Annual influenza vaccination is strongly recommended for patients with chronic pulmonary diseases, such as bronchial asthma, chronic obstructive pulmonary disease (COPD), and interstitial pulmonary diseases. However, many of these patients regularly receive systemic and/or inhaled corticosteroid therapy, and the impact of corticosteroid therapy on influenza vaccine
efficacy and safety is unclear. Patients with chronic pulmonary diseases were enrolled in the study and divided into three groups based on their maintenance therapy: (A) without corticosteroid therapy (17 males, three females; mean age, 72.3 ± 7.9), (B) oral corticosteroid therapy (four males, seven females; mean age, 66.1 ± 10.6), and (C) inhaled corticosteroid therapy (eight males, nine females; mean age, 62.4 ± 16.0). All patients received influenza vaccine, and serum hemagglutination inhibition (HI) antibodies against influenza strains A/H1N1,
A/H3N2, and B were measured at baseline (before vaccination) and 4-6 weeks after vaccination. Sufficient antibody titers or
significant increases were observed after vaccination compared with titers before vaccination in all three groups. No systemic reactions were reported. Long-term oral/inhaled corticosteroid therapy was not associated with vaccination side effects and did not affect the immune response to the influenza vaccine

Abe, Shuichi

Igarashi, Akira

Inoue, Sumito

Kubota, Isao

Shibata, Yoko

Takabatake, Noriaki

Eldorado - Ressourcen aus und für Lehre, Studium und Forschung

EXCLI Journal 2013;12:760-765 – ISSN 1611-2156 Received: April 25, 2013, accepted: August 23, 2013, published: August 29, 2013  760 Original article: INFLUENCE OF CORTICOSTEROID THERAPY ON THE SERUM ANTIBODY RESPONSE TO INFLUENZA VACCINE IN  ELDERLY PATIENTS WITH CHRONIC PULMONARY DISEASES  Sumito Inoue*, Yoko Shibata, Noriaki Takabatake, Akira Igarashi, Shuichi Abe, Isao Kubota  Departments of Cardiology, Pulmonology, and Nephrology Yamagata University School of Medicine, Yamagata, Japan  * Corresponding author: Sumito Inoue; 2-2-2, Iida-Nishi, Yamagata, 990-9585, Japan;  Tel: +81-23-628-5302; Fax: +81-23-628-5305; E-mail: sinoue@med.id.yamagata-u.ac.jp  ABSTRACT Annual influenza vaccination is strongly recommended for patients with chronic pulmonary diseases, such as bronchial asthma, chronic obstructive pulmonary disease (COPD), and inter-stitial pulmonary diseases. However, many of these patients regularly receive systemic and/or inhaled corticosteroid therapy, and the impact of corticosteroid therapy on influenza vaccine efficacy and safety is unclear. Patients with chronic pulmonary diseases were enrolled in the study and divided into three groups based on their maintenance therapy: (A) without cortico-steroid therapy (17 males, three females; mean age, 72.3 ± 7.9), (B) oral corticosteroid thera-py (four males, seven females; mean age, 66.1 ± 10.6), and (C) inhaled corticosteroid therapy (eight males, nine females; mean age, 62.4 ± 16.0). All patients received influenza vaccine, and serum hemagglutination inhibition (HI) antibodies against influenza strains A/H1N1, A/H3N2, and B were measured at baseline (before vaccination) and 4-6 weeks after vaccina-tion. Sufficient antibody titers or significant increases were observed after vaccination com-pared with titers before vaccination in all three groups. No systemic reactions were reported. Long-term oral/inhaled corticosteroid therapy was not associated with vaccination side effects and did not affect the immune response to the influenza vaccine.  Keywords: Corticosteroid, influenza vaccine, chronic pulmonary disease    INTRODUCTION Influenza is a major public health prob-lem that causes significant morbidity and mortality worldwide (Lambert and Fauci, 2010; Igarashi et al., 2011). Yearly vaccina-tion prevents influenza-related complica-tions and reduces influenza prevalence (Nichol et al., 2007). Elderly patients with chronic pulmonary diseases such as bron-chial asthma, chronic obstructive pulmo-nary disease (COPD), and interstitial pul-monary diseases are strongly recommended to receive an annual influenza vaccine to prevent disease symptom exacerbation or loss of pulmonary function due to respirato-ry tract infection (Nichol et al., 2007; Inoue et al., 2003, 2009). However, many patients with chronic pulmonary diseases regularly receive systemic or inhaled corticosteroid, and it is well known that systemic cortico-steroid administration restrains immune re-sponses, such as antibody production (Bax-ter and Harris, 1975). Despite this, few studies have investigated the influence of steroid therapy on influenza vaccine effica-cy and safety, and the effects of regular oral or inhaled corticosteroids on these parame-EXCLI Journal 2013;12:760-765 – ISSN 1611-2156 Received: April 25, 2013, accepted: August 23, 2013, published: August 29, 2013  761 ters were unclear. In this study, we evaluat-ed the efficacy and safety of the influenza vaccine in elderly patients with chronic pulmonary diseases who were receiving oral or inhaled corticosteroids.  