Accepted: 3 June 2016 DOI: 10.1111/irv.12400
ORIGINAL ARTICLE
Contribution of influenza viruses to medically attended acute respiratory illnesses in children in high-income countries: a meta-analysis Sarah A. Buchan1 | Travis S. Hottes1 | Laura C. Rosella1,2,3 | Natasha S. Crowcroft1,2 | Dat Tran4 | Jeffrey C. Kwong1,2,3,5,6 1 Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada 2
Public Health Ontario, Toronto, ON, Canada 3
Institute for Clinical Evaluative Sciences, Toronto, ON, Canada 4
Aim: The burden of disease in children attributable to influenza viruses is difficult to quantify given the similarity of symptoms caused by infection due to influenza and other viruses. This uncertainty impacts clinical decision-making and estimates of burden. We aimed to systematically review the literature to determine the proportion of healthy children presenting for health care with an acute respiratory illness (ARI) who
Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
have laboratory-confirmed seasonal influenza (PROSPERO ID#CRD42014013896).
5
Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
influenza in healthy children aged ≤5 years who presented for health care in high-
6
lect data on positivity and other relevant study elements.
University Health Network, Toronto, ON, Canada Correspondence Sarah Buchan, Dalla Lana School of Public Health, Toronto, ON, Canada. Email: [email protected]
Method: We searched Ovid MEDLINE, EMBASE, Scopus, and references of included articles. We included studies that used polymerase chain reaction methods to test for income countries with an influenza-like or ARI. A standardized form was used to colResults: Seventeen studies covering 12 different influenza seasons were included. The proportion of influenza positivity ranged from 11% to 56%. Subgroup analyses were performed by influenza season, continent, healthcare setting, age group, and vaccination status. Higher influenza positivity was reported among children aged 3–5 years compared with children aged ≤2 years, and for unvaccinated children. Conclusion: The minority of healthy patients aged ≤5 years with medically attended influenza-like or acute respiratory symptoms have laboratory-confirmed influenza virus infection, although this varied by influenza season. Prevention efforts should be targeted accordingly. Statement: Most influenza-like illnesses are not laboratory-confirmed and have similar clinical presentations. Consequently, the true contribution of influenza to acute respiratory infections in children remains uncertain. Our systematic review estimates that this proportion ranges from 11% to 56%. This finding can help both clinicians and public health professionals target prevention. KEYWORDS
acute respiratory illness, child, influenza, meta-analysis, polymerase chain reaction
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 444 wileyonlinelibrary.com/journal/irv | © 2016 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.
Influenza and Other Respiratory Viruses 2016; 10: 444–454
| 445
Buchan et al.
1 | INTRODUCTION
with ILI/ARI, as defined by individual studies (see Table 1 for defini-
Annual epidemics of seasonal influenza continue to cause substan-
oped by the World Bank.12 No language restrictions were placed on
tial morbidity and mortality among children.1–3 Previous studies have
the initial review, although only full-text articles available in English,
used non-specific outcomes such as influenza-like illness (ILI) or acute
French, or Spanish were included. We excluded studies in which PCR
respiratory illness (ARI) to estimate disease burden and vaccine effec-
methods were not used or not used exclusively, studies that tested
tiveness.4 However, other respiratory viruses cause similar symptoms,
all participants (not just those with ILI/ARI), studies in which all par-
making it challenging to distinguish infections due to influenza viruses
ticipants were >5 years of age or which did not report results for this
tions). High-income categorization was based on the definition devel-
from others. This uncertainty impacts clinical decision-making and
age group separately, studies of children with underlying medical con-
the estimation of the true burden of influenza, as well as vaccine effec-
ditions, studies that did not report each influenza season separately,
tiveness.6,7 Laboratory testing identifies the specific virus responsible
studies that reported outbreak investigations, studies reporting inter-
for the illness, but is not routinely performed in clinical practice; thus,
im estimates for an ongoing influenza season, studies that focused on
the true contribution of influenza in the pediatric population remains
diagnostic techniques, genetic characterization, clinical characteristics
uncertain.
