Safety of LAIV Vaccination in Asthma or Wheeze: A Systematic Review and GRADE Assessment Open Access

Asthma is a highly prevalent, chronic disease affecting an estimated 7.7% of the total US population in 2021.¹ Approximately one-quarter of children experience recurrent wheezing in early childhood (aged <11 years), with or without a formal diagnosis of asthma.² In addition to experiencing wheezing, dyspnea, and chest tightness,³ individuals with asthma are at increased risk of complications associated with influenza such as asthma exacerbation or development of pneumonia.⁴ 

Inactivated influenza vaccines (IIVs) are recommended by the Centers for Disease Control and Prevention (CDC) for people with asthma to reduce the risk of exacerbating underlying asthma or its complications related to influenza infection.⁴ Live attenuated influenza vaccine (LAIV) is indicated for use by the US Food and Drug Administration in persons aged 2 to 49 years, with a warning and precaution that children younger than 5 years with asthma may be at increased risk of wheezing after LAIV.⁵ An increased risk of hospitalization and wheezing was observed in children aged 6 to 23 months during early clinical trials, and therefore, LAIV is not indicated in this age group.^5,6 The CDC states a contraindication to the use of LAIV in children aged 2 to 4 years with asthma or a history of wheezing in the past 12 months, as well as a precaution (defer use) for persons older than 5 years with asthma, based on early safety signals indicating an increased risk of wheezing after vaccination.^5–9 Subsequent studies evaluating LAIV use in individuals aged 2 to 49 years with asthma or recurrent wheeze found no increased risk of asthma exacerbations, wheezing, or hospitalization in this population.^10–24 Subsequent regulatory approvals and policy recommendations outside the US have not included warnings for children with mild to moderate asthma or a history of wheezing.^25–27 

We conducted a Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessment to assess the certainty of systematically identified evidence published on the safety of LAIV in individuals aged 2 to 49 years with asthma and/or wheeze compared with IIV or no vaccine, or before and after LAIV use.

Our aim was to conduct a balanced evaluation of the safety of LAIV in patients with asthma or recurrent wheeze compared with IIV or no vaccine, or before and after LAIV administration. A systematic literature review (SLR) was designed and conducted to identify relevant evidence on safety outcomes after LAIV vs IIV, placebo, or no vaccination, or before vs after LAIV administration, in individuals aged 2 to 49 years. The GRADE framework was applied to evaluate the certainty of the evidence identified.

The SLR was designed to identify relevant evidence on the safety of LAIV vs IIV, placebo, or no vaccination, or comparing safety before vs after LAIV administration, in patients aged 2 to 49 years diagnosed with mild-to-moderate persistent asthma or recurrent wheeze. Evidence on the safety of LAIV in patients with asthma of any severity or any definition of wheeze was also considered and assessed separately, where appropriate.

The protocol for the SLR and GRADE assessment was developed at SLR conception. The research question and eligibility criteria for the SLR were developed in accordance with the Population/Problem, Intervention, Comparator, Outcome, Study design (PICOS) framework (Supplemental Table 1). Relevant publications reported safety outcomes after LAIV in children or adults aged 2 to 49 years with a diagnosis of asthma (any severity) and/or wheeze (any definition) compared with IIV, placebo, or no vaccine, or before vs after LAIV administration.

Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CCTR), and the Cochrane Database of Systematic Reviews (CDSR) were searched (database inception to November 10, 2022) via the Ovid research platform. Duplicate records between databases were removed automatically within the platform. Searches were updated on August 27, 2024, via the Elsevier (Embase and MEDLINE) and the Ovid research platforms (MEDLINE, CCTR, and CDSR), covering the period from August 10, 2022, to August 27, 2024. Duplicate records between databases searched within the same platform were removed automatically, and duplicates between platforms were removed using EndNote (Clarivate Analytics EndNote software [Version 21]).

Screening was completed using web-based SLR software (DistillerSR, version 2.35, DistillerSR Inc.; 2023. Accessed November 2022) without the aid of machine-learning algorithms or classifiers. Titles and abstracts were screened by a single reviewer against the predefined PICOS criteria using positive exclusion methodology (Supplemental Table 1). Full texts of records included at first-pass screening were reviewed against the same criteria by a single reviewer to confirm eligibility. At each screening stage, approximately 10% of records were screened independently by a second reviewer. Disagreements between reviewers’ decisions were resolved via discussion, and the screening criteria were refined if required.

