Methods

Randomisation: no details.
Blinding: double‐blind, but no details of method used.
Number excluded: no details.
Withdrawals: 2 (one from each group due to extraneous viral infection.)
Baseline characteristics: antibody levels to influenza A and B measured and baseline lung function tests.
Jadad score:3

Participants

Location:Houston, Texas.
Participants: 19 healthy adult volunteers with a history of asthma. 17 had data analysed, 11 given vaccine and 6 placebo.
Asthma definition and severity: history of intermittent wheezing, 15 patients using intermittent or continuous bronchodilator therapy.
Exclusion criteria: acute respiratory illness, allergy to egg, pregnancy.

Interventions

Vaccine Type: Intranasal bivalent (H3N2+H1N1) influenza A vaccine. 0.25 ml per nostril.
Placebo: Allantoic fluid, 0.25 ml per nostril.

Outcomes

Early: Lung function tests on days 0, 3‐4, and 7; performed in the mornings (no bronchodilators taken before testing). The authors regarded a reduction in FEV1 of 13% (or greater) from baseline to be clinically significant.
Bronchodilator therapy and hospital admission were also reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

B ‐ Unclear

Methods

Randomisation: by hospital number
Blinding: none (cross‐over with no placebo)
Number excluded: no details
Withdrawals: none
Baseline characteristics: not compared.
Jadad score:1

Participants

Location: Denver, Colorado. Residential Asthma Care Centre.
Number and age of participants: 79 children (age 6 to 16 years) in residential centre.
Asthma definition and severity: reversible obstructive airways disease, moderately severe (two thirds on long‐term corticosteroids).
Inclusion criteria: not received influenza vaccine prior to admission to the centre.
Exclusion criteria: allergy to egg.

Interventions

Vaccination Type: Bivalent (A/Port Chalmers/1/73 and B/Hong Kong/5/72) vaccine containing killed influenza virus. 0.25 ml or 0.5 ml given.
Placebo: none
crossover trial with 2 week washout)

Outcomes

Early: Change in peak flow and mean number of nebulised treatments given.
Late: Not included as no randomisation and retrospective data audited.

Notes

First arm of crossover trial included. Data expressed as Mean difference in % change in predicted Peak Flow, and Nebuliser usage, between vaccinated and non‐vaccinated groups. SD calculated from published SEM. CAUTION: No baseline comparability of the two groups is reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

High risk

C ‐ Inadequate

Methods

Randomisation took place by the manufacturer when packing vaccine and placebo, from a computer generated list.
Blinding: double‐blind with active or placebo vaccines used
Number excluded: 696 children enrolled out of 3220 invited by GPs
Withdrawals: 3 lost diaries from vaccine group and 5 from placebo group
Baseline characteristics: comparable
Jadad score:5

Participants

Location: Rotterdam, Netherlands community based study.
Number and age of participants: 696 children mean age 10.5 years (SD 3.2)
Asthma definition and severity: children selected from GP files based on prescribed asthma medication. Mean FEV1 89% predicted and 16% had ever been hospitalised for asthma
Inclusion criteria: maintenance therapy for asthma or more than 52 doses of relief medication during the previous 12 months
Exclusion criteria were other chronic diseases, allergy to chicken protein and insufficient understanding of the Dutch language

Interventions

Vaccination type: inactivated influenza vaccine intramuscular injection. The vaccine composition for 1999‐2000 was a combination of A/Sydney/5/97 H3N2‐like, A/Beijing/262/95‐like and B/Beijing/184/93‐like strains and for 2000‐2001 A/Moscow/10/99 H3N2‐like, A/New Caledonia/20/99 H1N1‐like and B/Beijing/184/93‐like strains as advised by the World Health Organisation

Placebo group: The placebo consisted of a buffered phosphate solution with the same pH value and similar appearance as the inactivated influenza vaccine.