of patients, or describing the use of surveillance systems, studies that
5
While other reviews have examined the contribution of influen-
only reported on the 2009 A(H1N1) pandemic season, and studies
za viruses to burden in sub-Saharan Africa or to acute lower respi-
of co-infections that did not report influenza separately. Conference
ratory infections (ALRI),
8,9
this study fills a gap in knowledge of the
contribution to ILI/ARI in pediatric populations. To our knowledge,
proceedings and abstracts, non-peer-reviewed reports, reviews, letters, editorials, case reports, and case series were excluded.
no other published systematic reviews have quantified the contribution of influenza viruses to medically attended respiratory illness in children in high-income countries. The objective of this study was to
2.3 | Review process
systematically review the published peer-reviewed literature evidence
The titles and abstracts of retrieved articles were reviewed for gen-
to determine the proportion of healthy children aged ≤5 years pre-
eral relevancy (SB). Studies meeting the predefined inclusion criteria
senting for health care with ILI/ARI who have laboratory-confirmed
were included for full-text review, performed independently by two
seasonal influenza.
reviewers (SB and TSH). The inter-rater reliability for studies selected for inclusion in the review was good (κ=0.79, 95% CI, 0.64–0.94), and
2 | METHODS 2.1 | Search strategy We developed a detailed search strategy in consultation with a scien-
any disagreements (n=7 studies) were resolved through discussion and consensus.
2.4 | Data extraction
tific librarian to identify articles related to children aged ≤5 years in
We used a standardized data extraction form to collect data on the
high-income countries (population) who had an ILI/ARI (exposure) and
following study elements: study publication details (author, journal,
were tested for influenza with polymerase chain reaction (PCR) meth-
year of publication), study design, influenza season(s) and period
ods (outcome). This strategy was applied to Ovid MEDLINE, EMBASE,
of circulation, age groups, country of study, study setting (hospital,
and Scopus (from inception to August 6, 2014). Search terms included
emergency department, physician office), outcome with case defini-
“influenza,” “flu,” “polymerase chain reaction,” “PCR,” “laboratory-
tion, number of participants studied, and number testing positive for
confirmed,” “child,” “infant,” and “adolescent.” Similar terms were com-
influenza.
bined with an “OR” operator and distinct terms linked with an “AND” operator. The full search strategy is outlined in File S1. Reference lists of included studies were also searched. The search strategy, along
2.5 | Outcome
with the inclusion and exclusion criteria, was outlined in a registered
The outcome of interest was the proportion of swabbed children test-
study protocol (PROSPERO ID #CRD42014013896).10 The results
ing positive for influenza after presenting for health care with ILI/
of our systematic review and meta-analysis are reported accord-
ARI.
ing to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.11
2.6 | Assessment of risk of bias We used a Newcastle–Ottawa scale adapted for cross-sectional stud-
2.2 | Study selection
ies by Herzog et al.13 to assess the quality of included studies as they related to our outcome: the proportion tested who were influenza
We included experimental, observational, and surveillance studies that
positive. Given the nature of our study question, we chose a tool that
used PCR methods to test for influenza infection in healthy children
related to our outcome over one that assessed the quality of the study
aged ≤5 years in high-income countries who presented for health care
in general. This scale evaluated the quality of the study as it related
2011–2012
2008–2009 2003–2004, 2004–2005
2007–2008
2010–2011
2008–2009
2010–2011
Test-negative case–control
Test-negative case–control
Surveillance
Test-negative case–control
Test-negative case–control
Test-negative case–control
Test-negative case–control
Test-negative case–control
Test-negative case–control
Test-negative case–control
Belongia, 201520
Castilla, 201326
Chatzpolou, 201227
Eisenberg, 200821
Fielding, 201133
Janjua, 201222
Jiminez-Jorge, 201228
Kelly, 201134
Martinez-Baz, 201329
Pebody, 201330 2010–2011
