http://informahealthcare.com/jas ISSN: 0277-0903 (print), 1532-4303 (electronic) J Asthma, 2014; 51(8): 825–831 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/02770903.2014.915567

WORK RELATED ASTHMA

Protective effects of influenza A (H1N1) pandemic 2009 vaccination against the onset of influenza-like illness and asthma exacerbation in Japanese children Yukako Yokouchi, MD, PhD1,2, Hiroshi Katsumori, MD, PhD2,3, Seigo Shirakawa, MD, PhD2,4, Maya Fujiwara, MD, PhD2,3, Kyoko Kashima, MD2,3, Ryo Kozawa, MD2,3, and Yuji Koike, MD, PhD1 1

Department of Pediatrics, Disaster Medical Center, Tokyo, Japan, 2Department of Pediatrics, Tokyo Rinkai Hospital, Tokyo, Japan, 3Department of Pediatrics, Kawakita General Hospital, Tokyo, Japan, and 4Department of Pediatrics, Fraternity Memorial Hospital, Tokyo, Japan

Abstract

Keywords

Background: Vaccination against influenza A(H1N1)pdm09 in Japan started in October 2009. Children with asthma are considered as a high-risk group and are recommended to preferentially receive the vaccine. Objective: To identify the clinical effects of vaccination in Japanese children with and without asthma. Methods: We conducted a cross-sectional, questionnaire-based survey to compare vaccination rates, vaccine effectiveness against physician-diagnosed influenza A infection (PDIA), and consecutive asthma exacerbations between children with and without asthma. Results: Of the 460 children included in this study, those with asthma had higher vaccination rates (46.5%, 67/144) than those without asthma (30.4%, 96/316). Influenza A infections were diagnosed in 28 of 163 vaccinated children (17.2%) compared to 164 of 297 unvaccinated children (55.2%, p50.001). Comparison of positive influenza diagnosis rates between vaccinated and unvaccinated children with and without asthma showed that unvaccinated children with asthma had an elevated odds ratio (13.235; 95% confidence interval [CI], 5.564–32.134) and that treatment for asthma exacerbations was needed in a larger proportion of unvaccinated children. Vaccine effectiveness against PDIA was 87% (95% CI, 78–93%) overall, 92% (95% CI, 81–96%) in children with asthma and 81% (95% CI, 63–91%) in children without asthma, respectively. Conclusions: The administration of an inactivated, split-virus, non-adjuvanted monovalent A(H1N1)pdm09 vaccine during the pandemic period reduced the number of physician-diagnosed influenza A infections and asthma exacerbations in children with asthma. Therefore, we strongly recommend that highrisk children with a history of asthma receive vaccines during pandemics.

Asthmatic, high-risk group, pediatrics, pandemic, vaccine

Introduction The influenza A(H1N1)2009 pandemic was caused by novel swine-origin triple reassortant influenza virus, which emerged first in Mexico and rapidly spread worldwide [1]. Early epidemiologic reports and preliminary studies suggested that teenagers and young adults were most susceptible to the virus [2], and the infection caused severe lower airway inflammation and pneumonia with severe asthma exacerbation associated with increased hospitalization and mortality [3]. The (H1N1)pdm09 epidemic in Japan started as isolated outbreaks in small clusters between May and July 2009 [4,5]; the number of cases increased from mid-August to peak in November 2009 [6]. Nationwide vaccination for

Correspondence: Yukako Yokouchi, MD, PhD, Department of Pediatrics, Disaster Medical Center, 3256 Midori-cho, Tachikawa, Tokyo 190-0014, Japan. Tel: +81-42-526-5511. Fax: +81-42-5265535. E-mail: [email protected]

History Received 10 November 2013 Revised 12 April 2014 Accepted 13 April 2014 Published online 22 May 2014

A(H1N1)pdm09 started in October 2009, with vaccine priority given to healthcare workers, pregnant women, individuals with underlying diseases, children 1–9 years old, and caregivers of infants aged below 1 year [5]. Sub-cutaneous injection of an inactivated, split-virus, nonadjuvanted, monovalent A(H1N1)pdm09 vaccine was mainly used for children by the end of January 2010 [7]. The seed virus was A/California/07/09(H1N1). A single dose contained 15 mg of hemagglutinin antigen in 0.5 mL. One or two injections of 0.2 mL/dose were administered to children aged 0.5–5 years, 0.3 mL/dose to children aged 6–13 years, and a single 0.5 mL dose to children aged over 13 years. The effectiveness and safety of these vaccines in certain Japanese populations, including health care workers [8,9] and pregnant women [10] have been evaluated in previous reports. Nishiura [7] has reported that these vaccines reduce risks for infection and clinical attack among children exposed to A(H1N1)pdm09 virus in their households. Asthma has been shown to be a strong risk factor for severe outcomes of A(H1N1)pdm09 infection, especially in