Data were extracted from eligible publications into a prespecified data extraction spreadsheet (Microsoft Excel) by a single reviewer and were cross-checked by a second reviewer. Any discrepancies were addressed via discussion. Outcomes extracted included study characteristics and eligibility criteria, overall and specific participant group characteristics, outcome measures used, follow-up time for relevant outcomes, data points and variability, main study conclusions, and limitations.

A risk-of-bias (ROB) assessment was performed on the selected studies to evaluate the risk that the study would overestimate or underestimate the true intervention effect. The Cochrane Risk of Bias 2 (ROB2) assessment was used for randomized controlled trials (RCTs),²⁸ and the “Risk of Bias In Non-randomised Studies – of Interventions” (ROBINS-I) tool was used for nonrandomized studies,²⁹ as recommended in the GRADE handbook.³⁰ 

Comparative studies meeting the eligibility criteria of the SLR were included in the GRADE assessment unless they were reported only as a congress abstract or were early studies on cold recombinant influenza vaccine. The evidence included in the GRADE assessment was not considered sufficiently homogeneous to combine via meta-analysis, mainly due to differences in outcome measurements (eg, for asthma severity or recurrent wheeze); therefore, a narrative approach to evidence synthesis was used. The certainty of evidence in relation to the research question was assessed in line with the guidance published in the GRADE handbook and by the CDC Advisory Committee on Immunization Practice (ACIP).^30,31 Evidence was stratified by potential effect modifiers where possible, including the presence or absence of wheeze, asthma severity (mild, moderate, severe), and participant age (2 to 4 years, 5 to 17 years, 18 to 49 years, 2 to 49 years).

During SLR conceptualization, patient-important outcomes for the GRADE assessment were predefined based on the literature and were ranked as “critical,” “important,” or “not important,” according to their relevance to decision-making. Outcomes were refined after completion of the SLR. Outcome categories selected for consideration in the GRADE assessment are outlined in Table 1. Only outcomes that were rated as “critical” or “important” were included in the GRADE assessment. The outcomes were stratified by diagnosis: asthma, recurrent wheeze, and asthma and/or wheeze.

A GRADE assessment was performed across prespecified, patient-important outcomes, per the GRADE handbook,³⁰ with evidence rated as “high,” “moderate,” “low,” or “very low,” according to the confidence that the true effect lies close to the estimated effect.³⁰ The body of evidence was divided between 3 reviewers for assessment. Reviewers worked concurrently to assess their allocated portion but conversed freely throughout to ensure alignment of approach. Final certainty-of-evidence ratings for all evidence were agreed upon by all reviewers and the project lead.

An evidence profile and a summary-of-findings table outlining the certainty rating, a narrative synthesis, and reasons for evidence grading, as appropriate, were populated for each comparison using the GRADEpro GDT software.³² 

Systematic searching of Embase, MEDLINE, CCTR, and CDSR databases (November 10, 2022) identified 421 unique records on the safety of LAIV in individuals with asthma (any severity) and/or wheeze (any definition; Figure 1). Thereafter, 333 records were excluded after title/abstract screening and a further 60 after full-text review, resulting in the inclusion of 28 full-text publications (reporting 24 unique studies). Backward citation searching from 3 published SLRs revealed an additional 7 publications for potential inclusion, none of which met the eligibility criteria. A further 36 unique records were identified when the searches were updated on August 27, 2024, of which 35 had been published since the original searches were conducted. Titles and abstracts of all additional records were screened against the predefined PICOS criteria using the same methodology as the original SLR. Two full texts were screened to confirm eligibility; neither met the criteria for inclusion, meaning no additional publications were identified in the SLR update.

Nine of the 24 unique studies identified in the SLR were not considered in the GRADE assessment. Studies excluded were single-arm studies, those that made no comparison before and after LAIV use,^13,33,34 those that were abstract-only publications,^35–37 or those that reported early evidence on cold recombinant intranasal influenza vaccines,^38–40 which were not considered relevant to the research question considered in the GRADE assessment. A total of 15 studies reported in 15 publications were included in the GRADE assessment^{10–12,14–22,24,41,42}; 1 study (NCT03600428) was reported in 2 publications,^24,41 and 1 publication¹⁰ reported data from 2 studies.^6,43 An ROB assessment for all outcomes was performed using published evidence. The overall ROB was considered “high” for all RCTs due to concerns around deviations from intended interventions (sample size calculations) and outcome measurements (eg, patient-/caregiver-reported outcomes; Supplemental Table 2). For observational studies, the ROB ranged from “moderate” to “severe,” mostly because of the potential for bias due to confounding, missing data, and measurement outcomes (Supplemental Table 3).

