The safety of inactivated influenza vaccine in adults and children with asthma. Influenza vaccination in children with asthma: randomized double-blind placebo-controlled trial. Influenza vaccination in adults with asthma: safety of an inactivated trivalent influenza vaccine. Lack of clinical exacerbations in adults with chronic asthma after immunization with killed influenza virus. Effects of inactivated influenza virus vaccination on bronchial reactivity symptom scores and peak expiratory flow variability in patients with asthma. Randomised placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma. Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma. Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Effect of live attenuated, cold recombinant (CR) influenza virus vaccines on pulmonary function in healthy and asthmatic adults.
Influenza causes substantial morbidity in adults and children with asthma, and vaccination can prevent influenza and its complications. However, there is concern that vaccination may cause exacerbations of asthma.
                To investigate the safety of the inactivated trivalent split-virus influenza vaccine in adults and children with asthma, we conducted a multicenter, randomized, double-blind, placebo-controlled, cross-over trial in 2032 patients with asthma (age range, 3 to 64 years). The order of injection of vaccine and placebo was assigned randomly, with a mean of 22 days between the injections. Each day during the two weeks after each injection, the patients recorded peak expiratory flow rates, symptoms thought to be related to the injection, use of asthma medications, unscheduled health care visits for asthma, and asthma-related absences from school or work. The primary outcome measure was an exacerbation of asthma in the two weeks after the injections.
                The frequency of exacerbations of asthma was similar in the two weeks after the influenza vaccination and after placebo injection (28.8 percent and 27.7 percent, respectively; absolute difference, 1.1 percent; 95 percent confidence interval, -1.4 percent to 3.6 percent). The exacerbation rates were similar in subgroups defined according to age, severity of asthma, and other factors. Among symptoms thought to be associated with the injection, only body aches were more frequent after the vaccine injection than after placebo injection (25.1 percent vs. 20.8 percent, P<0.001).
                The inactivated influenza vaccine is safe to administer to adults and children with asthma, including those with severe asthma. Given the morbidity of influenza, all those with asthma should receive the vaccine annually. There is little evidence that influenza vaccination reduces asthma exacerbations. We determined whether influenza vaccination is more effective than placebo in 6-18-year-old children with asthma. We performed a randomized, double-blind, placebo-controlled trial. Parenteral vaccination with inactivated influenza vaccine or placebo took place approximately November 1, and children were followed until April 1 of the next year. Airway symptoms were reported in a diary. When symptom scores reached a predefined level, a pharyngeal swab was taken. Primary outcome was the number of asthma exacerbations associated with virologically proven influenza infection. Three hundred forty-nine children were assigned placebo, and 347 were assigned vaccine. Pharyngeal swabs positive for influenza were related to 42 asthma exacerbations, 24 in the vaccine group and 18 in the placebo group, a difference of 33% favoring placebo (31% after adjustment for confounders; 95% confidence interval, -34% to 161%). Influenza-related asthma exacerbations were of similar severity in both groups; they lasted 3.1 days shorter in the vaccine group (95% confidence interval, -6.2 to 0.002 days, p = 0.06). We conclude that influenza vaccination did not result in a significant reduction of the number, severity, or duration of asthma exacerbations caused by influenza. Additional studies are warranted to justify routine influenza vaccination of children with asthma. Despite recommendations in most countries for giving inactivated influenza vaccine to people with asthma, only a minority currently receive it. One reason for low vaccine coverage has been concern that vaccination may induce exacerbations of asthma. In this randomized trial, 291 patients between 18 and 65 years of age received either an inactivated influenza vaccine followed 14 days later by a saline placebo or placebo followed by the vaccine. Each patient received 1 dose of vaccine and 1 dose of placebo. The percentage of patients reporting at least one asthma exacerbation within 14 days after injection was similar following vaccine or placebo (28.3% and 25.5%, respectively). The combined exacerbation rate during the first 14-day interval was higher (31.5%) than that during the second 14-day interval (22.4%, P = 0.0135), indicating that the occurrence of exacerbations was not likely to be related to the sequence of injections. The percentages of individuals with solicited systemic symptoms were 56.6% and 44.8% after vaccine or placebo injection, respectively. We conclude that influenza vaccination did not increase the incidence of asthma exacerbations compared to placebo in this study and the vaccine was well tolerated. The results thus support annual influenza vaccination