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Does primary immunisation cause C-Reactive Protein to rise in premature infants?

Three Part Question

In [premature neonates] does [primary immunisation] result in elevation of [C-Reactive Protein levels]?

Clinical Scenario

A premature neonate has received their first set of immunisations. Routine blood investigations two days following reveal a raised C-Reactive Protein (CRP). Other than a low-grade fever, the infant has been otherwise well. Can this raised CRP be explained by preceding immunisation or is it a sign of an evolving sepsis illness?

Search Strategy

Medline: 1950 to July 2008 and Embase: 1980 to 2008 week 30, both using the OVID interface.
[Immunisation OR Vaccination] AND [C-Reactive Protein OR CRP]
Limits: Human; Infant: Birth to 23 months (Medline); Birth to 1 year (Embase)

Search Outcome

No systematic reviews were identified. Twenty-four papers were identified of which five were relevant.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Pourcyrous et al
239 preterm infants in a neonatal unit (mean gestation age 28 weeks) receiving their first vaccination - either (i) a single vaccination [DTaP, Hib, IPV, HBV or PCV7] and the remainder 3 days later or (ii) two or more vaccinations simultaneously with the remainder 3 days later.Prospective observationalSerum CRP before immunisation and 12 hourly post immunisation for 36 hours.85 % of infants receiving multiple vaccinations had a CRP > 16 mg/L (max 108). CRP also rose in infants receiving DTaP (24%), PCV7 (54%) and Hib (70%), but not with IPV or HBV.Multiple subgroups mean each has relatively small number of subjects.
17 infants (mean age 20 weeks) presenting to an emergency department with vaccine-associated adverse reactions (fever; local swelling; seizure or hypotonic hyporesponsiveness; persistent crying; vomiting) Retrospective observational Serum CRP at time of presentation. CRP raised (>5 mg/L) in 13 cases (mean 21 +/- 5mg/L). 9 infants admitted to hospital; lumbar puncture performed in 4 infants; intravenous antibiotics started in 2. Culture results all negative. Small study group of non-premature infants. Only representative of infants attending with adverse reactions, although this group may be of clinical importance. Various combinations of vaccines had been given (6 in total).
Balkundi et al
12 infants in a neonatal unit given DTP and Hib immunisation Prospective observational CRP level for 48 hours post immunisation Median CRP value < 4 mg/L pre-immunisation, rising to 10.4 mg/L 24 hours post-immunisation and 18 mg/L (range 4.2 - 48.g mg/L) 48 hours postimmunisation Small study group. Wide range of CRP responses. One (included) infant screened for infection during study; it is unclear whether this infant was septic, if so this may have affected the results.
Pourcyrous et al
(i) 79 premature infants (mean gestational age at birth 28 weeks) in a neonatal unit receiving first (79) or second (2) set of immunisations (DTwP, Hib, HBV +/- IPV) (ii) 10 further premature infants (mean gestational age at birth 27 weeks) receiving DTaP with Hib, HBV and IPV given two days later.Prospective observationalSerum CRP before immunisation and 12 hourly post immunisation until CRP normal.(i) Following immunisation CRP rose from < 10 mg/L to a maximum (mean) of 40 +/- 20 mg/L at 32 +/- 9 hours after immunisation in 78 of the 79 infants (the remaining infant later proved to have a T-cell disorder). CRP normalised at a mean of 82 +/- 27 hours. Two infants received antibiotics (cultures negative).The two differences between the study groups (DTwP cf DTaP and concurrent cf delayed) make it difficult to interpret the results. Small second study group.
Ellison et al
48 preterm infants (mean gestational age at birth 26.4 weeks) receiving first vaccination (either DTaP, Hib, HepB and IPV or DTaP, Hib and Hep B) in a neonatal unit.Retrospective observational Adverse events during the 48 hours pre-immunisation and post-immunisation.Infants were signficantly more likely to have a temperature > 48 degrees centigrade post-immunisation. 4 infants underwent septic work up post-immunisation (either due to increased oxygen requirement or apnoea requiring stimulation). In each CRP was increased (range 15 to 58 mg/L). In each cultures were negative.Retrospective study. Small study group. CRP measured only in infants with worrying adverse reactions.


These studies consistently suggest that many premature infants have elevated CRP levels following immunisation. This occurred more often when multiple vaccinations are administered concurrently (as is the practice in the UK) rather than singularly. CRP rises to peak at approximately 32 hours after immunisation and may be of the order of 40 mg/L, and often higher, often without corresponding clinical signs. Although none of the studies fully represent current immunisation practice in the United Kingdom (DTaP/IPV/Hib as Prevenar; PCV as Prevenar for the 2 month immunisation), however the vaccines may be similar enough to extrapolate these results. Following immunisation some infants had significant clinical events suggestive of a sepsis illness and were started on intravenous antibiotics. In none of the studies did any of these infants have positive cultures.

Clinical Bottom Line

Immunisation, particularly the concurrent administration of multiple vaccines, can cause signficantly elevated CRP levels in premature infants. This information may help clinicians rationalise the use of antibiotics in such infants.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.


  1. Pourcyrous M, Korones SB, Arheart KL, Bada HS Primary immunization of premature infants with gestational age <35 weeks: cardiorespiratory complications and C-reactive protein responses associated with administration of single and multiple separat J Pediatr 2007; 151(2): 167-72
  2. Korczowski B Procalcitonin and C-reactive protein in vaccination-associated adverse reactions. Pediatr Infect Dis J 2004; 23(3): 283.
  3. Balkundi DR, Nycyk JA, Cooke RW Immunisation and C reactive protein in infants on neonatal intensive care units. Arch Dis Child 1994; 71(2): F149.
  4. Pourcyrous M, Korones SB, Crouse D, Bada HS Interleukin-6, C-reactive protein, and abnormal cardiorespiratory responses to immunization in premature infants. Pediatrics 1998; 101(3): E3.
  5. Ellison VJ, Davis PG, Doyle LW Adverse reactions to immunization with newer vaccines in the very preterm infant. J Paediatr Child Health 2005; 80(8): 565-9.