Outcomes

Primary outcome: Influenza‐related asthma exacerbations (number, duration and severity).
Secondary outcomes were adverse effects of the vaccination including airway symptoms, the number, duration and severity of all asthma exacerbations, proportion of days with symptoms of upper respiratory tract (URTI) and/or lower respiratory tract (LRT), use of asthma medication and other medication, consultations of a specialist or GP, admittance to hospital for airway problems, rising of antibody‐titre against influenza, and the number of serologically proven influenza infections

Notes

Power calculations suggested 600 patients needed to be enrolled.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Low risk

A ‐ Adequate

Methods

Cross‐over design.
Randomisation: central pharmacy labelled injections and kits
Blinding: double blind, contents of syringes not divulged until the end of the trial
Number excluded: no details
Withdrawals: reported 2009 out of 2032 received both injections
Baseline characteristics: only reported for the whole study population
Jadad score: 5

Participants

Location: 19 centres in the USA
Participants: 1240 adults and 712 children with (mostly with mild‐to‐moderate persistent asthma). Asthma was physician diagnosed.
Inclusion criteria: stable asthma taking prescribed asthma treatment in preceeding 12 months, with no exacerbations in previous 2 weeks.
Exclusion criteria: allergy to egg or thiomersal, inability to use peak flow meter, no telephone, history of Guillan‐Barre syndrome, influenza vaccination in previous 6 months, febrile illness in preceeding 24 hours.

Interventions

Vaccination type: Heat‐killed trivalent split‐virus influenza type A and B vaccine (Fluzone, Aventis‐Pasteur).
Placebo: identical syringe containing saline.
Random order of injections with 4 weeks between doses.

Outcomes

Primary outcome: Exacerbation of asthma within 14 days of vaccination.
(Definition as one or more of PEF fall of 30% or more from personal best, increase in daily use of albuterol above average use reported in 2 weeks before randomisation [4 or more puffs or 2 nebulisations for relief of symptoms], increase in systemic steroids, unscheduled use of health care for asthma)
Secondary outcomes:
Decrease of >20% from best personal PEF, average PEF, symptoms, days off school or work, increase in preventer medication.

Notes

Bubble sizes were noted to be larger in the placebo syringes.
Authors provided unpublished data on exacerbations in first time and repeat vaccinees.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Low risk

A ‐ Adequate

Methods

Randomisation: Stratified by four morbidity categories
Blinding: Double‐blind
Exclusions: Those in high risk groups (25 asthmatics were however included in the study)
Withdrawals: none but one patient in the placebo group had incomplete data.
Baseline characteristics: no data
Jadad score: 5

Participants

Location: Netherlands
Patients were all aged 60 or over. Of the 1838 patients participating in the study 25 had asthma (no details of definition or severity but severe cases likely to have been excluded). Of these 14 received vaccine and 11 received placebo.
Exclusion criteria: Age under 60, living in old peoples' homes or nursing homes, belonging to a high risk group (interpreted differently by general practitioners).

Interventions

Vaccination type: purified split vaccine H1N1, H3N2, B45/90, B1/87 given intramuscularly.
Placebo:Physiological saline intramuscularly.

Outcomes

Early: adverse reactions (recalled by the patients after 4 weeks).
Late: Serologically confirmed influenza.

Notes

No serologically confirmed influenza was seen in either the immunised or the placebo group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Low risk

A ‐ Adequate

Methods

Randomisation: Stratified by baseline FEV1 (no details of allocation concealment)
Blinding: single blind
Number excluded: no details
Withdrawals: not stated
Baseline characteristics: FEV1 comparable in each group
Jadad score: 1

Participants

Location: Wurzburg, Germany
Number and age of participants: 52 asthmatic patients (age not stated)
Asthma definition and severity: Reversible airways obstruction. 9 included patients used systemic steroids.
Inclusion criteria: 20% rise in FEV1 following Fenoterol, or 20% spontaneous change in FEV1 recordings or documented breathing difficulty with deterioration in lung function.