All ages
All ages
Pediatric
All ages
All ages
All ages
UK, Europe
Spain, Europe
Australia, Oceania
Spain, Europe
Canada, North America
Australia, Oceania
USA, North America
Greece, Europe
Spain, Europe
USA, North America
UK, Europe
Country, continent
≤5 y
≤5 y
6 mo–5 y
≤4 y
6 mo–2 y
≤4 y
6–59 mo
≤2 y
≤5 y
≤5 y
≤5 y
Included age range
Physician office
Mix: Physician office, Hospital
Physician office; Emergency Department
Physician office
Physician office
Physician office
Physician office
Physician office
Mix: Physician office, Hospital
Mix: Physician office, Hospital
Physician office
Healthcare setting(s)
Acute respiratory illness with fever or complaint of feverishness
Sudden onset of any general symptom (fever or feverishness, malaise, headache, or myalgia) in addition to any respiratory symptom (cough, sore throat, or shortness of breath)
Documented fever with oral temperature >38°C, with at least one acute respiratory symptom or sign
Sudden onset of symptoms, and at least one of these four systemic symptoms (fever or feverishness, malaise, headache, myalgia), and at least one of these three respiratory symptoms (cough, sore throat, shortness of breath), in the absence of other suspected clinical diagnosis
Acute onset of fever and cough and the presence of ≥1 of the following: sore throat, arthralgia, myalgia, or prostration
History of fever, cough, and fatigue/malaise
Presenting complaint of cough, earache, fever (identified through medical documentation or parent report), nasal congestion/runny nose, shortness of breath/rapid or shallow breathing, sore throat, vomiting after cough, or wheezing
Not reported
Sudden onset of any general symptom (fever or feverishness, malaise, headache, or myalgia) in addition to any respiratory symptom (cough, sore throat, or shortness of breath)
Acute respiratory illness with symptoms of feverishness, chills, or cough
Acute respiratory illness with physician-diagnosed fever or complaint of feverishness
Case definition
317
19
289
103
38
(continues)
2007–2008: 14 2008–2009: 9
2003–2004: 362 2004–2005: 752
42
84
213
294
Sample size (Total)
2007–2008, 2008–2009
Pediatric
Pediatric
All ages
All ages
All ages
Study population
|
2007–2008
2012–2013
Test-negative case–control
Andrews, 201425
Influenza season(s)
Study design
Study author, publication year
T A B L E 1 Characteristics of included studies
446
Buchan et al.
Study design
Surveillance
Test-negative case–control
Surveillance
Test-negative case–control
Test-negative case–control
Surveillance
Study author, publication year
Rezza, 200631
Staat, 201123
Sung, 200936
Treanor, 201224
Turner, 201435
Zambon, 200132
TABLE 1 (continued)
1995–1996, 1996–1997, 1997–1998
2012–2013
2010–2011
2005–2006
2005–2006, 2006–2007
2004–2005
Influenza season(s)
All ages
All ages
All ages
Pediatric
Pediatric
All ages
Study population
UK, Europe
New Zealand, Oceania
USA, North America
Hong Kong, Asia
USA, North America
Italy, Europe
Country, continent
≤5 y
6 mo–5 y
6 mo–2 y
≤5 y
6–59 mo
≤2 y
Included age range
Physician office
Hospital
Mix: Physician office, Emergency Department, Hospital
Hospital
Physician office; Hospital; Emergency Department
Physician office
Healthcare setting(s)
Symptoms of fever, cough, and respiratory tract illness
Severe acute respiratory infection defined as a patient requiring hospitalization with a history of a fever or a measured temperature ≥38°C and cough and onset within the past 7 d
ARI with a duration of ≤7 d with documented fever or history of feverishness or cough
Sudden onset (37.5°C and at least one other symptom (headache, malaise, myalgia, chills or sweats, retrosternal pain, asthenia) and one respiratory symptom (cough, sore throat, nasal congestion, or runny nose)
Case definition
1995–1996: 190 1996–1997: 108 1997–1998: 132
334
784
475
2005–2006: 268 2006–2007: 260
14
Sample size (Total)
Buchan et al.
| 447
|
448
Buchan et al.
to domains of selection, comparability, and outcome. We extracted a
stabilize the variance,15 in order to compare the results. The analysis
proportion from the studies that was not directly reported; therefore,
was run in R Statistical Software using the meta package to provide a
the statistical test criterion in the outcome domain was deemed not
prediction interval to estimate the range of values that future studies
applicable to this study.