MATERIALS AND METHODS Patient characteristics This prospective study was carried out between October 2004 and April 2005. A total of 48 patients with chronic respiratory diseases, with or without oral or inhaled corticosteroid treatment, were recruited from Yamaguta University Hospital and enrolled in the study (those who received both oral and inhaled corticosteroid were excluded). The patients were classified into three groups based on their maintenance therapy: (A) without corticosteroid therapy (17 males, three females; mean age, 72.3 ± 7.9), (B) oral corticosteroid therapy (four males, seven females, mean age, 66.1 ± 10.6; median corticosteroid dose: 10.0 mg/ day (2.5–25 mg/day), equivalent to predni-solone), or (C) inhaled corticosteroid thera-py (eight males, nine females; mean age, 62.4 ± 16.0; median inhaled corticosteroid dose: 800 μg/day (400–1600 μg/day), equi-valent to budesonide). All patients with chronic respiratory diseases were stable be-fore receiving vaccination. Patient charac-teristics are summarized in Table 1.  Study protocol All patients received a single subcuta-neous inoculation of the trivalent influenza vaccine from the same lot containing he-magglutinin of influenza HA1 (A/Beijing), HA2 (A/Taiwan), and HB (B/Panama), from Mitsubishi Tanabe Pharma Co. Osaka, Japan. Blood samples were collected to measure antibody titers against influenza A and B antigens before vaccination and 4-6 weeks after vaccination. Serum antibody titers were measured with hemagglutination inhibition (HI) as-says. The serum samples were serially di-luted and co-incubated with influenza anti-gen and 0.5 % chicken red blood cells. The HI titter was determined as the reciprocal of the highest serum dilution resulting in non-agglutination of red blood cells. Vaccina-tion efficacy was evaluated by seroconver-sion, defined as a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer ≥ 1:40 or a pre-vaccination HI titer ≥ 1:10 and a minimum four-fold rise in post-vaccination HI antibody titer and seroprotection, de-fined as a post-vaccination HI titer of ≥ 1:40 (Chotirosniramit et al., 2012).    Table 1: Patients' profiles   A B C n 20 11 17 Male/female 17/3 4/7 8/9 Mean age, years old (mean ± SD) 72.3 ± 7.9 66.1 ± 10.6 62.4 ± 16.0     Chronic obstructive pulmonary disease 12 0 1 Bronchial asthma 1 0 16 Interstitial pneumoia 1 8 0 Diffuse panbronchitis 3 0 0 Bronchiectasis 2 0 0 Sarcoidosis 0 2 0 Aftereffects of pulmonary tuberculosis 1 0 0 Lung cancer 0 1 0 A: Control patients; B: patients treated by systemic corticosteroid;  C: patients treated by inhaled corticosteroid EXCLI Journal 2013;12:760-765 – ISSN 1611-2156 Received: April 25, 2013, accepted: August 23, 2013, published: August 29, 2013  762 Statistical analysis Data are shown as mean ± standard de-viation (SD). Pre- and post-vaccination HI titers were compared with paired t tests. Possible influences of oral or inhaled ster-oid therapy were evaluated with Chi-squared tests.  RESULTS Serum antibody responses against influ-enza vaccine antigens were increased from baseline values in all three groups (Fig-ure 1). In group A, we observed significant increases in HA1 and HA2 titers. Although there was no significant difference in HB antibody HI titer between pre- and post-vaccination, HB antibody HI titers were sufficient for seroprotection. Group B ex-hibited significant increases in HI titers for HA2 and HB. Although there was no sig-nificant difference in HA1 antibody HI titer between the two time points, the HI titers were high enough for seroprotection. In group C, significant increases in HI titers against HA1 and HB were noted. Although we did not observe a significant difference in HA2 antibody HI titer levels between pre- and post-vaccination, the levels were high enough to confer seroprotection.  Vaccination effectiveness findings are summarized in Table 2. In patients who re-ceived inhaled corticosteroid therapy, the ratio of seroconversion or seroprotection for HB was significantly higher than in patients without corticosteroid therapy. A local re-action was observed at the injection site within several days after vaccination in one patient, but no systemic reactions were ob-served.  DISCUSSION We investigated the efficacy and safety of the influenza vaccine in elderly patients with chronic pulmonary diseases receiving oral or inhaled corticosteroid therapy. Maintenance treatment with oral or inhaled corticosteroid therapy in this population did not reduce the serological response to influ-enza vaccination. In fact, Table 2 shows that the serological response to HB was significantly reduced in patients without corticosteroid therapy. Overall, nine of 20 control patients (without corticosteroid therapy) did not show a serological re-sponse after vaccination. Our findings sug-gest that inhaled corticosteroid did not exert a significant immunosuppressive effect. In patients with chronic pulmonary dis-ease, respiratory tract infection is the most prevalent cause of acute