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Three Part Question

In [children with asthma] does [influenza vaccination] reduce the [number of asthma exacerbations associated with influenza]?

Clinical Scenario

A twelve year old boy presents for a routine asthma follow up appointment during the autumn. He takes 200mcg per day of inhaled budesonide and uses his salbutamol 3-4 times per week. His mother asks if the flu vaccine will make it less likely that he will have an asthma exacerbation over the winter.

Search Strategy

Primary sources
Medline 1966-April week 3 2006 using the OVID interface
{exp Infant/ or exp Child/ or exp Adolescent/ or exp Child, Preschool/ } AND {exp Influenza Vaccines/ or {exp Vaccination/ and exp Influenza, Human/}} AND {exp Asthma/}.
Pubmed and Embase: No further relevant articles were found.
Secondary sources
The references of relevant papers found by this method revealed one further relevant paper which was included in the analysis (Kramarz et al (1)).

Search Outcome

117 papers found of which 4 were relevant (see Table)

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kramarz P et al 2001 USA	Asthmatic children aged 1-6 yrs: 22,231 in 1993-94 38,669 in 1994-95 70,753 in 1995-96	Retrospective cohort study (level 2b)	No. of asthma exacerbations (hospitalization or emergency department visit	Adjusted rate ratio (vaccinated/	Traditional cohort analysis shows increased risk of asthma exacerbation in vaccinated children (p=0.0001 for each cohort) Significant reduced rate of exacerbations only shown after correction of crude odds ratio using 'self control analysis' in 1994-95 and 1995-96.
			Traditional cohort analysis
			1993-94	2.2 (95% CI 1.8-2.6)
			1994-95	1.5 (95% CI 1.3-1.7)
			1995-96	1.4 (95% CI 1.2-1.5)
			Self-control analysis
			1993-94	0.78 (95% CI 0.55-1.10 p=0.15)
			1994-95	0.59 (95% CI 0.43-0.81) p=0.001
			1995-96	0.65 (95% CI 0.52-0.80) p=0.0001
Smits AJ et al 2002 The Netherlands	349 asthmatic children aged 0-12 yrs	Retrospective cohort study (level 2b)	Attack rate of acute respiratory disease	26.1% in non-vaccinated children vs. 21.5% in vaccinated children. The protective effect was limited to children under 6 years of age	Outcome measure was rate of acute respiratory disease and influenza infection was not documented. Those who were vaccinated attended primary care more frequently.
			*Crude odds ratio of acute respiratory disease (all)	0.78 (95% CI 0.57 to 1.2, p=0.17)
			*Crude odds ratio of acute respiratory disease (<6 years)	0.52 (95% CI 0.29 to 0.93, p=0.018)
			* = calculated from raw data in the paper using STATA v8.0 statistical software.
Christy C et al 2004 USA	800 children aged 1-19 years randomly selected from population of 1400 enrolled in 2 large paediatric teaching practices in Rochester, New York.	Retrospective cohort study (level 2b)	Odds of hospitalisation	1.9 (95% CI 0.9 to 3.9, p=0.10)	Numbers presented in paper not internally consistent – those in abstract differ to those in results. Authors conclude that vaccination may have been a marker for 'bad asthma' or increased clinical contact.
			Odds of a clinic visit	2.9 (95% CI 2.0 to 4.1, p<0.001)
			Odds of an emergency department visit	2.0 (95% CI 1.2 to 3.1, p=0.01)
Bueving HJ et al 2004 The Netherlands	696 asthmatic children aged 6-18 yrs	Randomized double-blind placebo-controlled trial (level 1b)	Crude odds ratio of asthma exacerbation with virologically proven influenza infection	1.33 (95% CI 0.69 to 2.57, p=0.39) - more in vaccine group.	Primary end-point failed to demonstrate a benefit of vaccination (in fact showed trend towards harm). Small number of asthma exacerbations in each group with virologically proven influenza infection.
			Adjusted odds ratio of asthma exacerbation with virologically proven influenza infection	1.31 (95% CI 0.59 to 2.09, p=0.44)
			Duration of exacerbations	2.0 days shorter in vaccine group (95% CI –4.9 to 0.9, p=0.19)