can be expected to fall within.18 Forest plots were created for each subgroup in order to examine clinical (e.g., age, setting, influenza season) and methodological (e.g.,
2.7 | Data synthesis and analysis
study design, study quality) heterogeneity. Statistical heterogeneity
A stratified meta-analysis was planned a priori due to anticipated
was assessed using the Cochran Q statistic (with P
ORIGINAL ARTICLE
Contribution of influenza viruses to medically attended acute respiratory illnesses in children in high-income countries: a meta-analysis Sarah A. Buchan1 | Travis S. Hottes1 | Laura C. Rosella1,2,3 | Natasha S. Crowcroft1,2 | Dat Tran4 | Jeffrey C. Kwong1,2,3,5,6 1 Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada 2
Public Health Ontario, Toronto, ON, Canada 3
Institute for Clinical Evaluative Sciences, Toronto, ON, Canada 4
Aim: The burden of disease in children attributable to influenza viruses is difficult to quantify given the similarity of symptoms caused by infection due to influenza and other viruses. This uncertainty impacts clinical decision-making and estimates of burden. We aimed to systematically review the literature to determine the proportion of healthy children presenting for health care with an acute respiratory illness (ARI) who
Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
have laboratory-confirmed seasonal influenza (PROSPERO ID#CRD42014013896).
5
Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
influenza in healthy children aged ≤5 years who presented for health care in high-
6
lect data on positivity and other relevant study elements.
University Health Network, Toronto, ON, Canada Correspondence Sarah Buchan, Dalla Lana School of Public Health, Toronto, ON, Canada. Email: [email protected]
Method: We searched Ovid MEDLINE, EMBASE, Scopus, and references of included articles. We included studies that used polymerase chain reaction methods to test for income countries with an influenza-like or ARI. A standardized form was used to colResults: Seventeen studies covering 12 different influenza seasons were included. The proportion of influenza positivity ranged from 11% to 56%. Subgroup analyses were performed by influenza season, continent, healthcare setting, age group, and vaccination status. Higher influenza positivity was reported among children aged 3–5 years compared with children aged ≤2 years, and for unvaccinated children. Conclusion: The minority of healthy patients aged ≤5 years with medically attended influenza-like or acute respiratory symptoms have laboratory-confirmed influenza virus infection, although this varied by influenza season. Prevention efforts should be targeted accordingly. Statement: Most influenza-like illnesses are not laboratory-confirmed and have similar clinical presentations. Consequently, the true contribution of influenza to acute respiratory infections in children remains uncertain. Our systematic review estimates that this proportion ranges from 11% to 56%. This finding can help both clinicians and public health professionals target prevention. KEYWORDS
acute respiratory illness, child, influenza, meta-analysis, polymerase chain reaction
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 444 wileyonlinelibrary.com/journal/irv | © 2016 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.
Influenza and Other Respiratory Viruses 2016; 10: 444–454
| 445
Buchan et al.
1 | INTRODUCTION
with ILI/ARI, as defined by individual studies (see Table 1 for defini-
Annual epidemics of seasonal influenza continue to cause substan-
oped by the World Bank.12 No language restrictions were placed on
tial morbidity and mortality among children.1–3 Previous studies have
the initial review, although only full-text articles available in English,
used non-specific outcomes such as influenza-like illness (ILI) or acute
French, or Spanish were included. We excluded studies in which PCR
respiratory illness (ARI) to estimate disease burden and vaccine effec-
methods were not used or not used exclusively, studies that tested
tiveness.4 However, other respiratory viruses cause similar symptoms,
all participants (not just those with ILI/ARI), studies in which all par-
making it challenging to distinguish infections due to influenza viruses
ticipants were >5 years of age or which did not report results for this
tions). High-income categorization was based on the definition devel-
from others. This uncertainty impacts clinical decision-making and
age group separately, studies of children with underlying medical con-
the estimation of the true burden of influenza, as well as vaccine effec-
ditions, studies that did not report each influenza season separately,
tiveness.6,7 Laboratory testing identifies the specific virus responsible
studies that reported outbreak investigations, studies reporting inter-
for the illness, but is not routinely performed in clinical practice; thus,
im estimates for an ongoing influenza season, studies that focused on
the true contribution of influenza in the pediatric population remains
diagnostic techniques, genetic characterization, clinical characteristics
uncertain.
