff was used to define the severity of fever in almost all the trials. All routes of temperature (oral, rectal, and axillary) measurements were considered.
Pain was graded as none, mild (light reaction to touch), moderate (protesting in response to touch or pain with limb movement), or severe (child resists limb movement or keeps limb immobile).
Seroprotection: defined as an antibody concentration $0.1 IU/ mL for diphtheria and tetanus, 0.15 mg/mL for H. influenzae type b, and 10 mIU/mL for Hepatitis B.
Booster vaccine response to PT, FHA and PRN, one month after the administration of the booster dose of DTPa combined vaccine was defined as appearance of antibodies in subjects who are seronegative (that is, with concentrations ,5 ELU/mL) just before booster dose and at least two-fold increase of prevaccination antibody concentrations in those who are seropositive (that is, with concentrations $5 ELU/mL) just before booster dose.
For comparison purpose, an acceptable decreased immunogenicity of all the mentioned vaccines is that the final antibody concentrations should not be below the above mentioned seroprotective/seropositive titers after primary or booster vaccination series. For these database searching, a combination of following search terms were adopted: acetaminophen, paracetamol, ibuprofen, analgesics, antipyretics, adverse reactions, vaccination, immunization, DTwP, diphtheria tetanus-toxoid, whole-cell pertussis, DTaP, acellular pertussis, Streptococcus pneumoniae, Haemophilus influenzae type B, inactivated poliovirus, IPV, pneumococcal 7valent conjugate, pneumococcal 10-valent conjugate, pneumococcal 13-valent conjugate, PCV, measles, mumps, rubella, MMR, meningococcal conjugate, varicella zoster, hepatitis A, hepatitis B, rotavirus, influenza, or pneumococcal polysaccharide. To identify RCTs, which results had remained unpublished; we searched the NIH clinical trial register (www.clinicaltrials.gov). Trials that focused on the therapeutic effects of antipyretics post-vaccination were excluded from the analysis. Articles obtained from this search were cross-referenced and bibliographies were checked for all relevant information. No language restrictions were applied. The search details are given in Appendix S1.

Data extraction
Data extraction was done using a data extraction form that was designed and pilot tested a priori. Two authors independently extracted data from the included studies, including year, setting (country, setting, type of participants, vaccination schedule followed, type of vaccines administered), exposure/intervention (type of antipyretic, dose and schedule of administration, protocol deviation, type of placebo), results (outcome measures, effect, significance), and sources of funding/support. Disagreements in extracted data were resolved through discussion.

Assessment of risk of bias in included studies
Two review authors independently assessed the methodological quality of the selected trials by using methodological quality assessment forms. We undertook quality assessment of the trials using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions [10]. Any disagreements between the two review authors were resolved by discussion with the third author. Trials were assessed with respect to the extent to which investigators minimised the potential for bias to occur and addressed other issues in relation to methodological quality. Publication bias that might affect the cumulative evidence was also assessed. Primary outcomes: local reactions (area of redness or discoloration in the vaccinated limb during the 2 days after vaccination, increase in mid-limb circumference during the 2 days after vaccination), and a persistent reaction (area of redness or discoloration present on the third day after vaccination). Secondary outcomes: Fever $38.0uC (during the next 2 days), local reactions (area of redness or discoloration in the vaccinated limb during the next 6 days after vaccination), itching (during next 6 days), and pain (during next 2 days).
In groups 1 and 2 in addition, if the axillary temperature was .38.0uC or if they were irritable, acetaminophen (10 mg/kg) was given, every 4 to 6 hr interval.

Data synthesis including assessment of heterogeneity
The data from various studies were pooled and expressed as, odds ratio (OR) with 95% confidence interval (CI) for dichotomous data, and mean difference (MD) with 95% CI for continuous data. A p-value of ,0.05 was considered significant. Assessment of heterogeneity was done by I-squared (I 2 ) statistics. If there was a high level of heterogeneity (.50%), we tried to explore this by subgroup analysis if there were adequate number of trials. A fixed effects model was initially conducted. If significant heterogeneity existed among trials (.50%), potential sources of heterogeneity were considered, and where appropriate, a random effects model was used. RevMan (Review Manager) version 5.2 was used for all the analyses [22].

