Articles
Severity of influenza illness by seasonal influenza
vaccination status among hospitalised patients in
four South American countries, 2013–19: a surveillancebased cohort study
Annette K Regan, Carmen Sofia Arriola, Paula Couto, Lindsey Duca, Sergio Loayza, Francisco Nogareda, Walquiria Aparecida Ferreira de Almeida,
Julian Antman, Soraya Araya, Marcela Alejandra Avendaño Vigueras, Silvia Carolina Battaglia Paredes, Ivan Fedor Brstilo, Patricia Bustos,
Maria Eugenia Fandiño, Rodrigo Fasce, Carlos Maria Giovacchini, Cecilia Isaura González Caro, Marta von Horoch, Maria del Valle Juarez,
Nathalia Katz, Maria Fernanda Olivares, Daiana Araújo da Silva, Erica Tatiane da Silva, Viviana Sotomayor, Natalia Vergara,
Eduardo Azziz-Baumgartner, Alba Maria Ropero
Summary
Lancet Infect Dis 2023;
23: 222–32
Published Online
October 4, 2022
https://doi.org/10.1016/
S1473-3099(22)00493-5
See Comment page 136
For the Spanish translation of the
abstract see Online for
appendix 1
For the Portuguese translation of
the abstract see Online for
appendix 2
School of Nursing and Health
Professions, University of
San Francisco, Orange, CA, USA
(A K Regan PhD); Fielding
School of Public Health,
University of California
Los Angeles, Los Angeles, CA,
USA (A K Regan); Influenza
Division, Centers for Disease
Control and Prevention,
Atlanta, GA, USA
(C S Arriola PhD, L Duca PhD,
E Azziz-Baumgartner MD);
Health Emergencies Program
(P Couto MD) and Department
of Family, Health Promotion,
and Life Course (S Loayza MD,
F Nogareda MPH,
A M Ropero MPH),
Pan American Health
Organization, Washington, DC,
USA; Ministry of Health Brazil,
Brasília, Federal District, Brazil
(W A F de Almeida MD,
D A da Silva MSc); Surveillance
Area, Directorate of
Epidemiology (J Antman MSc,
M E Fandiño MSc,
C M Giovacchini MPH) and
Directorate for the Control of
Immunopreventable Diseases
(M d V Juarez MD,
N Katz PGCert ID), Ministry of
Health, Buenos Aires,
Argentina; Consultant to The
Task Force for Global Health,
Decatur, GA, USA (J Antman);
222
Background Although several studies have reported attenuated influenza illness following influenza vaccination,
results have been inconsistent and have focused predominantly on adults in the USA. This study aimed to evaluate
the severity of influenza illness by vaccination status in a broad range of influenza vaccine target groups across
multiple South American countries.
Methods We analysed data from four South American countries (Argentina, Brazil, Chile, and Paraguay)
participating in REVELAC-i, a multicentre, test-negative design, vaccine effectiveness network including
41 sentinel hospitals. Individuals hospitalised at one of these centres with severe acute respiratory infection were
tested for influenza by real-time RT-PCR, and were included in the analysis if they had complete information
about their vaccination status and outcomes of their hospital stay. We used multivariable logistic regression
weighted by inverse probability of vaccination and adjusted for antiviral use, duration of illness before admission,
and calendar week, to calculate the adjusted odds ratios (aORs) of intensive care unit (ICU) admission and inhospital death (and combinations of these outcomes) among influenza-positive patients by vaccination status for
three target groups: young children (aged 6–24 months), adults (aged 18–64 years) with pre-existing health
conditions, and older adults (aged ≥65 years). Survival curves were used to compare length of hospital stay by
vaccination status in each target group.
Findings 2747 patients hospitalised with PCR-confirmed influenza virus infection between Jan 1, 2013, and
Dec 8, 2019, were included in the study: 649 children (70 [10·8%] fully vaccinated, 193 [29·7%] partially vaccinated)
of whom 87 (13·4%) were admitted to ICU and 12 (1·8%) died in hospital; 520 adults with pre-existing medical
conditions (118 [22·7%] vaccinated), of whom 139 (26·7%) were admitted to ICU and 55 (10·6%) died in hospital;
and 1578 older adults (609 [38·6%] vaccinated), of whom 271 (17·2%) were admitted to ICU and 220 (13·9%) died
in hospital. We observed earlier discharge among partially vaccinated children (adjusted hazard ratio 1·14 [95% CI
1·01–1·29]), fully vaccinated children (1·24 [1·04–1·47]), and vaccinated adults with pre-existing medical
conditions (1·78 [1·18–2·69]) compared with their unvaccinated counterparts, but not among vaccinated older
adults (0·82 [0·65–1·04]). Compared with unvaccinated individuals, lower odds of ICU admission were found for
partially vaccinated children (aOR 0·64 [95% CI 0·44–0·92]) and fully vaccinated children (0·52 [0·28–0·98]), but
not for adults with pre-existing conditions (1·25 [0·93–1·67]) or older adults (0·88 [0·72–1·08]). Lower odds of
in-hospital death (0·62 [0·50–0·78]) were found in vaccinated versus unvaccinated older adults, with or without
ICU admission, but did not differ significantly in partially vaccinated (1·35 [0·57–3·20]) or fully vaccinated young
children (0·88 [0·16–4·82]) or adults with pre-existing medical conditions (1·09 [0·73–1·63]) compared with the
respective unvaccinated patient groups.
Interpretation Influenza vaccination was associated with illness attenuation among those hospitalised with influenza,
although results differed by vaccine target group. These findings might suggest that attenuation of disease severity
might be specific to certain target groups, seasons, or settings.
Funding US Centers for Disease Control and Prevention.
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND
4.0 license.
www.thelancet.com/infection Vol 23 February 2023
Articles
Research in context
Evidence before this study
A comprehensive understanding of the value of influenza
vaccines requires evaluation of the health effects of vaccination
in people with breakthrough infections (eg, reduced illness
severity). Based on a PubMed and MEDLINE search (using the
search terms “severity” and “influenza vaccine*” and
“effectiveness” with no date or language restrictions), several
studies have documented a reduced risk of intensive care unit
(ICU) admission, community-acquired pneumonia, invasive
mechanical ventilation, and death among vaccinated patients
with breakthrough infections. Although results of such studies
suggest that influenza vaccination might reduce the severity of
influenza illness, the heterogeneity of findings across these
studies is large, and results predominantly draw upon data
from the adult population in the USA. To better quantify the full
value of influenza vaccines, especially in settings where health
authorities might struggle to justify sustained investments in
seasonal influenza vaccines, evidence across broad settings and
population groups is needed.