of patients, or describing the use of surveillance systems, studies that
5
While other reviews have examined the contribution of influen-
only reported on the 2009 A(H1N1) pandemic season, and studies
za viruses to burden in sub-Saharan Africa or to acute lower respi-
of co-infections that did not report influenza separately. Conference
ratory infections (ALRI),
8,9
this study fills a gap in knowledge of the
contribution to ILI/ARI in pediatric populations. To our knowledge,
proceedings and abstracts, non-peer-reviewed reports, reviews, letters, editorials, case reports, and case series were excluded.
no other published systematic reviews have quantified the contribution of influenza viruses to medically attended respiratory illness in children in high-income countries. The objective of this study was to
2.3 | Review process
systematically review the published peer-reviewed literature evidence
The titles and abstracts of retrieved articles were reviewed for gen-
to determine the proportion of healthy children aged ≤5 years pre-
eral relevancy (SB). Studies meeting the predefined inclusion criteria
senting for health care with ILI/ARI who have laboratory-confirmed
were included for full-text review, performed independently by two
seasonal influenza.
reviewers (SB and TSH). The inter-rater reliability for studies selected for inclusion in the review was good (κ=0.79, 95% CI, 0.64–0.94), and
2 | METHODS 2.1 | Search strategy We developed a detailed search strategy in consultation with a scien-
any disagreements (n=7 studies) were resolved through discussion and consensus.
2.4 | Data extraction
tific librarian to identify articles related to children aged ≤5 years in
We used a standardized data extraction form to collect data on the
high-income countries (population) who had an ILI/ARI (exposure) and
following study elements: study publication details (author, journal,
were tested for influenza with polymerase chain reaction (PCR) meth-
year of publication), study design, influenza season(s) and period
ods (outcome). This strategy was applied to Ovid MEDLINE, EMBASE,
of circulation, age groups, country of study, study setting (hospital,
and Scopus (from inception to August 6, 2014). Search terms included
emergency department, physician office), outcome with case defini-
“influenza,” “flu,” “polymerase chain reaction,” “PCR,” “laboratory-
tion, number of participants studied, and number testing positive for
confirmed,” “child,” “infant,” and “adolescent.” Similar terms were com-
influenza.
bined with an “OR” operator and distinct terms linked with an “AND” operator. The full search strategy is outlined in File S1. Reference lists of included studies were also searched. The search strategy, along
2.5 | Outcome
with the inclusion and exclusion criteria, was outlined in a registered
The outcome of interest was the proportion of swabbed children test-
study protocol (PROSPERO ID #CRD42014013896).10 The results
ing positive for influenza after presenting for health care with ILI/
of our systematic review and meta-analysis are reported accord-
ARI.
ing to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.11
2.6 | Assessment of risk of bias We used a Newcastle–Ottawa scale adapted for cross-sectional stud-
2.2 | Study selection
ies by Herzog et al.13 to assess the quality of included studies as they related to our outcome: the proportion tested who were influenza
We included experimental, observational, and surveillance studies that
positive. Given the nature of our study question, we chose a tool that
used PCR methods to test for influenza infection in healthy children
related to our outcome over one that assessed the quality of the study
aged ≤5 years in high-income countries who presented for health care
in general. This scale evaluated the quality of the study as it related
2011–2012
2008–2009 2003–2004, 2004–2005
2007–2008
2010–2011
2008–2009
2010–2011
Test-negative case–control
Test-negative case–control
Surveillance
Test-negative case–control
Test-negative case–control
Test-negative case–control
Test-negative case–control
Test-negative case–control
Test-negative case–control
Test-negative case–control
Belongia, 201520
Castilla, 201326
Chatzpolou, 201227
Eisenberg, 200821
Fielding, 201133
Janjua, 201222
Jiminez-Jorge, 201228
Kelly, 201134
Martinez-Baz, 201329
Pebody, 201330 2010–2011
All ages
All ages
Pediatric
All ages
All ages
All ages
UK, Europe
Spain, Europe
Australia, Oceania
Spain, Europe
Canada, North America
Australia, Oceania
USA, North America
Greece, Europe