symptom exacer-bation (Inoue et al., 2003, 2009). This is especially true in COPD patients; respirato-ry tract infections due to influenza virus or rhinovirus induce secondary bacterial infec-tion and severe respiratory failure (Igarashi et al., 2011; McManus et al., 2008). Pa-tients with chronic pulmonary diseases are strongly urged to receive an annual influen-za vaccination, and many of them also re-ceive oral and/or inhaled corticosteroid treatment. We did not find any significant  Table 2: The ratio of seroconversion or seroprotection after vaccination  Ratios p values seroconversion  or seroprotection A control B oral CS C inhaled CS A vs B A vs C B vs C HA1 19/20 10/11 16/17 0,6573 0,9058 0.7475 HA2 20/20 10/11 17/17 0,1705 ND 0.2055 HB 9/20 6/11 14/17 0.6109 0.0196 0.1117 Numbers are those responding (seroconversion or seroprotection) / total vaccinated. Response ratios are evaluated by the Chi-square test. CS: corticosteroid. ND: p value for control vs inhaled corticoster-oid was not caluculated because all subjects were positive for seroconversion or seroprotection EXCLI Journal 2013;12:760-765 – ISSN 1611-2156 Received: April 25, 2013, accepted: August 23, 2013, published: August 29, 2013  763  Figure 1: Pre- and post-vaccination antibody titers against HA1, HA2, and HB. Group A, patients without corticosteroid therapy; Group B, patients with oral corticosteroid therapy; and Group C, pa-tients with inhaled corticosteroid therapy       EXCLI Journal 2013;12:760-765 – ISSN 1611-2156 Received: April 25, 2013, accepted: August 23, 2013, published: August 29, 2013  764 differences in antibody production against influenza strains between patients with or without corticosteroid therapy. A few stud-ies have investigated the influence of corti-costeroids on influenza vaccine-induced antibody production (Kubiet et al., 1996; Hanania et al., 2004), but ours is the first report that shows effective antibody pro-duction against influenza in elderly patients with chronic pulmonary diseases who were receiving oral or inhaled corticosteroid.  It is well known that long-term systemic corticosteroid therapy is immunosuppres-sive (Lipworth, 1999). Indeed, we found that pre-vaccination antibody titers were lower in patients treated with oral or in-haled corticosteroid compared to patients without steroid therapy. Despite this obser-vation, there were no significant post-vaccination differences between the groups. These results suggest that vaccinating pa-tients with chronic pulmonary diseases who receive corticosteroid treatment against in-fluenza is effective. There are some limitations in our study. First, it was performed at a single center, so the number of subjects enrolled was not large. Second, the dose of systemic steroid was relatively low in this study population, so the effects of high-dose corticosteroid treatment on antibody production against influenza is still unknown. Third, only one patient treated with inhaled corticosteroid was infected with influenza A, and one pa-tient without corticosteroid therapy was in-fected with influenza B during the study period. As such, we could not investigate any potential preventative effect of the cor-ticosteroid treatment on influenza infection. Fourth, most patients had received the flu vaccine for multiple consecutive years, and many exhibited high antibody titers before vaccination; therefore, we cannot ignore the influence of previous vaccinations on anti-body titer levels. In conclusion, influenza vaccination is safe and effectively stimulates antibody production even in patients treated with oral or inhaled corticosteroid. Further investiga-tion in a much larger population will be necessary to confirm our results.   REFERENCES Baxter JD, Harris AW. Mechanism of glu-cocorticoid action: general features, with reference to steroid-mediated immunosup-pression. Transplant Proc 1975;7:55-65.  Chotirosniramit N, Sugandhavesa P, Aurpibul L, Thetket S, Kosashunhanan N, Supindham T et al. Immune response to 2009 H1N1 vaccine in HIV-infected adults in Northern Thailand. Hum Vaccin Immu-nother 2012;8:1854-9.  Hanania NA, Sockrider M, Castro M, Holbrook JT, Tonascia J, Wise R et al. Im-mune response to influenza vaccination in children and adults with asthma: effect of corticosteroid therapy. J Allergy Clin Im-munol 2004;113:717-24.  Igarashi A, Tokairin Y, Hirono O, Kato T, Kubota I. Two cases of mixed infection fol-lowing 2009 H1N1 influenza pneumonia [article in Japanese]. Nihon Kokyuki Gakkai Zasshi 2011;49:226-31.  Inoue S, Nakamura H, Otake K, Saito H, Terashita K, Sato J et al. 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Influence of corticosteroid therapy on the serum antibody response to influenza vaccine in elderly patients with chronic pulmonary diseases

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Influence of corticosteroid therapy on the serum antibody response to influenza vaccine in elderly patients with chronic pulmonary diseases

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