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unvaccinated populations [11–15]. Thus, children with a past history of asthma were considered a high-risk group early in the pandemic and were recommended to preferentially receive the vaccine. Kloepfer et al. [16] showed that children with asthma had increased susceptibility for A(H1N1)pdm09 infection compared to children without asthma, which was concluded before widespread A(H1N1)pdm09 vaccine release to avoid confounding results with immunological effects of the virus and false positive test results resulting from use of the live virus vaccine. Although the effectiveness of A(H1N1)pdm09 vaccines are widely reported [9,10,17–43], there are few reports that discuss the effectiveness in patients with asthma [19,44,45]. Here we conducted a cross-sectional, questionnaire-based survey to determine the clinical effect of influenza A(H1N1)pdm09 vaccination against outbreak of influenzalike illness (ILI) with influenza A infection during pandemic period of A(H1N1)pdm09 and consecutive asthma exacerbation in Japanese children with and without asthma.

J Asthma, 2014; 51(8): 825–831

Identification of children with and without asthma Subjects were categorized as having asthma if a physician had diagnosed asthma or if the subject had a recurrent history of cough, dyspnea and wheezing followed regularly by a physician. Asthma status was determined based on the use of short-acting beta2-agonist treatments and the frequency of symptoms including night-time awakening, interference with normal activities, requirement of systemic corticosteroid therapy, and emergency room visits or hospitalization during the month before influenza diagnosis. Asthma exacerbation was defined as acute or subacute episodes characterized by a progressive increase in one or more typical asthma symptoms (dyspnea, coughing, wheezing and difficulty in breathing) requiring treatment with a short-acting beta2-agonist bronchodilator or systemic corticosteroids. Identification of physician-diagnosed influenza A infection (PDIA)

This study was a cross-sectional questionnaire-based survey designed to compare monovalent A(H1N1)pdm09 vaccine coverage (at least 1 dose 14 days before symptom onset) and vaccine effectiveness among Japanese children with and without asthma who visited a secondary medical care hospital.

Definitive diagnosis of influenza A(H1N1)pdm09 infection was made by general practitioners or physicians in rural hospitals when patients had typical symptoms of ILI, with or without a positive rapid antigen test result for influenza A during the pandemic period (May 2009 to February 2010). For patients exhibiting with ILI who had negative results by rapid antigen test, or whom diagnosed without performing a rapid antigen test, the presence of family members or classmates with confirmed influenza A infections was an important deciding factor while making a diagnosis. ILI diagnosis was based on guidelines from the Centers for Disease Control and Prevention (i.e. febrile patients [4100  F ¼ 37.78  C] with cough and/or sore throat).

Study population

Statistical analysis

Children under 18 years of age and their caregivers who visited the outpatient clinic at Tokyo Rinkai Hospital, a secondary medical care hospital located in eastern Tokyo, from February through March 2010 were consecutively recruited to participate in the study. Questionnaires were distributed to collect data about influenza A(H1N1)pdm09 vaccination history, past history of asthma and regular medication, ILI during the pandemic period (May 2009 to February 2010), method of influenza A testing and treatment, and asthma exacerbation associated with infection. Data on asthma control status were collected from the questionnaire and patient medical records.

Baseline data of children with and without asthma are summarized with descriptive statistics, including counts and percentages and mean ± SD for continuous and categorical variables, respectively. Student’s t-test was used for normally distributed continuous data to evaluate the statistical significance of mean differences between groups. Chi-square or Fisher’s exact tests were used to compare categorical data where applicable. p50.05 was considered significant. Data were fit to logistic regression models to estimate odds ratio (OR) and their corresponding 95% confidence intervals (CI). Multivariate analysis was performed to adjust the main results for all pertinent covariates. Vaccine effectiveness (VE) was calculated using the formula: (1  OR)  100, where OR is the adjusted odds ratio estimated by the model. JMP statistical software package (Version 11; SAS Institute, Inc., Cary, NC) was used for the analysis.

Methods This study was approved by an institutional review board, in accordance with approved published guidelines, prior to performing research and publishing the data. Study design

Exclusion criteria Exclusion criteria included: (1) age less than six months; (2) presence of comorbid conditions other than asthma that could influence influenza susceptibility, including hemoglobinopathies, cardiopulmonary diseases, neurodevelopmental diseases, chronic renal diseases, immunosuppression and autoimmune diseases, as well as endocrine and metabolic diseases; (3) refusal to participate in the study; and (4) insufficient information from medical records or incomplete questionnaire responses that made it impossible to determine ILI, influenza A(H1N1)pdm infection or asthma status.