Interventions

Vaccination types:
1. Split virus vaccine A/90/70, A/1/77, B/8/73 (injection in deltoid)
2. Subunit vaccine A/92/77, A/1/77, B/8/73 (injection in deltoid)
Placebo: Saline injection (in deltoid)

Outcomes

Lung function measurements in Clinic, (two weeks before and after treatment). Home measurement of peak flow (best of three, twice daily) and symptoms recorded by patients (including breathing difficulty).

Notes

No lung function measurements documented, only "no significant change in lung function following either vaccination or placebo" (even in the patients on systemic steroids).

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

B ‐ Unclear

Methods

Randomisation: no details
Blinding: placebo saline injection given
Number excluded: not stated
Withdrawals: not stated
Baseline characteristics: similar PC20 at baseline
Jadad score:3

Participants

Location: Istanbul, Turkey
Number and age of participants: 59 asthmatic children, all atopic, aged 6.5 to 15 years.
Asthma definition and severity:
no details
Inclusion criteria: symptom free in the past 2 weeks.
Exclusion criteria: no details

Interventions

Vaccination type: Inactivated influenza vaccine given subcutaneously
Placebo: saline subcutaneously

Outcomes

PC20 for methacholine challenge before vaccine and after 24 hours.
Daily peak flow, symptoms and rescue medication in the week after vaccination.

Notes

PC20 (SD) in the placebo group was 7.02 (9.3) before challenge and 7.3 (3.6) after 24 hours. In the vaccine group PC20 was 9.5(10.6) before vaccine and 9.8(9.3) afterwards.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

B ‐ Unclear

Methods

Randomisation: no details
Blinding: none (no placebo)
Number excluded: not stated
Withdrawals: none
Baseline characteristics: serology only
Jadad score:1

Participants

Location: Minami‐Fukuoka chest hospital, Japan. In‐patients on asthma ward.
Number and age of participants: 49 children mean age 11.1 years (SD 2.7)
Asthma definition and severity: institutionalised asthmatic children
Inclusion criteria: in‐patients on the asthma ward
Exclusion criteria: allergy to eggs or chicken feathers

Interventions

Vaccination Type: intranasal cold‐adapted recombinant trivalent influenza vaccine (H1N1, H3N2, B). Dose 0.3 ml by nasal spray.
Placebo: none

Outcomes

Early: asthma attacks
Late: febrile illness with 4 fold rise in antibody titre.

Notes

Serology at the start was NOT comparable with 17/19 in the vaccinated group having a starting titre over 1:64 whereas only 8/25 in the non‐vaccinated group had a starting titre over 1:64

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

B ‐ Unclear

Methods

Randomisation: sealed envelopes, computer‐generated randomisation code provided by vaccine manufacturer.
Blinding: double‐blind
Number excluded: 74 out of 361 patients who agreed to participate
Withdrawals: 25 (8 withdrawn and 17 excluded due to missing data)
Baseline characteristics: comparable PEF in both groups.
Possible order effects and interactions were explored by ANOVA; none were found in the primary analyses.
Jadad score: 5

Participants

Location: nine respiratory centres and two asthma clinics in the United Kingdom.
Number and age of participants: 287 adults randomised, aged 19‐75 years (median 51.7 years).
Asthma definition and severity: "recurrent episodes of airway obstruction that resolved on treatment" as diagnosed by a clinical specialist. 90% were on inhaled corticosteroids and 17% on maintenance oral steroids. Mean PEF at baseline was 67% predicted.
Inclusion criteria: stable asthma (requiring no active revision of medication).
Exclusion criteria: hypersensitivity to eggs, chicken or influenzal protein. Treatment with an investigational drug during the 30 days before recruitment.

Interventions

Crossover design with two intramuscular injections given two weeks apart in random order.
Vaccination Types: Two trivalent vaccines containing either inactivated split‐virus or surface antigen preparations containing 15 mcg of haemagglutinins to A/Singapore/6/86 (H1N1), A/Johannesburg/33/94(H3N2) and B/Beijing/184/93.
Placebo: phosphate‐buffered solution and saline (in identical syringes).

