Fever and febrile seizures in NZ children following 2010 trivalent inactivated influenza

vaccines

Helen Petousis-Harris, Nikki Turner, Tracey Poole, Department of General Practice and Primary Health Care

Immunisation Advisory CentreUniversity of Auckland

Co-investigators: Robert Booy, Gary Reynolds

Background• April 2010 Western Australia detected increase in

spontaneous reporting of febrile convulsions, single brand?– Estimated 1/110 within 4-6 hours in ≤ 5 year olds

• April 2010 NZ no signals from CARM– 24th April total of 4 reports

• Rapid analysis of ED and admission data for Ak region children hospitals (1.5 million)– No more FC than normally expected (~25 each per week)

Actions taken

Australia April 23rd• Influenza programme for

children under five years suspended

• Insufficient data on other brands to support their continued use

New Zealand April 26th• Recommendation not to

give Fluvax brand to under 5s as precaution

• Stocks of Fluvax exhausted anyway

Collaboration between Australian NCIRS, sanofi pasteur and IMAC

Research• NZ in unique position to evaluate the safety of several brands of flu

vaccine in young children• TIVs used for 2010: Vaxigrip, Fluvax, Influvac

– All A/California/7/2009(H1N1),A/Perth/16/2009 (H3N2), B/Brisbane/60/2008– (also one monovalent A/California/7/2009(H1N1): Celvapan)

OBJECTIVES

1. Assess rate of febrile reactions following Vaxigrip and Fluvax in ≤ 5 years2. Assess rate of febrile convulsion following Vaxigrip and Fluvax in ≤ 5 years3. Assess reactogenicity of these vaccines in other age groups

Methodology• Primary care practices (practice nurses)

identify consecutive vaccinees and run telephone questionnaire

• Administer brief 6 (7) item survey• Vaccine identified by batch number• Three 2010 studies (total of 4142 doses)

– 473 x 18 – 55 years (IMAC)– 100 x 6 years – 18 years (CSL)– 3569 x 6mos – 5 years (Sanofi) 1

1. Petousis-Harris H, Poole T, Booy R, Turner N. Fever following administration of two inactivated influenza vaccines – A survey of parents of New Zealand infants and children 5 years and under. Vaccine.(2011) 29: 2933-2937.

Definitions• Fever either reported or measured

– If measured then defined as ≥38°C– further defined into ≥38°C, ≥39°C and ≥40°C.

• Major Febrile Events– Fever + ED/hospital visit– Fever + GI symptoms (vomiting)– Fever + musculoskeletal symptoms– Fever and malaise/lethargy– Fever and neurological symptoms

• Rigors• Altered consciousness• Convulsive seizure

– Defined as per Brighton Collaboration definitions

Bonhoeffer J. Fever as an Adverse Event following Immunisation Case Definition and Guidelines of Data Collection, analysis and Presentation. Vaccine 2003:1 -6.Bonhoeffer J, Menkes J, Gold MS, de Souza-Brito G, Fisher MC, Halsey N, et al. Generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004;22(5-6):557-62.

Verification of cases

• Clinical records obtained and/or further information sought via clinician interview for following:– Sought medical attention– Reported any neurological symptoms

Recall bias

• Ability of parents to recall events as time between vaccination and survey increased

• Logistic regression – Outcome

• fever recalled within 24 hours or not – Explanatory variables

• Lag time from vaccination to survey• Vaccine• Age and age squared in months• Summer/winter (May-Oct, Nov-Apr)

RESULTS FOR INFANTS AND CHILDREN

Results - recruitmentParents of children identified by

practice as having received Influenza vaccine

2586

Parents able to be contacted

2259 (87%)

Parents completed survey

2244 (99%)

Parents declined15 (1%)

Parents uncontactable

327 (13%)

There were 3188 children and 2244 parents/caregivers in our sample providing data for 3569 doses of vaccine. There was an average of 1.1 doses given per child.

Characteristics of vaccinees

VariableVaxigrip®

N=2545

Fluvax®

N=798P Value

Mean age of vaccinees (Months) 35.05 35.25 0.79

No history of underlying medical

conditions

1854 (73%)

 587 (74%) 0.7

Atopy (asthma, eczema, hayfever) 508 (20%) 150 (19%) 0.47

Cardiovascular condition 51 (2.0%) 13 (1.6%) 0.5

Other medical condition incl renal,

cancer, diabetes180 (7%) 64(8%) 0.37

Administration of paracetamol

before vaccine administration155 (6.1%) 69 (8.6%) 0.01

Mean time (days) from last dose to

questionnaire

Mean 136 days

Range 1 - 332

Mean 197 days

Range 32-332 

 

<0.000

Major febrile events occurring in Vaxigrip® and Fluvax® recipients

Vaxigrip®N=2545

Fluvax®N = 798

Relative Risk(95% CI)

P Value

Convulsion/seizure level 1* 0 (0%) 2 (0.38%) N/A 0.06

Convulsive seizures level 1-3 0 (0%) 3 (0.38%) N/A 0.01

Febrile with rigor/floppy/delirium 0 (0%) 12(1.5%) N/A <0.0000

Febrile with vomiting 10 (0.4%) 54 (6.8%)

17.15

(8.78 – 33.53)<0.0000

Febrile with malaise/lethargy/irritability/headache

61 (2.4%) 124 (15.5%)6.38

(4.75 – 8.56)<0.0000

*Witnessed loss of consciousness and tonic/clonic seizure.

Comparison of febrile events in children ≤5 years following 3559 doses of 2010 flu

vaccine

0%5%

10%15%20%25%30%35%

VaxigripFluvaxInfluvac

Celvapan, 10 doses, 2 medical advice, one fever and vomiting and one fever. 3 fevers within 24 hours

OTHER AGE GROUPS AND 2011 DATA

6 - 9 yearsFluvax (n=42) Vaxigrip (n=36) Fluarix (n=130)

Any fever recalled

6 (14%) 0 (0%) 4 (3%)

Fever within 24 hours

5 (12%) 0 (0%) 2 (3%)

Sought medical attention

2 (5%) 0 (0%) 0 (0%)

Youth aged 10 – 17 years

• Active surveillance (post vaccine diary)– 69 diaries post Fluvax. 1/69 fever of 38.2°C

Fluvax (n=13) Vaxigrip (n-22)

Any fever recalled

0 (0%) 0 (0%)

Fever within 24 hours

0 (0%) 0 (0%)

Sought medical attention

0 (0%) 0 (0%)

Adults aged 18 – 70 years

• Active surveillance (post vaccine diary)– 156 diaries. No fevers– Local reactions

Fluvax (n=209) Vaxigrip (n=262)

Any fever recalled

10 (5%) 14 (5%)

Fever within 24 hours

9 (4%) 11 (4%)

Sought medical attention

1 (0.5%) 0

Ethnicity a risk for feverChildren 6/12 – under 6 years

Fever within 24 hours0%

5%

10%

15%

20%

25%

30%

35%

40%

EuropeanMaoriPacificAsian

N=329 Male/Female 19%/26%

Conclusions• Febrile convulsions high following a single brand of flu vaccine 13-38 per 10,000

dosesCf with:

wDTP vaccine 6-9 per 100,000MMR 25-34 per 100,000

• UK enhanced passive surveillance found 2/10,000 and 1.4/10,000 following H1N1– No excess in reporting

• Not all brands/years equivalent

• Further attention and resources to support programme design and planning and to maintain public confidence.

Thank you