Influenza burden, prevention, and treatment in asthma‐A scoping review by the EAACI Influenza in asthma task force

To address uncertainties in the prevention and management of influenza in people with asthma, we performed a scoping review of the published literature on influenza burden; current vaccine recommendations; vaccination coverage; immunogenicity, efficacy, effectiveness, and safety of influenza vaccines; and the benefits of antiviral drugs in people with asthma. We found significant variation in the reported rates of influenza detection in individuals with acute asthma exacerbations making it unclear to what degree influenza causes exacerbations of underlying asthma. The strongest evidence of an association was seen in studies of children. Countries in the European Union currently recommend influenza vaccination of adults with asthma; however, coverage varied between regions. Coverage was lower among children with asthma. Limited data suggest that good seroprotection and seroconversion can be achieved in both children and adults with asthma and that vaccination confers a degree of protection against influenza illness and asthma‐related morbidity to children with asthma. There were insufficient data to determine efficacy in adults. Overall, influenza vaccines appeared to be safe for people with asthma. We identify knowledge gaps and make recommendations on future research needs in relation to influenza in patients with asthma.


| INTRODUCTION
Asthma is a heterogeneous chronic inflammatory lung disease characterized by intermittent airflow obstruction and increased reactivity to bronchoconstrictive triggers. Presently, an estimated 300 million people worldwide suffer from asthma. 1 In Europe, more than 30 million people are affected, with 6 million suffering severe symptoms and 1.5 million life-threatening attacks. 2 Asthma onset and acute asthma exacerbations (AAEs) have been strongly associated with respiratory viral and (to a lesser extent) bacterial infections. [3][4][5][6][7][8][9][10][11] Influenza viruses cause respiratory infections, typically during winter months. Most significant disease is caused by influenza A and B, which may escape immune pressure by undergoing antigenic drift and recombination; such genetic changes lead to new subtypes, which can cause epidemic or pandemic outbreaks. 12,13 Each year, influenza virus infection affects 5%-20% of the global population, 14 while annual vaccination greatly contributes to reduce related morbidity and mortality. 15 Upon vaccination, coordinated activity of innate and adaptive immune responses leads to generation of shortand long-lived antibody-producing plasma cells and memory B cells.
The importance of influenza as a cause of serious illness and AAE is increasingly appreciated. 16,17 Despite uncertainties about their effectiveness, influenza vaccines are widely recommended for those with asthma. 18 To address uncertainties over the prevention and management of influenza in patients with asthma, we performed a scoping review and discuss the current knowledge of the burden imposed by influenza on patients with asthma; current vaccine recommendations and vaccination coverage in various regions; the evidence regarding immunogenicity, efficacy, effectiveness, and safety of influenza vaccines; and the possible benefits of antiviral drugs in patients with asthma. We conclude by identifying knowledge gaps and future research needs in relation to influenza in asthma patients.

| ME TH ODS
We systematically searched relevant published, unpublished, and inprogress original research and systematic reviews that were pertinent to the subject matter of this EAACI Task Force. This involved searching databases of peer-reviewed published literature (Cochrane Library, EMBASE and CINAHL, MEDLINE, and Google Scholar) and research in progress (ie, http://www.controlled-trials.com/and http:// www.clinicaltrials.gov/) for the period 2000-2015. In addition, we wrote to a panel of international experts in an attempt to identify additional unpublished or in-progress work. There were no restrictions on language of publication.
We were particularly interested in randomized controlled trials (RCTs) on questions relating to the immunogenicity, efficacy, and/or effectiveness of influenza vaccine among patients with asthma, and epidemiological studies relating to the influenza incidence/prevalence and public health burden and safety of influenza vaccine. Systematic reviews with or without meta-analysis were of interest if they focused on any of the questions of interest.
The searches (see Appendix S1) were undertaken and allocated to relevant subgroup leads depending on the focus of the inquiry.