Added value of this study
On the basis of 2747 patients hospitalised with laboratoryconfirmed influenza virus infection at 41 sentinel sites, from a
Introduction
Globally, influenza contributes to 9·5 million hos­
pitalisations, 81·5 million hospital days, and 145 000 deaths
each year.1 Vaccination offers the best method of
preventing influenza illness, reducing illness in the
general population by 40–60%.2–6 Growing evidence
suggests that even in cases of breakthrough influenza
virus infection, vaccination could confer health benefits.
Several surveillance-based studies have reported reduced
severity of influenza illness among hospitalised vaccinees,
including lower odds of intensive care unit (ICU)
admission, shorter length of stay in ICU, and shorter
overall length of stay in hospital.7–12 For example, a recent
US study of 8354 older adults hospitalised with influenza
showed a 52–79% reduction in the odds of in-hospital
death, a 37% reduction in the odds of ICU admission, and
a shorter length of stay in hospital associated with
influenza vaccination.13 Nevertheless, such findings are
sporadic and have not been systematically documented,
especially in other vaccine target groups and in lowincome and middle-income countries.7,11 Despite a high
burden of influenza-associated hospitalisations and
deaths in South America,1,14 no study has evaluated the
potential health benefits of influenza vaccination
among patients hospitalised with breakthrough influenza
illnesses in this region. Furthermore, fewer global studies
have evaluated the possibility of illness attenuation among
children and adults with chronic medical conditions.
To better quantify the full value of influenza vaccines,
especially in settings where health authorities might
www.thelancet.com/infection Vol 23 February 2023
multicentre test-negative design network across four
countries, we found that influenza vaccination was associated
with reduced odds of admission to ICU, shorter lengths of
hospital stay, and reduced odds of in-hospital death in some
but not all patient groups. Lower odds of ICU admission were
found in partially and fully vaccinated children but not in
adults aged 18–64 years with pre-existing medical conditions
or older adults (aged ≥65 years), whereas odds of in-hospital
death were lower in vaccinated versus unvaccinated older
adults but not in the other vaccine target groups. These
findings might suggest that attenuation of disease severity is
specific to certain target groups, seasons, or settings,
potentially explaining the heterogeneity across previously
published results. However, further research is needed to
evaluate these specific effects.
Implications of all the available evidence
In combination with previous evidence, our findings support an
attenuation of influenza illness severity associated with
influenza vaccination. These results could be used to inform the
global health benefits of vaccination in support of sustained
investment in influenza vaccination programmes.
struggle to justify sustained investments in seasonal
influenza vaccines, we analysed data for patients
hospitalised with laboratory-confirmed influenza in four
South American countries.
Expanded Program on
Immunizations (S Araya MD)
and General Directorate of
Health Surveillance
(S C Battaglia Paredes MD,
M von Horoch MHSA), Ministry
of Public Health and Social
Welfare, Asunción, Paraguay;
Department of Immunizations
(M A Avendaño Vigueras MG,
I Brstilo MG,
C I González Caro MD), Public
Health Institute (P Bustos MSc,
R A Fasce BSc), and Department
of Epidemiology
(M F Olivares MG[c],
V Sotomayor MG,
N Vergara MG[c]), Ministry of
Health, Santiago, Chile; Fiocruz
Brasília, Rio de Janeiro, Brazil
(E T da Silva PhD)
Correspondence to:
Dr Annette K Regan, School of
Nursing and Health Professions,
University of San Francisco,
Orange, CA 92686, USA
akregan@usfca.edu
or
Dr Eduardo Azziz-Baumgartner,
Influenza Division, Centers for
Disease Control and Prevention,
Atlanta, GA 30329, USA
eha9@cdc.gov
Methods
Overview
This study was conducted as part of the Network for the
Evaluation of Vaccine Effectiveness in Latin America and
the Caribbean—influenza (Red para la Evaluación de
Vacunas En Latino América y el Caribe—influenza
[REVELAC-i]), a multicentre, test-negative design
network that annually evaluates influenza vaccine
effectiveness against severe acute respiratory infection in
sentinel surveillance hospitals participating in the Severe
Acute Respiratory Infections Network, the Pan American
Health Organization (PAHO) hospital-based influenza
surveillance network in the Americas.15–18 All sites apply a
common, publicly available protocol for data collection
for cases of severe acute respiratory infection.15 A case of
severe acute respiratory infection in REVEAC-i is defined
as the presence of an acute respiratory infection with a
history of fever or a measured fever of 38°C or higher,
cough, and onset within the past 10 days resulting in
hospitalisation. Nasal or nasopharyngeal swabs are taken
from all patients with severe acute respiratory infection
for the detection of influenza virus by real-time RT-PCR.
Demographic, clinical, and vaccine information recorded
include influenza vaccination status, previous vaccination
history, sex, age, smoking status, diagnosed pre-existing
223
Articles
medical conditions, hospital admission date, date of
symptom onset, antiviral medication use, and detection
of other respiratory viruses. Influenza surveillance teams
from each country are organised within their local area to
develop case investigations, capture official data, and
implement the study protocol.
Study population
See Online for appendix 3
We extracted data for all REVELAC-i sites contributing
data during the study period and with mostly complete
information on severity indicators (ie, <33% missing) in
Argentina, Brazil, Chile, and Paraguay (appendix 3 p 3).
We included only severe acute respiratory infection cases
with real-time RT-PCR-confirmed infection with influenza
A or B viruses, complete information about their
vaccination status, and documented outcomes of their
hospital stay, from one of 41 participating severe acute
respiratory infection sentinel hospitals across the four
countries, from Jan 1, 2013, to Dec 8, 2019. The study
population comprised three special-risk target groups for
influenza vaccination in participating countries: children
aged 6–24 months, adults aged 18–64 years with preexisting medical conditions (Chile only), and adults aged
65 years or older.19 These surveillance groups were selected
on the basis of eligibility according to the Expanded
Program on Immunization in participating countries.
Outcome variables
We examined indicators of severity of illness among
influenza-associated hospitalisations, including length of
hospital stay, admission to ICU, and death in hospital.
Patterns in ICU admission and in-hospital death
included the following: admission to ICU and discharge
from hospital; no admission to ICU and death in hospital;
and admission to ICU and death in hospital. The length
of hospital stay was defined as the time (in days) from
admission to discharge from hospital. We also examined
time to discharge as a bivariate outcome, comparing
participants with a length of stay of more than 5 days
versus 5 days or fewer.