in patients with asthma. The effects of immunization with killed influenza virus vaccine were assessed by comparison with placebo in a double-blind study of 318 adult patients with chronic asthma. The patients were randomly allocated to active vaccine and placebo. No difference was observed in peak expiratory flow rate or in clinical symptoms of bronchial obstruction between the groups receiving active vaccine and placebo during the first week after immunization. The data were analyzed separately for age, sex, duration of the disease, hypersensitivity to aspirin (acetylsalicylic acid), atopic status, patients with a history of attacks of asthma induced by viral infections, patients with a diurnal variation of baseline peak expiratory flow of 20 percent or more, and patients receiving continuous oral steroid medication, but none of these factors seemed to predict any short-term adverse effects of vaccination. Follow-up for eight months after the vaccination revealed no differences in asthmatic symptoms between the patients treated with active vaccine and those receiving placebo. The antiviral antibody response to vaccination was normal. The possible protection provided by the vaccination against exacerbation of asthma induced by influenza could not be evaluated, since the influenza epidemic expected during the season failed to occur in Finland. It is concluded that immunization with killed influenza vaccine is safe and is not associated with any significant side effects in adult patients with chronic asthma. Even though annual influenza vaccinations are recommended by many authorities, some doctors may be reluctant to vaccinate asthmatic patients because of the risk of inducing bronchial reactivity and exacerbating the asthma. In this study we investigated the effect of inactivated trivalent influenza vaccine on airway reactivity symptom scores and peak expiratory flow (PEF) variability in 24 patients with mild stable asthma. Baseline spirometry and methacholine challenge tests were performed on all patients. Patients were then asked to record their peak expiratory flow every morning and evening, complete daily symptom score charts (morning tightness, daytime asthma, cough, and night asthma), and note bronchodilator usage for 1 week. After baseline measurements, the patients were allocated to inactivated vaccine and placebo in a random and single-blind manner. The lung function measurements and methacholine challenge tests were repeated 1 week after vaccination and placebo administration at the same time of day. PD20 (mg/mL) methacholine doses were 3.06+/-3.0 mg/mL before vaccination, 2.96+/-3.2 mg/mL after vaccination, and 2.76+/-2.91 mg/mL after placebo administration. There were no significant changes in PD20 methacholine after influenza vaccination (p>0.05). There were also no significant changes in symptom scores, bronchodilator usage, and PEFR after vaccination (p>0.05). None of the patients experienced significant local or systemic side effects after vaccination. Immunization with inactivated influenza vaccine does not induce clinical exacerbations of asthma or airway hyperreactivity in patients with mild asthma. Despite current recommendations, many people with asthma do not receive annual vaccination against influenza, partly because of concern that vaccine may trigger exacerbations. Colds can trigger exacerbations, which may be mistaken for vaccine-related adverse events. We undertook a double-blind placebo-controlled multicentre crossover study to assess the safety of influenza vaccine in patients with asthma, with allowance for the occurrence of colds.
                We studied 262 patients, aged 18-75 years, who recorded daily peak expiratory flow (PEF), respiratory symptoms, medication, medical consultations, and hospital admissions for 2 weeks before the first injection and until 2 weeks after the second injection. Order of injection (vaccine and placebo) was assigned randomly. There was an interval of 2 weeks between injections. The main outcome measure was an exacerbation of asthma within 72 h of injection (defined as a fall in PEF of >20%).
                Among 255 participants with paired data, 11 recorded a fall in PEF of more than 20% after vaccine compared with three after placebo (McNemar's test p=0.06); a fall of more than 30% was recorded by eight after vaccine compared with none after placebo (binomial test p=0.008). However, when participants with colds were excluded, there was no significant difference in the numbers with falls of more than 20% between vaccine and placebo (six vs three; binomial test p=0.51), although the difference for PEF decreases of more than 30% approached significance (five vs none; binomial test, p=0.06). This association was confined to first-time vaccinees.
                Our findings indicate that pulmonary-function abnormalities may occur as a complication of influenza vaccination. However, the risk of pulmonary complications is very small and outweighed by the benefits of vaccination. Influenza infections can cause severe respiratory disease in high risk persons such as those with asthma, but immunization rates for high risk groups remain suboptimal. An investigational influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) administered by intranasal spray was shown previously to be effective in healthy adults and healthy children.