Section 4 Immunogenicity of influenza vaccines in asthma
Bae et al., hospitalized with pandemic H1N1 than with seasonal influenza. 24,[50][51][52][53] Asthma was also the most common comorbidity among pregnant women hospitalized with H1N1 infection, with a prevalence ranging from 8% to 33%. [54][55][56][57] Asthma represented a risk factor for hospitalization during influenza seasons in the general population, 58 with an OR of 2.6 (95% CI 1.6-4.0) in 2 Canadian studies, 59,60 and a relative risk (RR) of 4.47 (95% CI 1. 49-13.39) in Israel. 61 The same applied to children, 47,62,63 where asthma conferred a 4-fold risk of hospitalization (the United States, 64 Germany, 41 and Argentina 65 ), with a 21-fold risk observed in South Korea. 66 Interestingly, influenza-related hospitalization costs in children with asthma may be lower than in children with other chronic conditions and were very close to costs in children without comorbidity. 67 Asthma patients seemed to have a higher risk of being admitted to the intensive care unit (ICU) or to have a more severe disease course when hospitalized for influenza, 26 16-199.63) in China >15 years of age. 71 Severe disease was especially common in those developing pneumonia, 33 but did not seem to be related to the severity of underlying asthma. 51 In a multivariate analysis of H1N1 pediatric patients, asthma was associated with increased mortality in ICU-admitted children and adolescents (OR 1.34, P = .05). 68

| Influenza-induced acute asthma exacerbations
Influenza, like other respiratory viral infections, can lead to AAE and was found to account for 32.0% 72 and 9.8% 73 of AAEs in 2 studies of adult outpatients with asthma. However, the method used to identify the presence of influenza in AAE episodes largely determines the outcome. A direct comparison of molecular (PCR), serological, and immunofluorescent (IFA) detection in the same cohort of adults with asthma found influenza rates of 24.0%, 18.3%, and 2.0%, respectively, in AAEs. 74 Thus, the validity of studies that applied conventional influenza identification techniques such as cytopathic effect in cell culture followed by indirect immunofluorescence to confirm viral presence 75 is questionable. Among hospitalized adults with asthma patients, rates of influenza-induced AAE were reported at 10.0%, 76 19.0%, 77 20.7%, 78 and as high as 37.9%. 73 Available data on influenza-associated AAE among children vary considerably. For outpatient visits, 3 studies did not detect any influenza-positive samples, 75,79,80 while several groups identified influenza infection as the cause of AAE, with most reporting rates of influenza-positive samples between 2.4% and 15.5%. 63,[81][82][83][84] A recent study showed an accentuated propensity for loss of asthma control when children were infected with pH1N1 (38%) compared with other common respiratory virus infections. 85 Among children with asthma hospitalized for severe AAE, 3 studies reported an influenzaassociated burden of 2.6%, 82 3.4%, 86  However, vaccine uptake for clinical risk groups varied from 31% in Portugal to 82% in Northern Ireland, 88,91 as did influenza vaccination coverage of adults with asthma, with 30%-50% in Spain [92][93][94][95] and 40% in the UK. 96 Self-reported uptake of seasonal influenza vaccine among adults with asthma in the United States varied from 54% in the community to 71% in secondary care. 97 Children with asthma had significantly lower coverage rates of approximately 18%-20% in Spain, 93,98 15% in France, 99 and 2.5%-20% in Italy, across multiple seasons. 91 In comparison, in the United States vaccination coverage reached around 50% in adults and children. 100 To address the question of such historically low vaccination rates among those with asthma, many studies employed cross-sectional surveys to analyze the socio-demographic variables that predict vaccine uptake. The strongest factors associated with higher vaccine coverage were older age, recent contact with healthcare providers, nonsmoking status, presence of comorbidities, more severe asthma,  96,107,108 Reports of low effectiveness probably also contributed to poor uptake. 18,113,114 Healthcare worker endorsement of vaccination was highly predictive of adherence. 109,110,112  The success of vaccination programs was affected by complex factors such as the nature of healthcare provision (eg, free care or insurance-based), education levels, and cultural acceptance of the vaccine. Therefore, national health surveys with information on vaccination status linked with medical and socio-demographic details (such as that of Spain with data spanning more than 2 decades [92][93][94][95]117 ) can aid in assessing the impact of influenza vaccination, at population level.
Simple interventions such as allowing for year-round scheduling of appointments for vaccination can be effective. 118 Nevertheless, it is likely that only major policy shifts will lead to significantly higher vaccination rates, due to more clear and consistent messaging about the importance and acceptability of influenza vaccination to patients and healthcare workers alike. This is illustrated by the increase in influenza vaccination uptake among children with asthma from 36%  In children, 2 retrospective cohort studies found that influenza vaccination was associated with a reduction in the rate of asthma exacerbations 133 and fewer acute respiratory problems (only in those <6 years of age). 134 A survey found that vaccination in children with asthma was associated with less use of rescue prednisolone, 135 while a nested case-control study suggested that influenza vaccination was associated with fewer acute general practice visits for respiratory problems in children with long-term conditions. 136 However, another case-control study suggested that vaccination was associated with an increased risk of unscheduled attendance for asthma care. 137 In this study, the cases and controls were poorly balanced in terms of ethnicity and likelihood of vaccination in previous years. Although an adjusted analysis was undertaken, this may not have taken into account all the differences between the groups.
Only 1 study focused on adults with asthma. 132  were not related to vaccine hypersensitivity. 143 A common concern is the safety of egg-derived influenza vaccines in patients with egg allergy, a frequent comorbidity in children SCHWARZE ET AL.
| 1173 with asthma. The last case of anaphylaxis after influenza vaccination occurred more than 25 years ago at a time when the egg content of vaccines was much higher. The ovalbumin content of most current vaccines is <1.2 lg/mL, and an egg-free influenza vaccine is also available. Several studies demonstrated that influenza vaccines containing low levels of egg protein (≤1.2 lg/mL) were safe even in egg-allergic patients. [143][144][145][146][147][148][149] This also seemed to be true in egg-aller- should not be used in children with egg allergy and/or asthma. [153][154][155] 9 | AN TIVIRAL TREATMENT AGAINST