Vaccination status
Information on a patient’s influenza vaccination history,
including whether the patient had received a vaccine (yes
or no) and the date of the latest dose received, is collected
through surveillance records. For children, the number of
doses received when first vaccinated is also collected.
Vaccination status is checked at the time of admission.
Sources of information include vaccination cards and
electronic registries (if available). For those with missing
vaccine information, surveillance staff review the patient’s
clinical file and consult with the Expanded Program on
Immunization team to verify vaccination status.
For the purpose of our study, we considered adults
aged 18 years or older as vaccinated if they had a record of
vaccination with the southern hemisphere formulation
of influenza vaccine (appendix 3 p 4) at least 14 days
224
before symptom onset. For children aged 6–24 months,
we categorised participants as fully vaccinated if they had
received two doses of influenza vaccine at least 14 days
before symptom onset; and partially vaccinated if they
had received only one dose of influenza vaccine at least
14 days before symptom onset. Participants in any age
group were categorised as unvaccinated if they had no
record of influenza vaccination or had a record of
influenza vaccination after the onset of symptoms.
Patients who developed symptoms within 14 days
following vaccination (ie, indeterminate vaccination
status) were excluded from the analysis.
Covariate information
Covariates were selected a priori and included country,
surveillance year, calendar week of hospital admission,
and participant characteristics, including sex, age,
smoking status, diagnosis of pre-existing medical
conditions and number of conditions, previous influenza
vaccination, antiviral medication use, and duration of
illness at admission. We also considered the presence of
other respiratory viruses (coinfections) in a post hoc
analysis for children (ie, the population group with
sufficient coinfections for analysis). Missing covariate
data were imputed using the mice() package in R, with
multiple imputation done by chained equations with
20 imputed datasets.20
Statistical analysis
We analysed each influenza vaccine target group
separately. Within each priority group, we examined the
characteristics of hospitalised participants by influenza
vaccination status using χ² tests for categorical variables
and Wilcoxon rank-sum tests for non-normally distri­
buted continuous variables. To control for con­founding
by health-seeking behaviour, we calculated the inverse
probability of treatment weights using multi­
variable
logistic regression to estimate the predicted probability
of vaccination by baseline covariates for each vaccine
target group. We examined covariate balance after
applying the inverse probability of treatment weights by
plotting the standardised mean differences between
vaccinated and unvaccinated patients for the unweighted
and weighted samples (appendix 3 p 5).
To compare bivariate outcomes, we used multivariable
logistic regression models weighted by the inverse
probability of vaccination. Adjusted models also con­
trolled for antiviral medication use, duration of illness
before admission to hospital, and calendar week of
admission (fit using a cubic spline). Pooled odds ratios
(ORs) were calculated across imputed datasets using the
pool() function in R, which averages the estimates across
the 20 imputed datasets and calculates total variance
across the repeated analyses using Rubin’s rule.21
To examine time to discharge, we plotted survival
curves modelling the length of hospital stay by
vaccination status. To account for death as a competing
www.thelancet.com/infection Vol 23 February 2023
Articles
event, we performed survival analyses to compare the
time to discharge among vaccinated versus unvaccinated
patients, accounting for death as a competing event. Like
the analyses of binary outcomes, models were weighted
by inverse probability of vaccination and adjusted for
antiviral medication use, duration of illness before
admission, and calendar week of admission.
To examine how results might vary by virus subtype,
we modelled the odds of ICU admission or death by
virus subtype. For analysis of influenza A(H3N2), we
also did analyses restricted to years in which vaccine
strains closely matched circulating virus strains (ie, when
the vaccine would be most effective). To examine how
results might vary by number of pre-existing health
conditions, we modelled the odds of ICU admission or
death by the number of pre-existing medical conditions.
We also conducted sensitivity analyses of time to
discharge by evaluating the effect of excluding in-hospital
deaths on results.
4099 influenza-associated hospitalisations identified
275 excluded on the basis of symptom
onset date
24 with onset after hospital admission
251 with onset >10 days before
hospital admission
3824 meeting inclusion criteria
271 with indeterminable vaccination status
(<14 days before symptom onset) or
missing vaccination status
3553 with determinable influenza vaccination status
806 with missing outcome information
724 missing length of hospital stay
140 missing death status
35 missing ICU admission status
Role of the funding source
www.thelancet.com/infection Vol 23 February 2023
Figure 1: Selection of participants for inclusion in final analysis
*Missing data imputed: pre-existing condition (n=74), previous vaccination
status (n=121), antiviral use (n=106), smoking status (n=388).
Argentina
Number of patients
150
Brazil
Vaccination status
Unvaccinated
Vaccinated
100
50
0
Chile
Paraguay
200
Number of patients
150
100
50
20
Jan
17
ua
ry,
2
01
Jan
8
ua
ry,
Jan 201
9
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ry,
Jan 201
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20
Jan
14
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ry,
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01
Jan
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ry,
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0
Jan
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ry,
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01
Jan
7
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ry,
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0
Jan
18
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ry,
2
0
Jan
ua 19
ry,
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ua
Jan
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ry,
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13
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ry,
4099 hospitalised patients who were positive for influenza
infection were identified from the four countries between
Jan 1, 2013, and Dec 8, 2019 (figure 1). Of these cases,
2747 across all sentinel hospital sites from the four
countries met the eligibility criteria and were included in
the final analysis (figure 2), including 649 children aged
6–24 months, 520 adults aged 18–64 years with a preexisting medical condition, and 1578 adults aged 65 years
or older. In this final sample, we imputed information
on pre-existing medical conditions (n=78), previous
vaccination status (n=121), antiviral use (n=106), and
smoking status (n=622).
87 (13·4%) of 649 children were admitted to ICU, and
12 (1·8%) died in hospital (appendix 3 p 6); 72 viral
coinfections were identified. 70 (10·8%) children were
fully vaccinated and 193 (29·7%) were partially vaccinated.
Vaccination status was associated with country (p<0·0001),
asthma (p<0·0001), obesity (p=0·0329), cardiomyopathy
(p=0·0342), and antiviral medication use (p<0·0001), but
not with other covariates (table 1).