Table 1 outlines the predefined outcomes of interest for the GRADE assessment and those actually reported in the studies that were included.

The evidence included in the GRADE assessment is outlined in Figure 2. Here, we focus on outcomes after LAIV vs IIV in individuals aged 2 to 18 years; evidence pertaining to individuals older than 18 years, as well as comparisons made with placebo or no vaccine and before vs after LAIV, is reported in full in the supplemental information.

Four studies (reported in 5 publications^{12,14,24,36,41}) reported relevant outcomes after LAIV vs IIV in children and adolescents with asthma (mild, moderate/severe, or any severity).

Based on evidence of “moderate” certainty from a single study, there was no difference in the number of asthma exacerbations after LAIV vs IIV in children and adolescents aged 5 to 17 years with asthma of mild or moderate/severe severity (P = not applicable; “moderate” certainty evidence).²⁴ Evidence was downgraded in the ROB domain (Table 2).

Two studies reported no difference in the number of asthma exacerbations after LAIV vs IIV in individuals aged 5 to 17 years (“moderate” certainty; P = .71²⁴; P = not reported [NR]¹⁴). One study further showed no significant difference in the severity of asthma exacerbations assessed using the following surrogate measures: peak expiratory flow rate decrease of 20% or more from baseline (“very low” certainty; P = NR)²⁴ and change in baseline Asthma Control Test (ACT) or Children’s ACT score (“low” certainty; P = NR).²⁴ Evidence relating to the number and severity of asthma exacerbations was downgraded in the ROB domain and in the ROB and indirectness domains, respectively (Table 3).

A statistically significantly higher incidence of any respiratory adverse events (AEs; rhinitis, upper respiratory tract infection [URTI], coughing, pharyngitis, bronchospasm, bronchitis) was reported after LAIV vs IIV (P = .032) in a single study, with evidence downgraded for indirectness (“moderate” certainty).¹⁴ However, regarding individual respiratory AEs, there was a significantly higher incidence of rhinitis after LAIV vs IIV (P = .001) but no statistically significant difference in the incidence of other respiratory AEs between the 2 vaccine formulations (Table 3).¹⁴ 

Evidence on medically significant wheezing after influenza vaccination was mixed (“very low” certainty).^14,41 A significantly lower incidence of wheezing was reported after LAIV vs IIV in one RCT (P = .020),¹⁴ while descriptive analyses indicated a similar rate of mild/moderate/severe wheezing between treatment groups in the second RCT (P = NR).⁴¹ 

One observational study reported a significantly lower incidence of asthma-associated hospitalization, as assessed by inpatient/emergency department (ED) visits, after LAIV vs IIV in children and adolescents aged 2 to 18 years (total population; difference of differences, P = .04; “low” certainty).¹⁷ When stratified by asthma classification (current or recent persistent asthma, current or recent not-persistent asthma, remote history of asthma), a similar finding was observed across all subgroups, except for the subgroup with a remote history of asthma. Evidence was downgraded for indirectness and imprecision (Table 3). A second observational study reported no difference in asthma-associated hospitalization measured by hospitalization for lower respiratory events (LREs), defined by the authors as a diagnosis of asthma, wheezing, or croup (P = NR; “low” certainty).¹² Evidence was downgraded for indirectness (Table 3).

In 1 RCT, there was no difference reported in medically attended asthma-associated incidents after adjustment for asthma severity (P = .735; “moderate” certainty)²⁴ or use of rescue/reliever medications after LAIV vs IIV in children and adolescents aged 5 to 17 years (P = NR; “low” certainty).⁴¹ Evidence was downgraded in the ROB²⁴ and indirectness domains (Table 3).^24,41 

Six studies (reported in 5 publications^{10,16,19,20,42}) reported relevant outcomes after LAIV in individuals aged 2 to 17 years with a diagnosis or history of asthma and/or recurrent wheeze.