Outcomes

Outcome measures: primary clinical outcome was an asthma exacerbation within 72 hours of injection (defined as 20% fall in Peak Flow compared to lowest of the three days before vaccination). Also measured were change in mean PEF, inhaled Beta‐agonist use (72 hours before and after injection), antibiotic and oral steroid use for 7 days after injection, unscheduled medical attendance and hospital admission for 7 days after each injection. Symptom scores were also analysed for 72 hours before and after injection of vaccine or placebo.

Notes

Peak flow was examined using percentage change for individuals of the worst test for 3 days before and after injection and also using the mean test result over the same periods. On all occasions only the best of three blows was used for the analysis.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Low risk

A ‐ Adequate

Methods

Randomisation: Stratified by lung function results
Blinding: uncertain
Number excluded: no details
Withdrawals: no details
Baseline comparison: not reported
Jadad score: 1

Participants

Location: Germany
Number and age of participants: 80 asthmatics (?age) 28 given whole virus, 24 split virus and 28 subunit vaccine.
Asthma definition and severity: "reversible airways obstruction" stratified by %FEV1
Inclusion/Exclusion criteria: no details

Interventions

Vaccination type: Whole virus, Split virus and Subunit vaccines. (A/Texas, A/USSR, B/Hong Kong). Patients were revaccinated at 6 weeks.
No Placebo group in the study.

Outcomes

Pulmonary function measured for 7 days before vaccination and compared with 3 days after vaccination.
Daily home peak flow measurements before and after vaccination.

Notes

No placebo group and results stated as "no significant change in Lung function for individual or for the combined vaccines."

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

B ‐ Unclear

Methods

Randomisation: computer generated random numbers
Blinding: double‐blind (intranasal placebo used)
Withdrawals: none
Baseline: comparable
Jadad score: 4

Participants

Location: Two paediatric allergy practices in Seattle (Washington) and one in Stockton.
Participants: 48 children and adolescents (aged 9 to 17 years). 75% Caucasian in placebo group and 96% Caucasian in vaccinated group.
Asthma definition and severity:
Reversibility testing (>12% increase in morning FEV1 after albuterol), with FEV1 <80% predicted after withholding albuterol for 8 hours. Mean FEV1 75% predicted.
Exclusion criteria: intranasal corticosteroids, allergy to egg, acute febrile illness within one week, diagnosed with other pulmonary disease.

Interventions

Vaccination type: Intranasal influenza virus trivalent, types A and B, live, cold‐adapted (CAIV‐T).
Dose: single dose of 0.25 ml to each nostril
Placebo: Egg allantoic fluid with sucrose‐phosphate glutamate.

Outcomes

The primary outcome index was the percent change in percent predicted FEV1 before and after vaccination. Peak flows, clinical asthma symptom scores and nighttime awakening scores were measured daily from 7 days pre‐ to 28 days postvaccination

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

B ‐ Unclear

Methods

Randomisation: no details.
Blinding: double‐blind, but no details of method used.
Number excluded: no details.
Withdrawals: none
Baseline comparison: 13 out of the 22 participants had received influenza vaccine before but no data on how these fell into the vaccine or placebo groups. Mean FEV1 was 17% higher in the placebo group.
Jadad score: 3

Participants

Location: Newcastle, UK
Participants: 22 adults aged 19 to 71 years. 17 were randomised to vaccine and 5 to placebo.
Asthma definition and severity: all had FEV1 >60% predicted and >15% reversibility; all took inhaled beta‐agonists and 20 took inhaled steroids. All were non‐smokers and 13 had previously received influenza vaccination.
Exclusion criteria: none mentioned.

Interventions

Parallel design double blind.
Vaccine type: Inactivated surface antigen influenza vaccine 0.5 ml deep subcutaneous injection (Evans Medical Ltd).
Placebo: no details of placebo vaccination

Outcomes

Spirometry (FEV1) and airways responsiveness (PD 20 methacholine). Both were measured twice at an interval of two weeks before vaccination and compared with measurements at 48 and 96 hours post‐vaccination.