The distributions of length of hospital stay were similar
for fully vaccinated, partially vaccinated, and unvaccinated
children aged 6–24 months (appendix 3 p 8), with a median
duration of 5 days (IQR 3–8) in the unvaccinated and fully
vaccinated groups and 5 days (3–9) in the partially
vaccinated group. We observed moderate evidence to
support shorter hospital stay for partially vaccinated
children (adjusted hazard ratio [aHR] 1·14 [95% CI
1·01–1·29]) and fully vaccinated children (1·24 [1·04–1·47])
2747 included in final analysis after imputation of
missing covariate data*
ua
Results
2747 with complete outcome information
Jan
The US Centers for Disease Control and Prevention
(CDC) funded this study. CDC-affiliated authors were
involved in the study design, data collection, data
analysis, data interpretation, report writing, and the
decision to submit the paper for publication.
Date of admission
Date of admission
Figure 2: Distribution of influenza-associated hospitalisations from 2013 to 2019, by participating country
and influenza vaccination status
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Articles
Children aged 6–24 months
Unvaccinated Partially
(n=386)
vaccinated*
(n=193)
Country
··
Fully
vaccinated*
(n=70)
··
··
p value
Adults 18–64 years with pre-existing
medical conditions*
Older adults aged ≥65 years
Unvaccinated
(n=402)
Unvaccinated Vaccinated
(n=969)
(n=609)
<0·0001
··
Argentina
27 (7·0%)
24 (12·4%)
8 (11·4%)
··
Brazil
58 (15·0%)
56 (29·0%)
20 (28·6%)
··
21 (5·2%)
Chile
146 (37·8%)
82 (42·5%)
36 (51·4%)
··
Paraguay
155 (40·2%)
31 (16·1%)
6 (8·6%)
··
Year
··
··
··
0·10
0
Vaccinated
(n=118)
··
0
p value
0·0543
··
··
p value
<0·0001
··
69 (7·1%)
34 (5·6%)
··
11 (9·3%)
··
90 (9·3%)
104 (17·1%)
··
357 (88·8%)
105 (89·0%)
··
611 (63·1%)
440 (72·2%)
··
24 (6·0%)
2 (1·7%)
··
199 (20·5%)
31 (5·1%)
··
··
0·55
··
··
··
0·0001
2013
86 (22·3%)
58 (30·1%)
25 (35·7%)
··
23 (5·7%)
9 (7·6%)
··
143 (14·8%)
125 (20·5%)
··
2014
43 (11·1%)
29 (15·0%)
13 (18·6%)
··
45 (11·2%)
15 (12·7%)
··
113 (11·7%)
102 (16·7%)
··
2015
66 (17·1%)
25 (13·0%)
8 (11·4%)
··
78 (19·4%)
18 (15·3%)
··
174 (18·0%)
110 (18·1%)
··
2016
55 (14·2%)
25 (13·0%)
7 (10·0%)
··
38 (9·5%)
18 (15·3%)
··
111 (11·5%)
46 (7·6%)
··
2017
29 (7·5%)
11 (5·7%)
2 (2·9%)
··
59 (14·7%)
17 (14·4%)
··
194 (20·0%)
88 (14·4%)
··
2018
39 (10·1%)
17 (8·8%)
9 (12·9%)
··
58 (14·4%)
15 (12·7%)
··
135 (13·9%)
76 (12·5%)
··
2019
68 (17·6%)
28 (14·5%)
6 (8·6%)
··
101 (25·1%)
26 (22·0%)
··
99 (10·2%)
62 (10·2%)
··
0·21
57 (46–61)
56 (48–62)
0·21
77 (71–85)
78 (71–84)
0·96
Median age, years
1 (0·7–1·1)
Sex
1 (0·8–1·3)
··
1 (0·9–1·2)
··
··
0·28
··
··
0·0061
··
··
Male
174 (45·1%)
77 (39·9%)
35 (50·0%)
··
182 (45·3%)
71 (60·2%)
··
568 (58·6%)
343 (56·3%)
Female
212 (54·9%)
116 (60·1%)
35 (50·0%)
··
220 (54·7%)
47 (39·8%)
··
401 (41·4%)
266 (43·7%)
Smoking status
··
··
··
NA
··
0·11
··
··
0·39
··
··
<0·0001
Current smoker
NA
NA
NA
··
121 (30·1%)
26 (22·0%)
··
471 (48·6%)
209 (34·3%)
··
Non-smoker
NA
NA
NA
··
281 (69·9%)
92 (78·0%)
··
498 (51·4%)
400 (65·7%)
··
Number of pre-existing medical
conditions†
··
··
··
0·17
··
··
0·0425
··
··
0·0023
None
276 (71·5%)
123 (63·7%)
46 (65·7%)
··
NA
NA
··
226 (23·3%)
94 (15·4%)
··
1
107 (27·7%)
65 (33·7%)
23 (32·9%)
··
103 (25·6%)
34 (28·8%)
··
325 (33·5%)
222 (36·5%)
··
··
2
3 (0·8%)
3 (1·6%)
0
··
90 (22·4%)
14 (11·9%)
··
246 (25·4%)
167 (27·4%)
≥3
0
2 (1·0%)
1 (1·4%)
··
209 (52·0%)
70 (59·3%)
··
172 (17·8%)
126 (20·7%)
65 (33·7%)
22 (31·4%)
0·29
402 (100%)
118 (100%)
749 (77·3%)
516 (84·7%)
At least one pre-existing medical
condition†
106 (27·5%)
Type of pre-existing medical condition
··
Obesity
3 (0·8%)
Asthma
51 (13·2%)
··
0
11 (15·7%)
··
0·0329
··
··
25 (21·2%)
0·67
··
··
100 (10·3%)
58 (9·5%)
··
0·67
67 (16·7%)
38 (32·2%)
<0·0001
175 (18·1%)
145 (23·8%)
0·0079
0
0
0
NA
107 (26·6%)
38 (32·2%)
0·28
265 (27·3%)
174 (28·6%)
0·64
Metabolic condition
0
0
0
NA
91 (22·6%)
36 (30·5%)
0·0535
155 (16·0%)
132 (21·7%)
0·31
0·0342
88 (21·9%)
21 (17·8%)
0·41
261 (26·9%)
156 (25·6%)
0·60
0·58
119 (12·3%)
71 (11·7%)
0·77
0·0512
114 (11·8%)
69 (11·3%)
0·85
231 (23·8%)
167 (27·4%)
0·12
0·42
68 (17·6%)
52 (26·9%)
Immune system disorder
7 (1·8%)
4 (2·1%)
1 (1·4%)
0·94
58 (14·4%)
14 (11·9%)
Immunosuppressing condition‡
0
0
1 (1·4%)
0·0323
53 (13·2%)