In 1 RCT conducted in children aged 2 to 6 years, there was no difference in medically significant wheezing after LAIV vs IIV administration, defined as rate of wheezing illness, or as medically significant wheezing (P = NR; “very low” certainty).¹⁰ Evidence was downgraded for ROB, indirectness, and imprecision (Table 4). Similarly, there was no difference in medically significant wheezing after LAIV vs IIV in a different observational study conducted in children aged 2 to 17 years with a recent history of asthma/wheeze/respiratory airway disease (P = NR; “very low” certainty).⁴² Evidence was downgraded in the ROB and indirectness domains (Table 4).

In an RCT conducted in children aged 2 to 6 years, there was no difference in asthma-/wheeze-associated hospitalization after LAIV vs IIV as measured by hospitalization due to respiratory tract infection (P = NR; “very low” certainty)¹⁰ or in the rate of ED visits or hospitalizations for asthma reported in 2 observational studies (P = NR; “very low” certainty).^19,20 Evidence was downgraded for ROB, indirectness, and imprecision in all 3 studies^10,19,20 (Table 4). Limited reporting of the methodology by Ambrose et al,¹⁰ who reported a subgroup analysis of study reports previously published by Ashkenazi et al,⁶ and Belshe et al,⁴³ contributed to the “low” certainty rating of the evidence for number of ED visits and hospitalization for asthma.¹⁰ 

There was no difference in the number of medically attended asthma-/wheeze-associated incidents after LAIV vs IIV in children aged 2 to 6 years in 1 RCT; the certainty of evidence was “low” when measured using medically attended or medically documented wheezing (P = NR).¹⁰ Similarly, in an observational study, there was no difference in the rate of medically attended LREs (including asthma and wheeze; P = NR).¹⁶ Evidence was downgraded in the ROB,¹⁰ imprecision,¹⁰ and indirectness¹⁶ domains (Table 4). The observational study also showed no difference in the number of medically attended asthma/wheeze incidents after LAIV vs IIV in children aged 2 to 17 years, based on “low” certainty of evidence (P = NR).¹⁶ Evidence was downgraded for indirectness (Table 4).

Three observational studies^16,21,22 compared outcomes before and after LAIV use in individuals aged 2 to 18 years with a history of asthma and/or recurrent wheeze, and another observational study¹⁵ compared outcomes before and after LAIV use in those aged 5 to 18 years with intermittent wheezing. Two studies (1 RCT and 1 observational)^12,18 reported outcomes after LAIV vs placebo in individuals aged 2 to 17 years with asthma (moderate/severe or any severity). Consistent with the comparison between LAIV and IIV, there was no difference in patient-important safety outcomes before vs after LAIV or after LAIV vs no vaccine in children and adolescents with asthma or wheeze aged 2 to 18 years, based on “moderate” to “very low” certainty evidence.^{12,16,18,21,22} Full results are reported in Supplemental Tables 4–8.

A single observational study compared safety outcomes after LAIV vs IIV in individuals aged 2 to 49 years with a history of asthma or wheezing.¹¹ There was no difference in the risk of wheezing after LAIV vs IIV or no vaccination in children and adults aged 2 to 49 years with a history of asthma or wheezing, based on “very low” certainty evidence (Supplemental Tables 9 and 10).¹¹ 

This assessment evaluated the certainty of published evidence on the safety of LAIV in individuals aged 2 to 49 years with asthma and/or recurrent wheeze; most studies identified were in children and adolescents (aged 2 to 18 years), with only a single study reporting outcomes in adults aged 18 to 49 years. Most studies included in this GRADE assessment reported no difference in a range of asthma safety parameters after LAIV vs IIV (13 of 15 studies; 86.7%) across all age groups and across the spectrum of disease severity. Certainty of evidence ratings ranged from “very low” to “moderate,” which was driven by downgrading in the ROB, indirectness, and imprecision domains. Factors for evidence downgrading included small sample size and misalignment of follow-up periods, with some studies downgraded due to how the data were reported. Using study NCT03600428 as an example, the full methodology was NR via ClinicalTrials.gov but was reported in the publication^24,41; conversely, 1 publication¹⁰ reported data from 2 studies.^6,43 