INFLUENZA IN PATIEN TS WITH ASTHMA
For asthma patients with suspected influenza infection, treatment with antiviral medication as early as possible, prior to laboratory confirmation of influenza, is currently recommended. [156][157][158][159][160] As amantadine and rimantadine are limited by drug resistance, they have been replaced by neuraminidase inhibitors (NI). The currently marketed NIs are zanamivir and oseltamivir. However, postmarketing surveillance has revealed bronchospasm and worsening of lung function in a few cases when asthma patients were treated with zanamivir inhalation. 161 Therefore, the manufacturer does now not recommend zanamivir for patients with chronic respiratory disease, including asthma. 157,158 Oseltamivir was not associated with any significant respiratory adverse effects and is recommended for treatment and chemoprophylaxis of influenza in children and adults with high-risk chronic conditions, including asthma. [162][163][164] However, largescale telephone surveys in the United States showed that having asthma, in contrast to diabetes, was not associated with increased rates of antiviral treatment of influenza cases. 165 Data on the efficacy of NI in asthma patients 162,[166][167][168] are limited. A benefit of oseltamivir treatment was found in children in an RCT that showed significantly improved pulmonary function and fewer AAEs. 168 A meta-analysis, based on a single RCT, reported improved FEV1 after oral oseltamivir given to children with asthma and influenza infection, but no effects on peak flow or AAEs. 169 Two recent systematic reviews found that oseltamivir relieved influenza symptoms in otherwise healthy children, but had no effect on children with asthma who have influenza-like illness, 170,171 a finding that is currently controversial.
As high rates of resistance limit the effectiveness of the currently available antiviral drugs, new NI (laninamivir, peramivir) and an RNAdependent RNA polymerase inhibitor (favipiravir) are currently undergoing clinical trials. 172 Laninamivir showed similar efficacy and safety to oseltamivir in the treatment of influenza in asthma patients. 173