7 (5·9%)
19 (27·1%)
0·11
76 (18·9%)
29 (24·6%)
0·22
0·0218
90 (9·3%)
65 (10·7%)
0·19
12 (1·2%)
6 (1·0%)
Neurological condition
14 (20·0%)
<0·0001
··
95 (23·6%)
··
0·0006
Diabetes
Cardiomyopathy
50 (25·9%)
··
2 (2·9%)
NA
83 (21·5%)
31 (16·1%)
Renal condition
3 (0·8%)
4 (2·1%)
1 (1·4%)
0·41
62 (15·4%)
29 (24·6%)
Liver condition
6 (1·6%)
0
0
0·13
25 (6·2%)
3 (2·5%)
Previous influenza vaccination
··
··
··
NA
··
··
<0·0001
··
··
0·83
<0·0001
Yes
NA
NA
NA
··
44 (10·9%)
84 (71·2%)
··
192 (19·8%)
482 (79·1%)
··
No
NA
NA
NA
··
358 (89·1%)
34 (28·8%)
··
777 (80·2%)
127 (20·9%)
··
Antiviral medication use
Any antiviral medication use
≤2 days after symptom onset
≥3 days after symptom onset
No antiviral medication use
··
··
··
106 (27·5%)
80 (41·5%)
28 (40·0%)
24 (6·2%)
18 (9·3%)
7 (10·0%)
<0·0001
··
0·0112§
··
··
231 (57·5%)
63 (53·4%)
85 (21·1%)
25 (21·2%)
0·50
··
0·16§
··
··
493 (50·9%)
348 (57·1%)
155 (16·0%)
102 (16·7%)
0·0213
··
0·0931§
35 (9·1%)
27 (14·0%)
7 (10·0%)
··
130 (32·3%)
29 (24·6%)
··
218 (22·5%)
155 (25·5%)
··
280 (72·5%)
113 (58·5%)
42 (60·0%)
··
171 (42·5%)
55 (46·6%)
··
476 (49·1%)
261 (42·9%)
··
(Table 1 continues on the next page)
226
www.thelancet.com/infection Vol 23 February 2023
Articles
Children aged 6–24 months
Unvaccinated Partially
(n=386)
vaccinated*
(n=193)
Fully
vaccinated*
(n=70)
p value
Adults 18–64 years with pre-existing
medical conditions*
Older adults aged ≥65 years
Unvaccinated
(n=402)
Unvaccinated Vaccinated
(n=969)
(n=609)
Vaccinated
(n=118)
p value
··
0·95
p value
(Continued from previous page)
Time from symptom onset to admission,
days
0
··
··
··
0·71
··
··
··
0·19
77 (19·9%)
40 (20·7%)
8 (11·4%)
··
108 (26·9%)
30 (25·4%)
··
201 (20·7%)
153 (25·1%)
··
1–2
127 (32·9%)
63 (32·6%)
27 (38·6%)
··
132 (32·8%)
42 (35·6%)
··
340 (35·1%)
213 (35·0%)
··
3–4
98 (25·4%)
46 (23·8%)
20 (28·6%)
··
92 (22·9%)
27 (22·9%)
··
235 (24·3%)
134 (22·0%)
··
5–10
84 (21·8%)
44 (22·8%)
15 (21·4%)
··
70 (17·4%)
19 (16·1%)
··
193 (19·9%)
109 (17·9%)
Influenza virus type and subtype of
infection
··
··
··
0·96
··
··
0·54
··
··
··
0·12
Influenza A
311 (80·6%)
157 (81·3%)
56 (80·0%)
··
361 (89·8%)
103 (87·3%)
··
853 (88·0%)
519 (85·2%)
··
H3N2
126 (32·6%)
76 (39·4%)
26 (37·1%)
··
173 (43·0%)
53 (44·9%)
··
522 (53·9%)
348 (57·1%)
··
H1N1
169 (43·8%)
74 (38·3%)
27 (38·6%)
··
188 (46·8%)
50 (42·4%)
··
316 (32·6%)
162 (26·6%)
··
16 (4·1%)
7 (3·6%)
3 (4·3%)
··
··
15 (1·5%)
9 (1·5%)
··
75 (19·4%)
36 (18·7%)
14 (20·0%)
··
41 (10·2%)
15 (12·7%)
··
116 (12·0%)
90 (14·8%)
··
Yamagata
13 (3·4%)
10 (5·2%)
5 (7·1%)
··
28 (7·0%)
12 (10·2%)
··
41 (4·2%)
42 (6·9%)
··
Victoria
15 (3·9%)
8 (4·1%)
2 (2·9%)
··
6 (1·5%)
2 (1·7%)
··
13 (1·3%)
16 (2·6%)
··
No lineage information
47 (12·2%)
18 (9·3%)
7 (10·0%)
··
7 (1·7%)
1 (0·8%)
··
62 (6·4%)
32 (5·3%)
No subtype available
Influenza B
Viral coinfection detected
Yes
··
··
··
0
0·10
0
··
··
0·80
··
··
··
0·97
33 (8·5%)
25 (13·0%)
11 (15·7%)
··
3 (0·7%)
0
··
11 (1·1%)
6 (1·0%)
··
30 (7·8%)
20 (10·4%)
11 (15·7%)
··
3 (0·7%)
0
··
1 (0·1%)
1 (0·2%)
··
Parainfluenza
1 (0·3%)
2 (1·0%)
0
··
0
0
··
0
1 (0·2%)
··
Human metapneumovirus
2 (0·5%)
1 (0·5%)
0
··
0
0
··
1 (0·1%)
2 (0·3%)
··
Adenovirus
0
1 (0·5%)
0
··
0
0
··
5 (0·5%)
0
··
Other viruses
0
1 (0·5%)
0
··
0
0
··
4 (0·4%)
2 (0·3%)
··
··
958 (98·9%)
603 (99·0%)
··
Respiratory syncytial virus
No
353 (91·5%)
168 (87·0%)
59 (84·3%)
··
399 (99·3%)
118 (100%)
Data are n (%) or median (IQR), and summarise the characteristics from a single randomly selected imputed dataset. p values are from χ² tests for categorical variables and Wilcoxon rank sum tests for continuous
variables. NA=not applicable. *Full vaccination was defined as receipt of two doses of influenza vaccine for children aged 6–24 months; partial vaccination was defined as receipt of one dose of influenza vaccine
more than 14 days before symptom onset; for 22 children with no information on dose two, we assumed partial vaccination. †Diagnosis of at least one of the following pre-existing medical conditions: asthma,
diabetes, metabolic disorder, immune system disorder, nervous system disorder, renal disorder, and liver disorder. ‡Immunosuppressing condition included use of immunosuppressing medications or receipt of
transplant. §p values compare timing of antiviral medication use.