Spain, Europe
USA, North America
UK, Europe
Country, continent
≤5 y
≤5 y
6 mo–5 y
≤4 y
6 mo–2 y
≤4 y
6–59 mo
≤2 y
≤5 y
≤5 y
≤5 y
Included age range
Physician office
Mix: Physician office, Hospital
Physician office; Emergency Department
Physician office
Physician office
Physician office
Physician office
Physician office
Mix: Physician office, Hospital
Mix: Physician office, Hospital
Physician office
Healthcare setting(s)
Acute respiratory illness with fever or complaint of feverishness
Sudden onset of any general symptom (fever or feverishness, malaise, headache, or myalgia) in addition to any respiratory symptom (cough, sore throat, or shortness of breath)
Documented fever with oral temperature >38°C, with at least one acute respiratory symptom or sign
Sudden onset of symptoms, and at least one of these four systemic symptoms (fever or feverishness, malaise, headache, myalgia), and at least one of these three respiratory symptoms (cough, sore throat, shortness of breath), in the absence of other suspected clinical diagnosis
Acute onset of fever and cough and the presence of ≥1 of the following: sore throat, arthralgia, myalgia, or prostration
History of fever, cough, and fatigue/malaise
Presenting complaint of cough, earache, fever (identified through medical documentation or parent report), nasal congestion/runny nose, shortness of breath/rapid or shallow breathing, sore throat, vomiting after cough, or wheezing
Not reported
Sudden onset of any general symptom (fever or feverishness, malaise, headache, or myalgia) in addition to any respiratory symptom (cough, sore throat, or shortness of breath)
Acute respiratory illness with symptoms of feverishness, chills, or cough
Acute respiratory illness with physician-diagnosed fever or complaint of feverishness
Case definition
317
19
289
103
38
(continues)
2007–2008: 14 2008–2009: 9
2003–2004: 362 2004–2005: 752
42
84
213
294
Sample size (Total)
2007–2008, 2008–2009
Pediatric
Pediatric
All ages
All ages
All ages
Study population
|
2007–2008
2012–2013
Test-negative case–control
Andrews, 201425
Influenza season(s)
Study design
Study author, publication year
T A B L E 1 Characteristics of included studies
446
Buchan et al.
Study design
Surveillance
Test-negative case–control
Surveillance
Test-negative case–control
Test-negative case–control
Surveillance
Study author, publication year
Rezza, 200631
Staat, 201123
Sung, 200936
Treanor, 201224
Turner, 201435
Zambon, 200132
TABLE 1 (continued)
1995–1996, 1996–1997, 1997–1998
2012–2013
2010–2011
2005–2006
2005–2006, 2006–2007
2004–2005
Influenza season(s)
All ages
All ages
All ages
Pediatric
Pediatric
All ages
Study population
UK, Europe
New Zealand, Oceania
USA, North America
Hong Kong, Asia
USA, North America
Italy, Europe
Country, continent
≤5 y
6 mo–5 y
6 mo–2 y
≤5 y
6–59 mo
≤2 y
Included age range
Physician office
Hospital
Mix: Physician office, Emergency Department, Hospital
Hospital
Physician office; Hospital; Emergency Department
Physician office
Healthcare setting(s)
Symptoms of fever, cough, and respiratory tract illness
Severe acute respiratory infection defined as a patient requiring hospitalization with a history of a fever or a measured temperature ≥38°C and cough and onset within the past 7 d
ARI with a duration of ≤7 d with documented fever or history of feverishness or cough
Sudden onset (37.5°C and at least one other symptom (headache, malaise, myalgia, chills or sweats, retrosternal pain, asthenia) and one respiratory symptom (cough, sore throat, nasal congestion, or runny nose)
Case definition
1995–1996: 190 1996–1997: 108 1997–1998: 132
334
784
475
2005–2006: 268 2006–2007: 260
14
Sample size (Total)
Buchan et al.
| 447
|
448
Buchan et al.
to domains of selection, comparability, and outcome. We extracted a
stabilize the variance,15 in order to compare the results. The analysis
proportion from the studies that was not directly reported; therefore,
was run in R Statistical Software using the meta package to provide a
the statistical test criterion in the outcome domain was deemed not
prediction interval to estimate the range of values that future studies
applicable to this study.
can be expected to fall within.18 Forest plots were created for each subgroup in order to examine clinical (e.g., age, setting, influenza season) and methodological (e.g.,
2.7 | Data synthesis and analysis
study design, study quality) heterogeneity. Statistical heterogeneity
A stratified meta-analysis was planned a priori due to anticipated
was assessed using the Cochran Q statistic (with P