| CONCLUSIONS
We observed significant variation in the reported rates of influenza detection among AAE episodes in both children and adults, with higher rates observed in the latter age group. This may be attributed to major differences in inclusion criteria, disease definitions, virus detection methodology, small population sizes and the limited number of available studies. Therefore, it is presently unclear to what degree influenza causes exacerbation of underlying asthma.
All European Union countries currently recommend influenza vaccination of people with asthma, with TIV being the most widely used vaccine. Nonetheless, vaccination coverage varies between regions and is significantly lower among children with asthma. Several factors and misbeliefs have been shown to predict nonadherence to influenza vaccination, while healthcare worker endorsement highly promotes vaccination. Major policy shifts and health campaigns may help in raising awareness and improve guideline implementation.
The limited immunogenicity data suggest that good seroprotection and seroconversion can be achieved in children and adults with asthma. However, higher vaccine doses may be required in elderly patients. Available studies suggest increased efficacy of LAIV in reducing influenza illness in children/adolescents with asthma compared to TIV, but do not provide evidence of efficacy of TIV in reducing influenza illness in patients with asthma concurring with a recent systematic review. 18 There are some limited data to suggest that influenza vaccination reduces asthma-related morbidity in children in real-life settings, as has been concluded in another recent systematic review. 139 The only data to suggest that vaccination may have a beneficial impact in adults with asthma are from studies of patients with long-term or high-risk conditions, not just asthma. The effectiveness outcomes of these studies are difficult to interpret due to lack of an agreed definition for asthma and/or influenza, and insufficient information on the type of vaccination used. Lack of randomization is also a limitation, as differences in the characteristics of those who do and do not receive the vaccine, such as disease severity and socioeconomic status, may independently impact on the likelihood of asthma morbidity, and analyses may not control for all these differences. Despite these limitations, population-based effectiveness studies are the only way to assess the impact of vaccination in real-life healthcare settings.
Inactivated influenza vaccines appear to be safe for people with asthma, and, provided they have low egg protein content (≤1.2 lg/mL), also for those with egg allergy. LAIV is also safe in asthma and egg allergy with the exception of severe or acutely exacerbated asthma, where LAIV cannot be given. Oseltamivir is the NI that is currently used in asthma. Although it has moderately beneficial effects on influenza illness in healthy people, there are insufficient data to determine its efficacy and effectiveness in people with asthma. However, novel NIs are currently in development.

NEED S
• People with asthma are at high risk of more severe forms of influenza, with increased hospitalization and admission at healthcare facilities, therefore: • Education campaigns for both the general population and healthcare providers are needed to promote an increase in annual influenza vaccination, early case recognition, and consideration of early empirical antiviral therapy, and to reduce influenza-attributable healthcare utilization among patients with asthma.
• Large cohort and case-control studies using standardized definitions (for AAE), sensitive influenza detection methods, such as PCR, and comprehensive assessment of respiratory pathogens are necessary in both children and adults with asthma.
• There is a need to develop more internationally coordinated registries, for example, for Europe, that accurately collate vaccination status along with medical and socio-demographic details to assess the impact of public health interventions over time.
• Multiple sources of data must be used to record vaccination status (eg, self-reported as well as medical notes, vaccination card, or billing data).
• Targeted vaccination of children and at-risk groups is needed.
• Further studies of influenza vaccine immunogenicity, comparing healthy and asthmatic populations, are required to determine whether people with asthma have normal influenza vaccine responses or whether they require influenza vaccines with enhanced immunogenicity. The discovery and development of improved immune correlates of protection against influenza will enable more meaningful testing of vaccine immunogenicity.
• In view of the uncertainty around the degree of protection that influenza vaccination affords in people of all ages with asthma, further efficacy data need to be collected in this population. Data should be stratified by age and asthma severity, using adequately powered, randomized, placebo-controlled trials that compare both TIV and LAIV to nonvaccinated controls.
• Further studies are needed to evaluate the effectiveness of influenza vaccination in patients with asthma, but must be designed to minimize any risk of bias.
• Safety data in asthma with and without egg allergy are required for new influenza vaccines and, depending on egg protein content, for new LAIV batches.
• There is a need to collect more safety data on zanamivir in patients with chronic respiratory disease, and efficacy data on oseltamivir in children with asthma.
• Development and testing of new anti-influenza drugs among patients with asthma is needed.

ACKNOWLEDG MENTS
We thank Dr Ron Hogg (OmniScience SA, Geneva, Switzerland) for his excellent medical writing services and ADME Osterhaus (affiliation) for his endorsement of this review as the chair of the European Scientific Working Group on Influenza (ESWI). The work was supported by the European Academy of Allergy and Clinical Immunology (EAACI).

CONFLI CTS OF INTEREST
The authors declare that they have no conflicts of interest.

AUTHOR CONTRI BUTIONS
All authors are members of the EAACI Influenza in Asthma Task