Table 1: Characteristics of patients hospitalised with laboratory-confirmed influenza, by influenza vaccination status
compared with unvaccinated children (table 2; figure 3).
The probability of discharge within 14 days of admission
was 0·88 (95% CI 0·85–0·91) for unvaccinated children,
0·94 (0·91–0·97) for partially vaccinated children, and
0·94 (0·85–0·98) for fully vaccinated children (appendix 3
p 9).
Compared with unvaccinated children, lower odds of
ICU admission were observed for partially vaccinated
children (adjusted OR [aOR] 0·64 [95% CI 0·44–0·92])
and fully vaccinated children (0·52 [0·28–0·98]) aged
6–24 months. 12 (1·8%) of 649 children aged 6–24 months
died in hospital: eight (2·1%) of 386 unvaccinated
children, three (1·5%) of 193 partially vaccinated
children, and one (1·4%) of 70 fully vaccinated children
died in hospital. We observed no strong evidence for a
difference in the odds of death in partially vaccinated
(aOR 1·35 [95% CI 0·57–3·20]) or fully vaccinated
children (0·88 [0·16–4·82] relative to unvaccinated
children (table 2). Adjusted ORs changed little (±0·01)
www.thelancet.com/infection Vol 23 February 2023
when additionally adjusting for the presence of a
coinfection.
We found modest evidence that odds of the composite
outcome of ICU admission or in-hospital death were
lower in vaccinated versus unvaccinated children aged
6–24 months infected with influenza A(H1N1), but not in
those with influenza A(H3N2) infections (table 3).
Among children aged 6–24 months with no pre-existing
health conditions, we observed modest evidence of lower
odds of influenza-associated ICU admission or death
among those who were partially or fully vaccinated
compared with those who were unvaccinated (appendix 3
p 10). Because pre-existing health conditions were
present in only a small number of children, we were
unable to assess whether multiple pre-existing conditions
affected the association between vaccination status and
influenza severity.
Of the 520 adults aged 18–64 years with pre-existing
medical conditions and hospitalised with influenza,
227
Articles
Children aged 6–24 months
Unvaccinated
(n=386)
Partially vaccinated
(n=193)
Fully vaccinated
(n=70)
Adults aged 18–64 years with
pre-existing medical conditions
Older adults aged ≥65 years
Unvaccinated
(n=402)
Vaccinated
(n=118)
Unvaccinated
(n=969)
Vaccinated
(n=609)
Length of hospital stay, days
Median (IQR)
5 (3–8)
5 (3–9)
5 (3–8)
8 (4–15)
7 (4–11)
7 (4–13)
7 (4–11)
HR (95% CI)
1 (ref)
1·15 (1·03–1·30)*
1·25 (1·05–1·48)*
1 (ref)
1·31 (0·89–1·92)
1 (ref)
0·84 (0·67–1·05)
aHR (95% CI)
1 (ref)
1·14 (1·01–1·29)*
1·24 (1·04–1·47)*
1 (ref)
1·78 (1·18–2·69)*
1 (ref)
0·82 (0·65–1·04)
Length of stay >5 days
n (%)
158 (40·9%)
88 (45·6%)
30 (42·9%)
261 (64·9%)
76 (64·4%)
620 (64·0%)
375 (61·6%)
OR (95% CI)
1 (ref)
1·15 (0·80–1·63)
1·05 (0·63–1·78)
1 (ref)
0·98 (0·64–1·50)
1 (ref)
0·90 (0·73–1·11)
aOR (95% CI)
1 (ref)
0·98 (0·76–1·25)
0·79 (0·55–1·14)
1 (ref)
0·69 (0·53–0·90)*
1 (ref)
0·67 (0·57–0·79)*
ICU admission
n (%)
57 (14·8%)
24 (12·4%)
6 (8·6%)
111 (27·6%)
28 (23·7%)
167 (17·2%)
104 (17·1%)
OR (95% CI)
1 (ref)
0·82 (0·49–1·37)
0·54 (0·22–1·31)
1 (ref)
0·82 (0·51–1·31)
1 (ref)
0·99 (0·76–1·29)
aOR (95% CI)
1 (ref)
0·64 (0·44–0·92)*
0·52 (0·28–0·98)*
1 (ref)
1·25 (0·93–1·67)
1 (ref)
0·88 (0·72–1·08)
In-hospital death
n (%)
8 (2·1%)
3 (1·6%)
1 (1·4%)
OR (95% CI)
1 (ref)
0·75 (0·19–2·85)
0·68 (0·08–5·58)
45 (11·2%)
1 (ref)
10 (8·5%)
0·73 (0·36–1·51)
163 (16·8%)
1 (ref)
57 (9·3%)†
0·51 (0·37–0·70)*
aOR (95% CI)
1 (ref)
1·35 (0·57–3·20)
0·88 (0·16–4·82)
1 (ref)
1·09 (0·73–1·63)
1 (ref)
0·62 (0·50–0·78)*
ICU admission and discharge
n (%)
49 (12·7%)
21 (10·9%)
5 (7·1%)
82 (20·4%)
22 (18·6%)
100 (10·3%)
78 (12·8%)
OR (95% CI)
1 (ref)
0·83 (0·48–1·44)
0·52 (0·20–1·37)
1 (ref)
0·87 (0·51–1·47)
1 (ref)
1·24 (0·90–1·70)
aOR (95% CI)
1 (ref)
0·56 (0·38–0·84)*
0·50 (0·25–0·97)*
1 (ref)
1·20 (0·86–1·68)
1 (ref)
1·33 (0·93–1·51)
No ICU admission and in-hospital death
n (%)
0 (0%)
0 (0%)
0 (0%)
16 (4·0%)
4 (3·4%)
96 (9·9%)
31 (5·1%)†
OR (95% CI)
NE (ref)
NE
NE
1 (ref)
0·83 (0·27–2·53)
1 (ref)
0·47 (0·31–0·72)*
aOR (95% CI)
NE (ref)
NE
NE
1 (ref)
1·41 (0·48–1·87)
1 (ref)
0·73 (0·55–0·96)*
ICU admission and in-hospital death
n (%)
8 (2·1%)
3 (1·6%)
1 (1·4%)
OR (95% CI)
1 (ref)
0·75 (0·19–2·85)
0·68 (0·08–5·58)
29 (7·2%)
1 (ref)
6 (5·1%)
0·69 (0·28–1·71)
67 (6·9%)
1 (ref)
26 (4·3%)‡
0·60 (0·38–0·95)*
aOR (95% CI)
1 (ref)
1·35 (0·57–3·21)
0·88 (0·16–4·83)
1 (ref)
1·21 (0·73–2·01)
1 (ref)
0·46 (0·33–0·64)*
HRs were computed using Cox regression models with competing risk of death, weighted by inverse probability of treatment weights, and adjusted by antiviral use, duration
of illness before admission, and calendar week (fit as a cubic spline). Values >1 indicate earlier discharge for vaccinated individuals compared to unvaccinated. To calculate
aORs, logistic regression models were weighted by inverse probability treatment weights and adjusted for antiviral medication use, duration of illness at admission, and
calendar week (fit as a cubic spline); pooled ORs were calculated using the pool() function in R, which averages the estimates across the 20 imputed datasets and calculates
total variance across the repeated analyses using Rubin’s rule. HR=hazard ratio. aHR=adjusted hazard ratio. OR=odds ratio. aOR=adjusted odds ratio. NE=not estimated
(insufficient data). *95% CI does not overlap with 1 (significant difference compared with reference category). †Significant at p<0·001 based on χ² test for comparisons.