Results From February through March 2010, 1220 children under the age of 18 years and their caregivers visited the outpatient clinic at Tokyo Rinkai Hospital. Of these, 125 children were excluded because they were less than six months of age. An additional 181 children were excluded for comorbid conditions other than asthma that influenced their susceptibility to influenza. In addition, 401 children and their caregivers

Effectiveness of H1N1pdm vaccination in children

DOI: 10.3109/02770903.2014.915567

1220 outpatients 125 under age of 6 months 181 with comorbid conditions 401 declined participating the study 513 participants 52 uncompleted answers 1 onset in April 2009 460 subjects

AS(+) 144

Vac(+) 67

Vac(-) 77

AS(-) 316

Vac(+) 96

Vac(-) 220

Figure 1. Study populations. Eligible children were classified as children with asthma (AS(+)) or without asthma (AS()). The number of subjects vaccinated for A(H1N1)pdm09 (Vac(+)) and unvaccinated (Vac()) are shown.

Table 1. Characteristics of children with and without asthma (n ¼ 460).

Agea, mean ± SD (years) Gender, n (%) Male Female Vaccinated for H1N1pdm, n (%) Single dose Two dose Influenza A diagnosis, n (%) Positive rapid antigen test Clinical diagnosis

Children with Asthma (n ¼ 144)

Children without Asthma (n ¼ 316)

Overall (n ¼ 460)

7.7 ± 3.5b

6.7 ± 4.4b

7.0 ± 4.2

93 (64.6) 51 (35.4) 67 (46.5)c

180 (57.0) 136 (43.0) 96 (30.4)c

273 (59.3) 187 (40.7) 163 (35.4)

13 54 80 70 10

22 74 112 99 13

35 128 192 169 23

(9.0) (37.5)c (55.6)c (48.6)c (6.9)

(7.0) (23.4)c (35.4)c (31.3)c (4.1)

(7.6) (27.8) (41.7) (36.7) (5.0)

a

Age when subjects participated in the study. p ¼ 0.013; cp50.01.

b

declined to participate in the study. Of the remaining 513 participants, 52 were excluded for incomplete questionnaires, and one subject was excluded due to a previous influenza A diagnosis in April 2009. In total, 460 subjects who agreed to participate and who completed the questionnaire were included in the study (Figure 1). The final study subject population was older than the patient population excluded from the study, those who had declined to participate, or whose questionnaires were incomplete (mean age, 7.0 years versus 5.5 years). No difference in gender distribution was observed between the included and excluded patients. Baseline characteristics of the study subjects with and without asthma are shown in Table 1. The mean age was 7.0 years (range, 6 months to 17.7 years). Out of a total of 460 subjects, 144 (31.3%) had been diagnosed with bronchial asthma and received regular follow-ups from pediatricians. Asthma was categorized as ‘‘well controlled’’ in all children with asthma, with the use of short-acting beta2-agonist less than 2 days/week, night-time awakening less than 1–2 times/ month, no interference with normal activity, systemic

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corticosteroid treatment required 0–1 times/year, and no emergency room visits or asthma-related hospitalizations during the month before being diagnosed with influenza. The mean age was higher in children with asthma than in children without asthma (7.7 ± 3.5 versus 6.7 ± 4.5 years; p ¼ 0.013), and there was no difference in gender proportion between groups. Patients receiving regular asthma treatments included 70 (48.6%) who were administered both corticosteroid inhalers and leukotriene antagonists, 5 (3.5%) who received only corticosteroid inhalers, 50 (34.7%) who received only leukotriene antagonists, and 12 (8.3%) who were administered leukotriene antagonists and antihistamines or theophylline. Five children with asthma received no regular treatment but were administered antihistamines for comorbid allergic rhinitis. One hundred sixty-three children had received at least one dose of inactivated, split-virus, non-adjuvanted, monovalent influenza A(H1N1)pdm 09 vaccine 14 days before symptom onset. The overall vaccination rate was 35.4% (163/460). The group of children with asthma had a higher vaccination rate (46.5%, 67/144) compared to children without asthma (30.4%, 96/316). Using rapid diagnostic tests or ILI diagnosis, 192 patients (41.7%) were diagnosed as PDIA between July 2009 and February 2010. One hundred sixty-nine (36.7%) infections were confirmed by rapid influenza diagnosis tests. Of 23 children diagnosed as influenza A infection by a physician without laboratory confirmation, seven had a negative rapid antigen test result and 16 were diagnosed without performing the rapid antigen test. These children had a high fever with typical ILI and family members or classmates with confirmed influenza A infections. The peak rate of symptom onset was observed in November 2009. There was no reported increase of other influenza A subtypes in Japan during this pandemic period. Of 192 PDIA cases, 80 (41.7%) were asthmatic: 51 were treated with oseltamivir, 26 with zanamivir hydrate and three patients received no antiviral drug treatment. In addition, 16 (20%) used bronchodilator inhalers, eight (10%) received systemic corticosteroid at outpatient clinics, and seven (8.8%) were hospitalized for asthma exacerbation during influenza A infection. Of 112 children without a past history of asthma, 54 were treated with oseltamivir, 48 were treated with zanamivir hydrate and 10 received no antiviral drug. Within this non-asthmatic group, six (5.4%) were administered bronchodilator inhalers, because of wheezing and difficulty breathing, but neither of them received systemic corticosteroid nor hospitalized. Among 63 children with asthma who were not vaccinated and were diagnosed with influenza A infection, 14 were administered bronchodilator inhalers, eight received intravenous corticosteroids and seven were admitted for inpatient treatment of asthma exacerbation. Among 17 vaccinated children with asthma who were diagnosed with influenza A, only two were administered bronchodilator inhalers for asthma exacerbation. No patients from this group received corticosteroids or were admitted for treatment. Of 163 vaccinated children, influenza A infection was diagnosed in 28 (17.2%) children compared to 164 of 297 unvaccinated children (55.2%) (p50.01). Comparison of PDIA between vaccinated and unvaccinated children with and

