Nonatopic wheezing is a transient symptom that might be related to respiratory viral infections in young infants and might spontaneously disappear after they grow up. Atopic wheezing is a recurrent symptom with a greater risk of becoming asthma (11
) because of bronchial hyper-responsiveness. As children with recurrent wheezing frequently receive steroid treatment and therefore are at risk to acquire viral respiratory infections, it is highly recommended that they be vaccinated with influenza virus vaccine (12
). In reality, however, these children frequently receive delayed vaccination or even miss vaccination, and some studies reported that these populations should be closely monitored for timely vaccination (13
The average age of children with recurrent wheezing was older than that of healthy children, and the average age of vaccine-naive children with recurrent wheezing was older than that of vaccine-naive healthy children (). We can assume a tendency for delayed influenza virus vaccination in children with recurrent wheezing.
There is no absolute standardized criterion to evaluate the immunogenicity of influenza virus vaccines. However, the HI assay commonly is used to assess vaccine immunogenicity by measuring serum HI antibody titers against the three influenza virus vaccine strains and to evaluate postvaccination seroconversion rates, seroprotection rates, and GMTs, including GMTRs (14
). Specific antibodies against hemagglutinin of influenza virus offer protective immunity, and those antibodies produced by B cells are T cell dependent (17
). Therefore, antibody responses to influenza virus vaccines decrease in cases of alterations in the interactions between T cell and B cell immunity. Decreased helper T cell function alters overall immune responses (18
) and, as steroids are considered to affect T cell immunity, some experts assume that steroid treatment decreases vaccine immunogenicity (20
). In that context, this study was carried out. There are reports that temporary treatment with high-dose steroids for asthmatic patients does not influence immunogenicity (21
), as reported for long-term steroid therapy (23
). Moreover, another study demonstrated that steroids did not influence the immunogenicity of influenza virus vaccination, and aggravation of asthmatic symptoms was not noted after vaccination among asthmatic children (8
). According to these study results, the Committee on Infectious Diseases of the American Academy of Pediatrics strongly recommends timely vaccination for these children before the winter influenza season, with the exception of allowing delayed vaccination during the time of receipt of high-dose corticosteroids as long as the likelihood of immunization before the start of the influenza season is not compromised (27
Our study participants who were children with recurrent wheezing had more than two wheezing episodes during their first year of life. The average number was more than four. During this period, the children received inhaled or systemic steroid treatment more than 3 times. According to the study design, we excluded only children receiving long-term high-dose steroid treatment and those with acute fever; other children receiving steroids and those with wheezing symptoms were vaccinated. Generally for the pediatric population, the requirements are that the lower boundary of the two-sided 95% CI for the percentage of subjects achieving seroconversion for the HI antibody should meet or exceed 40% and the lower boundary of the two-sided 95% CI for the percentage of subjects achieving protective levels should meet or exceed 70% (28
). Both healthy children and children with recurrent wheezing sufficiently met these immunogenicity criteria (). The results showed that there was no difference between the two groups. Also, no difference in vaccine immunogenicity against vaccine strains between the steroid-treated and nontreated groups of children with recurrent wheezing was observed (). Previous studies have shown that young children tend to show lower immunogenicity for B strains than for A strains after influenza virus vaccination (30
). In our study, lower immunogenicity for the B strain (lower GMTR) also was demonstrated, similar to the aforementioned results ( and ). The rate of seroprotection against the B strain in the steroid-treated group was below 70%, but there was no statistically significant difference (). This result is similar to reports that the antibody response against the B strain in the steroid-treated group is lower than that in the non-steroid-treated group (32
) but is in contrast to the research of Park et al. indicating that the antibody response against the B strain in asthmatic patients who receive steroid treatment is higher (25
The immunogenicity of one-dose versus two-dose vaccination was evaluated in both groups. For healthy children, rates of seroprotection against the H1N1 and B strains were higher in the one-dose subgroup, and preimmunization and postimmunization GMTs against all vaccine strains were higher in the one-dose subgroup. The results were similar for children with recurrent wheezing except that the two-dose subgroup showed higher postimmunization GMTs against A/Perth(H3N2), like healthy children (), a trend that was not observed in an overall comparison of healthy children and children with recurrent wheezing (). The aforementioned results suggest that immune responses after influenza virus vaccination might be more active in the one-dose subgroup, because of older age, previous vaccination, and greater possibility of natural exposure. In a subanalysis according to previous influenza virus vaccination history, seroconversion and seroprotection rates and GMTRs showed no difference between healthy children and steroid-treated children with recurrent wheezing, except that rates of seroprotection against the B strain were below 70% for the two-dose subgroups of healthy and steroid-treated children (). These results suggest that short-term low-dose steroid treatment might not influence influenza virus vaccine immunogenicity. We need to consider that influenza virus vaccine immunogenicity might be affected by exposure to natural infection sources. This study was performed from autumn to the following early spring, during the annual influenza season in the northern hemisphere. During the study period, the first case of A(H3N2) influenza infection in South Korea was reported in December 2011. Since then, A(H1N1) influenza infection cases were continuously reported but with a lower incidence than in the previous year. B strain influenza spread widely across the nation in January and thereafter. Fortunately, the study closed before widespread infection caused by B strains. Among the study participants, only 1 subject fulfilled the clinical criteria of influenza-like illness. The patient was confirmed to have B strain infection, received conservative upper respiratory infection treatment in the outpatient clinic, and recovered fully without complications. In conclusion, our study demonstrates that inactivated TIV is able to induce protective immune responses in healthy children, as observed in previous studies (35
), as well as in children with recurrent wheezing.
Previous studies (36
) reported that the split inactivated influenza virus vaccine appeared to be safe and well tolerated, and adverse events generally were mild. There were no moderate-to-severe adverse events in either group in the study. The incidences of solicited local and systemic reactions and the incidences of adverse events of grade ≥2 showed no differences between the two groups.
This study has several limitations. First, the number of patients who participated in each cohort was small. A key characteristic of influenza virus vaccination is that it is mostly performed within a short period preceding seasonal outbreaks, unlike other vaccinations that are performed perennially, which limits the overall accrual of patients. Another concern is the lack of a placebo-treated patient group in our study design. However, the efficacy of influenza virus vaccination in healthy children is well established, precluding the need for additional placebo trials in our study. Our main objective in this study was to confirm comparable vaccine efficacy and safety between children with recurrent wheezing and healthy children. The two cohorts in our study were chosen with this objective in mind.
This study demonstrated that the immunogenicity and safety of inactivated trivalent split influenza virus vaccine are promising even among young children (under 3 years of age) with recurrent wheezing who have frequent wheezy respiratory symptoms or receive short-term low-dose steroid treatment, with immunogenicity similar to that found in healthy children of the same age. We hope that our study results are helpful for parents and physicians with regard to influenza virus vaccination.