Nevertheless, an RCT reported by Fleming et al¹⁴ and an observational study reported by Ray et al¹⁷ revealed differences in relevant non–asthma-/wheeze-related safety outcomes between individuals who received LAIV vs IIV. Fleming et al¹⁴ showed a significantly higher incidence of non–asthma-related AEs (P = .032) in children and adolescents aged 5 to 17 years with asthma (any severity) receiving LAIV vs IIV (“moderate” certainty rating). This was driven by a statistically significant increase in rhinitis after LAIV,¹⁴ which is a common side effect of LAIV resulting from the replication of the vaccine virus in the nasal passages.^5,44 Fleming et al¹⁴ further reported a lower incidence of wheezing after LAIV vs IIV (“very low” certainty rating) in individuals aged 5 to 17 years, with any severity of asthma.¹⁴ During the study period, the relative effectiveness of LAIV was significantly greater than for IIV (35% for antigenically similar strains; 32% for all strains), which may have contributed to a lower incidence of wheezing after LAIV vs IIV. However, absolute vaccine effectiveness could not be calculated in the absence of a placebo group.¹⁴ It is recognized that perceptions of wheezing differ between parents and health care providers,⁴⁵ which opens potential for variation in the recording of wheeze events.

A significantly lower incidence of asthma-related inpatient/ED visits (“low” certainty rating) was observed after LAIV vs IIV in an observational study of patients aged 5 to 17 years with asthma (any severity), reported by Ray et al.¹⁷ The authors note that residual confounding may result from factors including vaccination timing: in this report, vaccine choice may have been influenced by children presenting with symptoms suggesting an imminent asthma exacerbation (eg, cough or URTI), thus influencing the provider to use IIV rather than LAIV or to defer vaccination with either LAIV or IIV until the illness subsides, in line with the CDC best practice guidelines for vaccination.^17,46 Further, the potential for misdiagnosis of asthma symptoms is high during periods when respiratory infections are prevalent, especially in individuals with a history of asthma. Given that variation in diagnosis coding at the point of care is an inherent limitation of observational studies,⁴⁷ these results should be interpreted with caution.

Asthma severity was a key effect modifier in this assessment; however, definitions of severity varied, with few studies reporting outcomes stratified by disease severity. Of the studies that included patients with severe asthma, most showed little or no difference in outcomes with LAIV vs the comparator.^{17,18,21,22,24,42} However, patients with acute asthma symptoms within 2 to 4 weeks before enrollment were often excluded,^22,24,42 limiting the ability to draw conclusions in patients with poorly controlled asthma. Further, as suggested in the observational study by Tennis et al,¹⁹ providers may be avoiding LAIV use in individuals with severe or symptomatic asthma. They found that LAIV was administered less frequently in patients with recent inhaled corticosteroid use, ED visit, or asthma-related hospitalization compared with IIV.¹⁹ 

The results of studies reporting safety outcomes before vs after LAIV administration or LAIV vs no vaccine were consistent with those reporting outcomes after LAIV vs IIV, with no differences in critical safety outcomes reported in individuals aged 2 to 18 years with asthma or recurrent wheeze (“low” and “very low” certainty). A single study, reported by Baxter et al,¹¹ was identified as reporting critical safety outcomes in adults with asthma and/or wheezing. This study, in which 88% of the study participants were aged 2 to 17 years, demonstrated no difference in medically significant wheezing between LAIV and IIV or no vaccine groups, in children and adults aged 2 to 49 years with asthma and/or wheeze (“very low” evidence certainty).¹¹ This highlights the paucity of evidence available on safety outcomes in adults with asthma and/or wheeze. Consequently, the findings of the registrational study in which no asthma or wheeze signals were identified along with the available data from the pediatric population may need to influence the guidance on the use of LAIV in adults with mild or moderate asthma until further evidence becomes available.

Influenza poses a substantial risk to individuals living with asthma, even those with mild or well-controlled asthma.⁴⁸ Increasing annual influenza vaccination rates is a key goal of the US Department of Health and Human Services Healthy People 2030 initiative⁴⁹ and is especially important in populations with asthma.⁴⁸ The ACIP/CDC-stated contraindication and precaution against LAIV use in individuals with asthma and wheeze, which was driven by early labeling study safety concerns in this population,⁴ limits their available vaccination options.⁵⁰ 

Our assessment of the published evidence on the safety of LAIV in individuals with asthma and/or wheeze, which was conducted in line with the guidance used by the CDC when making evidence-based recommendations,³¹ suggests little or no difference in patient-important safety outcomes after LAIV vs IIV or no vaccine, or before and after LAIV. Revisiting the ACIP-stated contraindication and precaution against LAIV use in individuals with a history of wheezing or asthma has the potential to widen the influenza vaccine formulation options available to a population that is at risk of influenza-related complications and could be associated with increased uptake.