Comment(s)

Current Department of Health guidance suggests that influenza vaccination should be offered to all children with 'asthma requiring continuous or repeated use of inhaled or systemic steroids or with previous exacerbations requiring hospital admission' (DoH). This type of 'umbrella advice' therefore extends to many children with mild and/or well-controlled asthma. It is not unusual to be asked by parents of asthmatic children whether influenza vaccine is necessary. Historically, rates of influenza vaccine uptake amongst asthmatic children are known to be low (25% of eligible children) (Chung). One of the key barriers to influenza vaccination include physician endorsement of national recommendations (Rickert) with many doctors remaining ambivalent about the need for influenza vaccination for children with mild or moderate asthma. This view seems to be supported by the lack of convincing benefit shown in the published literature. We identified only one randomised placebo controlled trial of influenza vaccination in asthmatic children (Bueving). The primary endpoint of this study was the number of influenza-attributable asthma exacerbations during the study period. The authors found that the vaccine did not significantly reduce the number of exacerbations. In fact, in this study there were more asthma exacerbations in the vaccine group but this was not statistically significant. A secondary analysis suggested that the duration of exacerbations may be longer in unvaccinated children, but again this difference failed to reach statistical significance. Two out of the three cohort studies show an increased number of exacerbations in children who received the influenza vaccine (Kramarz, Smits, Bueving) but as inclusion was not randomised these studies may be subject to considerable bias. Hence children with more severe asthma may be more likely to attend primary care and to be vaccinated. Although no study shows convincing evidence of benefit overall, Smits et al demonstrated statistically significant beneficial effects in children under 6 years of age (crude odds ratio of acute respiratory disease 0.52 (95% CI 0.29 to 0.93, p=0.018)). Thus young children and those with particularly severe asthma may be most likely to benefit from vaccination.

Clinical Bottom Line

National guidelines continue to recommend inlfuenza vaccination for all children with asthma receiving inhaled corticosteroids. (Grade D) On the basis of the published evidence, there is little data to suggest benefit of influenza vaccination in asthmatic children. (Grade B) The need for vaccination in asthmatic children should be assessed on a case-by-case basis. Younger children and those with more severe asthma are more likely to benefit from vaccination. (Grade B)

References

1. Kramarz P, DeStefano F, Gargiullo PM, Chen RT, Lieu TA, Davis RL, Mullooly JP, Black SB, Shinefield HR, Bohlke K, Ward JI, Marcy SM, Vaccine Safety Datalink Team. Does influenza vaccination prevent asthma exacerbations in children? J Pediatrics 2001;138:306-310
2. Smits AJ, Hak E, Stalman WA, van Essen GA, Hoes AW, Verheij TJ Clinical effectiveness of conventional influenza vaccination in asthmatic children Epidemiol Infect 2002;128:205-211
3. Christy C, Aligne CA, Auinger P, Pulcino T, Weitzman M. Effectiveness of influenza vaccine for the prevention of asthma exacerbations. Arch Dis Child. 2004;89:734-735
4. Bueving HJ, Bernsen RM, de Jongste JC, van Suijlekom-Smit LW, Rimmelzwaan GF, Osterhaus AD, Rutten-van Molken MP, Thomas S, van der Wouden JC. Influenza vaccination in children with asthma: randomized double-blind placebo-controlled trial Am J Respir Crit Care Med 2004;169:488-493
5. Department of Health. 2005. The influenza immunization programme. Letter From the Chief Medical Officer the Chief Nursing Officer and the Chief Pharmaceutical Officer. [Online] Accessed 4/5/06.
6. Chung EK, Casey R, Pinto-Martin JA, Pawlowski NA, Bell LM. Routine and influenza vaccination rates in children with asthma. Ann Allergy Asthma Immunol 1998;80:318-322.
7. Rickert D, Santoli J, Shefer A, Myrick A, Yusuf H. Influenza vaccination of high-risk children: what the providers say. Am J Preventative Med 2006;30:111-8.