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J Asthma, 2014; 51(8): 825–831

without asthma showed a trend that children with asthma had an elevated odds ratio (13.235; 95% CI, 5.564–32.134) for PDIA without vaccination (Figure 2). Associations between PDIA with age, gender, asthma and (H1N1)pdm09 vaccination are summarized in Table 2. Children with asthma had an odds ratio of 3.73 (95% CI, 2.24–6.22) when adjusted for age, gender and (H1N1)pdm09 vaccination. Vaccination for (H1N1)pdm09 had an odds ratio of 0.13 (95% CI, 0.07–0.22) when adjusted for age, gender and asthma. The over all VE was 87% (95% CI, 78–93%). The VE for PDIA in children with and without asthma was 92% (95% CI, 81–96%) and 81% (95% CI, 63–91%), respectively (Table 3). The p value for interaction term between asthma status and vaccination was not statistically significant (p ¼ 0.19).

was substantially protective against ILI and influenza A(H1N1)pdm 09 infections, with an overall VE of 87%. This result is comparable with that reported by a recent systematic review and meta-analyses by Yin et al. [17] that reported VEs of monovalent A(H1N1)pdm 09 vaccines of 86 and 79% based on 11 case-control studies and two cohort studies, respectively. Subgroup analyses showed a summary VE of 89% from three case-control studies looking at only non-adjuvanted, inactivated vaccines [17]. The VE for seasonal influenza is known to vary according to the degree of antigenic match between viruses isolated from patients and vaccine strains. Belongia et al. [46] reported a VE less than 25% for mismatched subtypes, and an estimated 50–95% for well-matched subtypes [46]. Although the monovalent A(H1N1)pdm 09 vaccines in this review and our study differ in terms of virus propagation, antigen content, and use of adjuvant, they all use the monovalent-A/California/07/09(H1N1)-like seed virus; as there has been no significant genetic drift reported since this novel virus was isolated in April 2009 [18], vaccines specific to this non-changing virus explain the high VE. Several case-control and cohort studies were conducted after this review. Mahmud et al. [19] reported a populationbased case-control study in Canada with an adjusted VE of 55% for preventing laboratory-confirmed H1N1 infections with an adjuvanted, monovalent A(H1N1)pdm 09 vaccine. VE was 86% when vaccination occurred 14 days before testing, but was much lower (17%) when vaccines were administered 57 days before testing. [19]. Griffin et al. [20] prospectively estimated the effectiveness of a single dose of 4 monovalent A(H1N1)pdm 09 vaccines (3 non-inactivated, 1 live attenuated) between real-time reverse transcriptase polymerase chain reaction (RT-PCR) confirmed cases and negative controls with acute respiratory illness during the pandemic in the United States. Although the vaccines had been administered 14 days before testing, the adjusted effectiveness of the pandemic vaccines combined was 56%; the effectiveness was 62% for inactivated vaccines alone. In that study, participants aged 0.5–9, 10–49 and 50 years, the VE was 32, 89 and 26%, respectively. Low VE with one

Discussion The results of our cross-sectional questionnaire-based survey of Japanese children visiting a secondary medical care hospital suggest that the inactivated, split-virus, nonadjuvanted, monovalent influenza A(H1N1)pdm 09 vaccine

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Protective effects of influenza A (H1N1) pandemic 2009 vaccination against the onset of influenza-like illness and asthma exacerbation in Japanese children.

Vaccination against influenza A(H1N1)pdm09 in Japan started in October 2009. Children with asthma are considered as a high-risk group and are recommen...
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