Risk of bias in included studies
(3) Antibody response rate (measured by GMCs) after first booster vaccination ( between the prophylactic PCM group and no prophylactic PCM group. The GMC of anti-PRP, anti-PT, anti-FHA, anti-pertactin, anti-HBs, and anti-polio (type 1,2,3) did not show any significant difference between the prophylactic PCM group and no prophylactic PCM group. Though the GMC of all pneumococcal vaccines serotypes and some other vaccines decreased after prophylactic PCM, still the level of GMC in the prophylactic PCM group was well above the seroprotection level.
(4) Antibody response rate (measured by GMCs) after second booster vaccination (40-48 months age): There was significant difference in the GMC of the anti-pneumococcal IgG antibody between the prophylactic PCM and no prophylactic PCM group, for the following vaccine serotypes: serotype (9) Anorexia/loss of appetite: compared to the no prophylactic PCM group, there was a significant reduction in the anorexia/loss of appetite in the prophylactic PCM group after primary [OR, 0.61; 95%CI, 0.49-0.77], but not booster [OR, 0.85; 95%CI, 0.64-1.14] vaccinations.
(10) Vomiting: There was no significant difference between the prophylactic PCM and the no prophylactic PCM group regarding the reduction of vomiting.
(11) Diarrhea: There was no significant difference between the prophylactic PCM and the no prophylactic PCM group regarding the reduction of diarrhea.
(13) Nasopharyngeal carriage (NPC) rate of the organisms (S. pneumoniae, H. influenzae, and others) There was no significant difference either in the pneumococcal carriage rate (any serotype, vaccine serotypes, or any cross-reactive serotype) or in the H. influenza carriage rate between the prophylactic PCM and the no prophylactic PCM group. The significant finding of post-booster non-typeable H. influenzae carriage rate [OR, 0.61; 95%CI, 0.39-0.95] might be due to chance or inadequate randomization. (14) Days of parental work loss There was no significant difference between the prophylactic PCM and no prophylactic PCM group for the days of parental work loss.

Effect of prophylactic Ibuprofen (IB)
Primary outcome measures. (1) Febrile reactions $38.0uC (100.4uF) in the first 24-48 hrs: there was no significant difference between the prophylactic IB and no prophylactic IB groups regarding the reduction of febrile reactions $38.0uC (100.4uF) in the first 24-48 hrs of primary and booster vaccinations.
Secondary outcome measures. (1) High febrile reactions $ 39.0uC in the first 24-48 hrs: there was no significant difference between the prophylactic IB and no prophylactic IB group regarding the reduction of febrile reactions $39.0uC in the first 24-48 hrs of primary vaccination.
(2) Pain all grades: compared to the prophylactic IB group, there was a significant increase in the pain of all grades in the no prophylactic IB group after primary [ (4) Local redness: There was no significant difference between the prophylactic IB and no prophylactic IB group regarding the reduction of local redness after primary and booster vaccinations.
(5) Swelling/induration: compared to the prophylactic IB group, there was a significant increase in the swelling/induration in the no prophylactic IB group after primary [OR, 1.44; 95%CI, 1.06-1.94] vaccination.
(6) Prolonged cry: There was no significant difference between the prophylactic IB and no prophylactic IB group regarding prolonged cry after primary vaccination.
(7) Irritability/fussiness: There was no significant difference between the prophylactic IB and no prophylactic IB group regarding irritability/fussiness after primary vaccination. (9) Anorexia/loss of appetite: There was no significant difference between the prophylactic IB and no prophylactic IB group regarding anorexia/loss of appetite after primary vaccination.
(10) Vomiting: There was no significant difference between the prophylactic IB and no prophylactic IB group regarding vomiting after primary vaccination.
(11) Diarrhea: There was no significant difference between the prophylactic IB and no prophylactic IB group regarding diarrhea after primary vaccination.

Effect of prophylactic PCM and prophylactic IB
Primary outcome measure. (1) Antibody response rate (measured by GMCs) after primary vaccination (2, 3, 4, and 12 month age): This was reported in one trial [presented as conference abstract]. The trial employed 5 groups (Table 1), and the results were as follows. Pneumococcal anticapsular IgG GMCs were significantly lower (p,0.0125) in G3 (received paracetamol at vaccination and thereafter) versus G5 (no antipyretic) for 5 of 13 serotypes after the primary series. Pertussis FHA and tetanus IgG GMC was significantly lower among G4 (received ibuprofen at vaccination and thereafter) versus G5 (no antipyretic) after the primary series. No differences were observed for any antigens after the toddler dose. The trial concluded that prophylactic PCM may interfere with primary series immune response to pneumococcal antigens. Prophylactic IB did not interfere with pneumococcal responses, but may reduce response to pertussis FHA and tetanus antigens. These effects were not observed following the toddler dose. The clinical significance of these findings is unclear.

Publication bias
To assess whether there was a bias in the published literature, funnel plot was constructed using the OR and 1/SE values obtained from studies measuring the primary outcome (febrile reactions of $38.0uC in the first 24-48 hrs of PCM administration). In the absence of a publication bias, such a plot is expected to have a shape resembling an inverted funnel [23]. From the asymmetry of funnel plot generated, the possibility of publication bias in the analysis cannot be ruled out (Figure 4).