                To assess the safety and tolerability of CAIV-T in subjects 9 years of age and older with moderate to severe asthma.
                In this randomized, double blind, placebo-controlled study, spirometry was performed twice before vaccination to establish a baseline forced expiratory volume at 1 s (FEV1) and once 2 to 5 days thereafter. 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.
                The primary outcome index (percentage change in percent predicted FEV1) was not different between the two groups (0.2% vs. 0.4% for the treatment and placebo groups, respectively; P = 0.78). Secondary outcomes did not differ between the two groups; these included the number of subjects with a decrease in FEV1 > or =15% from baseline, reductions in peak flows > or =15%, > or =30% or > or =2 sd below baseline, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and after vaccination. The same proportion of subjects in each group experienced postvaccination symptoms within 10 days (92% and 91%, respectively; P = 1.0). No serious adverse event occurred.
                CAIV-T was generally safe and well-tolerated in children and adolescents with moderate to severe asthma. Despite their potential for increased morbidity, 75% to 90% of asthmatic children do not receive influenza vaccination. Live attenuated influenza vaccine (LAIV), a cold-adapted, temperature-sensitive, trivalent influenza vaccine, is approved for prevention of influenza in healthy children 5 to 19 years of age. LAIV has been studied in only a small number of children with asthma.
                Children 6 to 17 years of age, with a clinical diagnosis of asthma, received a single dose of either intranasal CAIV-T (an investigational refrigerator-stable formulation of LAIV; n = 1114) or injectable trivalent inactivated influenza vaccine (TIV; n = 1115) in this randomized, open-label study during the 2002-2003 influenza season. Participants were followed up for culture-confirmed influenza illness, respiratory outcome, and safety.
                The incidence of community-acquired culture-confirmed influenza illness was 4.1% (CAIV-T) versus 6.2% (TIV), demonstrating a significantly greater relative efficacy of CAIV-T versus TIV of 34.7% (90% confidence interval [CI] 9.4%-53.2%; 95% CI = 3.9%-56.0%). There were no significant differences between treatment groups in the incidence of asthma exacerbations, mean peak expiratory flow rate findings, asthma symptom scores, or nighttime awakening scores. The incidence of runny nose/nasal congestion was higher for CAIV-T (66.2%) than TIV (52.5%) recipients. Approximately 70% of TIV recipients reported injection site reactions.
                CAIV-T was well tolerated in children and adolescents with asthma. There was no evidence of a significant increase in adverse pulmonary outcomes for CAIV-T compared with TIV. CAIV-T had a significantly greater relative efficacy of 35% compared with TIV in this high-risk population. The effects of intranasal inoculation with live attenuated, CR influenza virus vaccines on pulmonary function in healthy and asthmatic adults were evaluated in placebo-controlled, double-blind studies. In 46 healthy adult volunteers, there were no statistically significant alterations in pulmonary function as measured by spirometry and histamine bronchoprovocation tests in the first week following monovalent CR influenza virus vaccine [type A (H3N2, H1N1) and type B]. Among healthy adults with pre-inoculation PC20s less than 10 mg ml-1, 8/12 were infected following vaccination but no significant alterations occurred in histamine bronchoprovocation. In 11 asthmatic adults, no statistically significant alterations in pulmonary function, as measured by spirometry, were noted during the first 7 days postinoculation with bivalent CR influenza virus vaccine type A (H3N2 and H1N1). Postinoculation respiratory illnesses were more common in CR influenza virus vaccine recipients than placebo recipients, but they were mild, consisting of afebrile pharyngitis and transient rhinorrhea. Attenuated CR influenza virus vaccines do not appear to impair pulmonary function during the first week following immunization of healthy and asthmatic adults.
Uncertainty remains about the degree of protection that vaccination affords against asthma exacerbations that are related to influenza infection. Evidence from more recently published randomised trials of inactivated split-virus influenza vaccination indicates that there is no significant increase in asthma exacerbations immediately after vaccination in adults or children over three years of age. We were unable to address concerns regarding possible increased wheezing and hospital admissions in infants given live intranasal vaccination.