‡Significant at p<0·05 based on χ² test for comparisons.
Table 2: Risk of severe influenza outcomes among individuals hospitalised with laboratory-confirmed influenza, by influenza vaccination status
139 (26·7%) were admitted to ICU and 55 (10·6%) died in
hospital (appendix 3 p 6). 118 (22·7%) were vaccinated
against influenza. Vaccination status was associated with
sex (p=0·0061), pre-existing asthma (p<0·0001) or renal
conditions (p=0·0218), previous vaccination against
influenza (p<0·0001), and number of pre-existing medical
conditions (p=0·0425), with the vaccinated group having a
higher proportion of patients with 3 or more pre-existing
medical conditions than the unvaccinated group (table 1).
The distributions of and median lengths of hospital
stay were similar for vaccinated (median 7 days
[IQR 4–11]) and unvaccinated adults with pre-existing
medical conditions (8 days [4–15]; appendix 3 p 8). We
observed moderate evidence of a shorter length of stay
for vaccinated compared with unvaccinated adults with
228
pre-existing conditions (aHR 1·78 [95% CI 1·18–2·69];
table 2). The probability of discharge within 14 days of
admission was 0·75 (95% CI 0·70–0·79) for unvaccinated
and 0·84 (0·76–0·89) for vaccinated adults with
pre-existing conditions (appendix 3 p 11). After excluding
patients who died before hospital discharge from the
analysis of length of hospital stay, the effect estimate was
attenuated (aHR 1·36 [95% CI 1·19–1·56]). We observed
no strong indication that the odds of ICU admission
(aOR 1·25 [95% CI 0·93–1·67]) and in-hospital death
(1·09 [0·73–1·63]) differed between groups.
Among adults with pre-existing medical conditions, we
observed moderate to strong evidence for a reduction in
the odds of ICU admission or death in vaccinated versus
unvaccinated patients with influenza A(H1N1) infection
www.thelancet.com/infection Vol 23 February 2023
Articles
www.thelancet.com/infection Vol 23 February 2023
Children aged 6–24 months
Cumulative incidence of discharge
1·00
0·75
0·50
Vaccination status
Unvaccinated
Partially vaccinated
Fully vaccinated
0·25
0
0
Number at risk
Unvaccinated 386
Partially vaccinated 193
Fully vaccinated 70
10
20
30
40
81
43
12
28
6
3
20
2
2
14
2
2
Adults aged 18–64 years with pre-existing
medical conditions
Cumulative incidence of discharge
1·00
0·75
0·50
0·25
0
Vaccination status
Unvaccinated
Vaccinated
0
Number at risk
Unvaccinated 402
Vaccinated 118
10
20
30
40
50
60
162
37
59
19
26
6
16
6
8
6
5
2
Adults aged ≥65 years
1·00
Cumulative incidence of discharge
(aOR 0·53 [95% CI 0·32–0·88]), but weak evidence for
such a reduction among those with influenza A(H3N2)
infection (1·49 [0·99–2·24]) or influenza B infection
(1·01 [0·21–4·89]; table 3). When we excluded seasons
with known mismatch for vaccine strains (ie, 2014 and
2017), the aOR for ICU admission or death in vaccinated
versus unvaccinated patients with influenza A(H3N2)
infection was reduced to 0·53 (0·17–1·71) but no
statistically significant difference was found between
groups. Odds of ICU admission or death in adults
hospitalised with influenza infection did not differ
significantly between vaccinated and unvaccinated
patients, regardless of number of pre-existing medical
conditions (appendix 3 p 10).
Of the 1578 older adults (aged ≥65 years) hospitalised
with influenza, 271 (17·2%) were admitted to ICU, and
220 (13·9%) died in hospital (appendix 3 p 6). 609 (38·6%)
were vaccinated. Vaccination status was associated with
country (p<0·0001), surveillance year (p<0·0001),
smoking status (p<0·0001), number of pre-existing
medical conditions (p=0·0023), receipt of previous
influenza vaccine (p<0·0001), and antiviral medication
use (p=0·0213; table 1).
Median length of hospital stay was the same for
vaccinated (7 days [IQR 4–11]) and unvaccinated (7 days
[4–13]) adults aged 65 years and older, with similar
distributions between groups (appendix 3 p 8). Survival
analyses showed no significant difference in length of
hospital stay in vaccinated versus unvaccinated patients
(aHR 0·82 [95% CI 0·65–1·04]; table 2). However, when
we excluded patients who died in hospital from the
analysis, we observed moderate evidence to support a
shorter length of stay among vaccinated older adults (1·25
[1·15–1·35]) compared with unvaccinated older adults.
The probability of discharge within 14 days of admission
was 0·81 (95% CI 0·78–0·83) for unvaccinated and 0·85
(0·82–0·88) for vaccinated older adults (appendix 3 p 11).