Summary of evidence
Prophylactic antipyretic administration significantly reduced the febrile reactions of $38.0uC after primary and booster vaccinations. Though there were statistically significant differences in the antibody responses between the two groups (being lower in the prophylactic PCM group), the prophylactic PCM group had what would be considered protective levels of antibodies (GMCs) to all of the antigens given after the primary and booster vaccinations. There was a significant reduction in the local and systemic symptoms after primary, but not booster vaccinations (except for any severe symptom, that had a significant reduction after booster but not primary vaccinations).
The present review does not find a strong evidence to support the conclusion of a well conducted RCT that questioned the administration of prophylactic PCM during administration of childhood vaccines. This RCT had concluded that although febrile reactions significantly decreased, prophylactic administration of PCM at the time of vaccination should not be routinely recommended since antibody responses to several vaccine antigens were reduced [7]. However, since the antibody response (GMC) was not reduced below seroprotection level, it is unlikely that prophylactic PCM would have any detrimental effect for individual child concerned. The same has been endorsed by AAP in their guidelines [9]. Regarding the new trial studying the effect of PCM and IB simultaneously, the results are more complicated, as it found differential effect of the antipyretics on the vaccine antigen responses [21].
The present review finds a benefit in favour of prophylactic antipyretic administration on both local and systemic symptoms post-vaccination, although the analyses included trials using mostly DTwP (6 trials) instead of DTaP (3 trials), the later being less reactive. The results of the RCT that has sparked the debate about the beneficial role of prophylactic antipyretic though cannot be ignored, but cannot be accepted with foolproof at the same time [7]. This is because of the following four points. First, there is only a small decrease in the GMC of vaccine antibody titers that may be of statistically significant but the clinical/epidemiological relevance is not clear. The latter is supported by the fact that, in spite of being a common practice for administration of prophylactic antipyretics after immunizations for decades, there have been significant reductions in invasive disease due to S. pneumoniae and H. influenzae type b serotypes. Second, the follow up study to the above RCT has shown that regardless of the administration of prophylactic PCM, there was no effect on the nasopharyngeal carriage rate post-booster vaccination [8]. Third, the development of fever or increase in the temperature postvaccination due to the release of endogenous cytokines (IL 1, TNF a), has been considered as a marker of immune response to respected vaccines. Fourth, the potential interference between different vaccines when co-administered with or without antipyretics should also be taken into consideration. For example, 30-60% lower anti-HBs GMTs occur when co-administered with HPV vaccines and that without antipyretics, which might further diminish the magnitude of the immune response. It has also been seen that the acellular pertussis vaccine is much less immunogenic than the whole cell, and PCV13 develops lower IgG concentra- tions than PCV7 to the common serotypes. If this is already the case, adding prophylactic PCM that could lower the immune response even lower, could be a problem. If there is already herd immunity, maybe a small decrease in efficacy at the individual level will take a long time to be noticed, and would raise the need for better surveillance programs for vaccine-preventable diseases in all countries. Because of these later two findings, there is concern that prophylactic antipyretic might decrease the postvaccination immune response further.
Besides these, the findings of another RCT [24] reporting about the infant sleep after immunization and relation of acetaminophen (paracetamol) use need mention here. This RCT found that paracetamol use post-immunization (not prophylactic) was associated with increase in the infant sleep duration. As sleep deprivation before or after has been associated with decreased antibody formation post-immunization in adults, this study postulates that use of acetaminophen post-immunization might facilitate the immune response. But this study neither studied the effect of prophylactic antipyretic nor measured the antibody response.

Limitations
Only two trials (from the same country) studied the antibody response (one trial) and carriage rate (one trial) as a result the data could not be pooled. Studies used different doses/schedules of antipyretic administration resulting in significant heterogeneity in the pooled result. The age of the participants or timing of administration also markedly differed among the studies. Only one study from developing country (India) made it difficulty in generalizing the present review findings.

Further area of research
Future trials should focus on the timing (before, with or after) and route (oral or rectal) of administration of paracetamol as well as on the subgroup of infants (term or preterm) for any correlation with the immune response. As there was no trial examining the prophylactic effect of ibuprofen on post-vaccination antibody response, future trials should focus on this. Any post-vaccination decrease in antibody titer noted in future studies should be correlated with the natural history of that particular disease. The mechanism underlying the decrease in immune/antibody response should also be explored. Immune response to varicella, hepatitis A, measles, MMR, and flu vaccine should also be studied, if feasible. Trials should also be conducted in developing countries where over-the-counter use of antipyretics (including prophylactic) are common. Other confounding factors that might affect the antibody response (e.g., infant sleep post-immunization) should also be studied.

Conclusions
Though prophylactic antipyretic administration leads to relief of the local and systemic symptoms after primary vaccinations, there is a reduction in antibody responses to some vaccine antigens without any effect on the nasopharyngeal carriage rates of S. pneumoniae & H. influenza serotypes. Future trials and surveillance programs should also aim at assessing the effectiveness of programs where prophylactic administration of PCM is given. The timing of administration of antipyretics should be discussed with the parents after explaining the benefits & risks.

Supporting Information
Checklist S1 PRISMA checklist.