A key strength of our study is the broad search strategy used to identify relevant evidence from multiple study types to inform the GRADE assessment. To ensure that all relevant evidence was captured, multiple databases were searched, and no limits on participant age or severity of illness were applied. The GRADE assessment was conducted using the GRADEPro software³² and was aligned with the methods outlined in the GRADE handbook.³⁰ 

Our approach to stratifying the identified evidence by patient age and asthma severity—2 key effect modifiers—in the GRADE assessment is both a strength and a limitation of our study. Stratification avoided the need to downgrade evidence for indirectness associated with these variables, adding granularity to the assessment; however, it also reduced the quantity of evidence for some comparisons, limiting our ability to draw meaningful conclusions. This was further confounded by the inability to obtain a summary estimate of effect across studies for each comparison using meta-analysis; therefore, the evidence could only be synthesized using a narrative approach.

SLR screening was conducted predominantly by a single reviewer, which potentially introduced bias. This was mitigated in part by a second review of approximately 10% of decisions on inclusion/exclusion by an independent reviewer. A total of 46 inclusion/exclusion decisions (original SLR, 41; SLR update, 5) underwent a second review at title/abstract screening, and 8 at full-text review (all as part of the original SLR). Of these initial decisions, 6 title/abstract publications (13%; original SLR, κ = 0.66; SLR update, κ = 1.00) and 2 full-text publications (25%; original SLR, κ = 0.38) were the subject of further discussion. Although the proportions of decisions requiring discussion were relatively high, this reflects the relatively small sample size and complexity of the review, and the use of positive exclusion methodology meaning that records were only excluded if it was clear at least 1 of the inclusion criteria was not met. All discrepancies were resolved by discussion. Additionally, all extracted data were cross-checked by a second reviewer.

Our aim was to assess safety outcomes after LAIV use in individuals with asthma, most of which were reported in individuals younger than 18 years. We considered safety outcomes alone without the consideration of benefit, resource use, equity, acceptability, or feasibility, many of which are established within the current vaccination framework. This approach aligns with that adopted by the ACIP when making evidence-based recommendations.⁵¹ 

While GRADE provides a reproducible framework for assessing evidence, the process itself is subjective, meaning that different certainty ratings and conclusions may be reached by other groups assessing the same or a similar research question.^52,53 Indeed, a study conducted by the GRADE Working Group showed worse agreement between individuals who independently provided evidence ratings than between those who discussed and compared their evidence ratings before reaching a final consensus.^54,55 Given the number of comparisons considered, the body of evidence was divided between 3 reviewers working concurrently, which is a potential limitation of this work. To ensure a balanced and consistent approach was adopted across all evidence in the assessment, reviewers openly conferred during the process of assessment, and the final certainty ratings were discussed and agreed upon by all reviewers as part of a working meeting. Generally, reviewers adopted a conservative approach with all studies downgraded in at least 1 domain.

Our study indicated little or no difference in patient-important safety outcomes after LAIV vs IIV or no vaccination, and before vs after LAIV, in patients with a history of asthma and/or recurrent wheeze. Permissive guidance for the use of LAIV would increase the options available to these individuals, expanding access to vaccination in a population at risk of influenza-related complications.

Sofie Norregaard, MSc, contributed to the conduct of the systematic literature review and GRADE assessment while employed by Prime Access (a division of Prime, Knutsford, UK). Editorial support, including figure preparation, formatting, proofreading, and submission, was provided by Isobel Markham, MSc; Tina Allen, BSc; and Claire Whitehead, BA, of Prime, Knutsford, UK, supported by AstraZeneca US according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M22-1460).

ACIP

Advisory Committee on Immunization Practice

ACT

Asthma Control Test

AE

adverse event

cACT

Children’s Asthma Control Test

CCTR

Central Register of Controlled Trials

CDSR

Cochrane Database of Systematic Reviews

ED

emergency department

GRADE

Grading of Recommendations, Assessment, Development, and Evaluation

IIV

inactivated influenza vaccine

LAIV

live attenuated influenza vaccine

LRE

lower respiratory event

LRTI

lower respiratory tract infection

NA

not applicable

NR

not reported

PEFR

peak expiratory flow rate

PICOS

Population/problem, Intervention, Comparator, Outcome, Study design

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT

randomized controlled trial

ROB

risk of bias

ROB2

Cochrane Risk of Bias 2

ROBINS-I

Risk of Bias in Non-randomised Studies – of Interventions

SLR

systematic literature review

URTI

upper respiratory tract infection