Notes

Data presented without standard deviations. The study was powered to detect a halving of the geometric mean PD 20.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Low risk

A ‐ Adequate

Methods

Randomisation: no details
Blinding: single‐blind (but much higher local reaction rate in vaccine group may have compromised this).
Withdrawals: none
Baseline comparison: no described
Jadad score: 3

Participants

Location: Ankara, Turkey
Participants: 24 volunteers with mild stable asthma. Mean age 39 years. 19 women. All non‐smokers. Mean FEV1 100 % predicted (range 73 to 150).
Exclusion criteria: pregnancy, acute respiratory illness, allergy to eggs.

Interventions

Cross‐over design, single blind.
One week wash‐out period.
Vaccine type: inactivated trivalent split antigen (Pasteur Merieux) 0.5 ml intra‐muscular injection.
Placebo: Saline placebo.

Outcomes

Asthma symptoms, morning and evening PEF, bronchodilator use all for one week following vaccination. Spirometry with methacholine challenge at baseline and 2 weeks after vaccination.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

B ‐ Unclear

Methods

Randomisation: stratified into three age groups (15‐29, 30‐49, 50 or more) Patients selected themselves by choosing a folded peice of paper marked A or B inside.
Blinding: double‐blind. Identical ampoules used with a code locked in the vaccine laboratory.
Number excluded: no data
Withdrawals: 328 recruited, 10 withdrew in first week, 27 in total lost to later follow‐up.
Baseline characteristics: comparable for asthma and influenza serology
Jadad score:5

Participants

Location: 9 centres in Finland, asthmatic patients living in the community.
Number and age of participants: 328 adults (age 17‐73)
Asthma definition and severity: moderate to severe asthma in need of daily treatment, all patients fulfilled the criteria for bronchial asthma set by the American College of Chest Physicians and the American Thoracic Society.
Inclusion criteria: ability to make reliable PEF measurements, non‐smokers for past two years, stable asthma for past two weeks, no viral infections for past six weeks.
Exclusion criteria: egg allergy, immunotherapy treatment, treatment with regular beta‐blockers or over 10 mg prednisolone daily, diabetes, bronchiectasis, chronic bronchitis, emphysema, cancer or chronic collagen disease.

Interventions

Vaccination Type: split influenza vaccine (H3N2, B) with subviron component (H1N1) 0.5 ml intramuscular injection.
Placebo: 0.5 ml intramuscular injection of physiological saline.

Outcomes

Early: daily PEF readings, symptom score, daily medication for first week.
Late: daily PEF readings, symptom score, daily medication for five months.

Notes

The incidence of influenza was very low in Finland in the follow‐up period. Sub‐group analysis was performed on the early outcomes to investigate the change in peak flow in different asthma types.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Low risk

A ‐ Adequate

Methods

Randomisation: no details
Blinding: unclear
Number excluded: none?
Withdrawals: 6/20 vaccine group, 8/25 placebo group discharged from hospital.
Baseline characteristics: serology only
Jadad score:2

Participants

Location: Minami‐Fukuoka chest hospital, Japan. In‐patients on asthma ward.
Number and age of participants: 45 children mean age 10.5 years (SD 2.5)
Asthma definition and severity: institutionalised patients with bronchial asthma (no details)
Inclusion criteria: in‐patients in asthma ward.
Exclusion criteria: not stated

Interventions

Vaccination Type: intranasal cold‐adapted recombinant trivalent influenza vaccine (H1N1, H3N2, B). Dose 0.3 ml both nostrils by nasal spray.
Placebo: saline innoculation.

Outcomes

Early: "Asthma attacks", school absence.
Late: Confirmed influenza (virus isolation or confirmed four‐fold antibody rises with fever)

Notes

Baseline serology was similar in vaccinated and placebo groups.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment (selection bias)

Unclear risk

B ‐ Unclear