Among older adults hospitalised with influenza, we
observed weak evidence in support of lower odds of ICU
admission in vaccinated versus unvaccinated patients
(aOR 0·88 [95% CI 0·72–1·08]), whereas odds of
in-hospital death were lower in vaccinated patients versus
unvaccinated patients (0·62 [0·50–0·78]). The odds of
in-hospital death with no ICU admission (0·73
[0·55–0·96]) and in-hospital death with ICU admission
(0·46 [0·33–0·64]) were lower for vaccinated older adults
compared with unvaccinated older adults.
When we examined the odds of severe influenza by
virus subtype, we observe weak evidence for a reduced
odds of ICU admission or death in vaccinated versus
unvaccinated older adults with influenza A(H1N1)
infection (aOR 0·75 [95% CI 0·56–1·01]) and influenza
A(H3N2) infection (0·98 [0·76–1·27]; table 3). After
removing seasons with known mismatch between
influenza vaccines and circulating wildtype virus, we
did not observe evidence for a difference in the odds of
ICU admission or death between vaccinated and
0·75
0·50
0·25
0
0
10
20
30
40
50
27
16
14
9
Time (days)
Number at risk
Unvaccinated 969
Vaccinated 609
341
194
110
53
55
22
Figure 3: Survival plots comparing length of hospital stay for vaccinated and
unvaccinated hospitalised patients
unvaccinated older adults with influenza A(H3N2)
infection (1·13 [0·80–1·61]). Odds of ICU admission or
in-hospital death were not significantly associated
with influenza vaccination among older adults when
229
Articles
Children aged 6–24 months
Unvaccinated
Partially vaccinated
Adults aged 18–64 years with
pre-existing medical conditions
Older adults aged ≥65 years
Fully vaccinated
Unvaccinated
Vaccinated
Unvaccinated
Vaccinated
3/26 (11·5%)
52/173 (30·1%)
17/53 (32·1%)
113/522 (21·6%)
78/348 (22·4%)
Influenza A(H3N2), 2013–19
n/N (%)
15/126 (11·9%)
11/76 (14·5%)
OR (95% CI)
1 (ref)
1·25 (0·54–2·90)
0·97 (0·26–3·63)
1 (ref)
1·10 (0·56–2·14)
1 (ref)
1·04 (0·75–1·45)
aOR (95% CI)
1 (ref)
1·29 (0·71–2·33)
1·05 (0·41–2·70)
1 (ref)
1·49 (0·99–2·24)
1 (ref)
0·98 (0·76–1·27)
Influenza A(H3N2), 2013–19 (excluding 2014 and 2017)
n/N (%)
9/76 (11·8%)
6/44 (13·6%)
3/13 (23·1%)
OR (95% CI)
1 (ref)
1·17 (0·38–3·59)
NE
21/82 (25·6%)
1 (ref)
0·63 (0·21–1·89)
5/28 (17·9%)
58/259 (22·4%) 44/188 (23·4%)
1 (ref)
1·06 (0·68–1·66)
aOR (95% CI)
1 (ref)
1·28 (0·57–2·88)
NE
1 (ref)
0·53 (0·17–1·71)
1 (ref)
1·13 (0·80–1·61)
Influenza A(H1N1), 2013–19
n/N (%)
9/74 (12·2%)
2/27 (7·4%)
OR (95% CI)
29/169 (17·1%)
1 (ref)
0·67 (0·30–1·50)
0·39 (0·09–1·73)
66/188 (35·1%) 12/50 (24·0%)
1 (ref)
0·58 (0·28–1·20)
107/316 (33·9%) 38/162 (23·5%)
1 (ref)
0·60 (0·39–0·92)*
aOR (95% CI)
1 (ref)
0·40 (0·21–0·74)*
0·38 (0·12–1·19)
1 (ref)
0·53 (0·32–0·88)*
1 (ref)
0·75 (0·56–1·01)
Influenza B, 2013–19
4/36 (11·1%)
1/14 (7·1%)
9/41 (21·9%)
3/15 (20·0%)
OR (95% CI)
n/N (%)
10/75 (13·3%)
1 (ref)
0·81 (0·23–2·83)
0·50 (0·06–4·34)
1 (ref)
0·89 (0·20–3·98)
33/116 (28·4%) 16/90 (17·8%)
1 (ref)
0·54 (0·28–1·07)
aOR (95% CI)
1 (ref)
0·40 (0·14–1·11)
0·32 (0·06–1·61)
1 (ref)
1·01 (0·21–4·89)
1 (ref)
0·58 (0·34–0·98)*
To calculate aORs, logistic regression models were weighted by inverse probability treatment weights and adjusted for antiviral medication use, duration of illness at
admission, and calendar week (fit as a cubic spline); pooled ORs were calculated using the pool() function in R, which averages the estimates across the 20 imputed datasets
and calculates total variance across the repeated analyses using Rubin’s rule. OR=odds ratio. aOR=adjusted odds ratio. NE=not estimated (insufficient data). *95% CI does not
overlap with 1 (significant difference compared with reference category).
Table 3: Risk of intensive care unit admission or in-hospital death among individuals hospitalised with influenza, by influenza vaccination status and
influenza virus type and subtype
analysed by number of pre-existing medical conditions
(appendix 3 p 10).
Discussion
Based on sentinel surveillance data from four countries,
our results indicate that influenza vaccination could offer
health benefits to some patients hospitalised with
breakthrough influenza virus infections. We observed
shorter lengths of hospital stay among partially and fully
vaccinated children aged 6–24 months and vaccinated
adults aged 18–64 years with pre-existing medical
conditions compared with unvaccinated individuals in
the respective age groups. Length of hospital stay was
also shorter among vaccinated older adults (aged
≥65 years) who did not die in hospital. Additionally, the
odds of ICU admission were lower among vaccinated
versus unvaccinated young children, and the odds of inhospital death were lower among vaccinated versus
unvaccinated older adults. Although the primary aim of
annual influenza vaccination is to prevent influenza
illness and subsequent complications, our results
suggest that influenza vaccination could also attenuate
the severity of influenza illness, even when breakthrough
infection occurs. In combination with the existing
literature,12,17,18,22,23 these results have important impli­
cations for understanding the health benefits of influenza
vaccination programmes globally.
Our findings align with those from previously
published investigations, indicating that even when
230
breakthrough infection occurs, illness might be less
severe for vaccinated patients.7,13 A 2021 narrative review
and pooled meta-analysis of eight studies of influenzahospitalised adults reported a 26% reduction in the odds
of ICU admission associated with influenza vaccination,
and five studies showed a 31% reduction in the odds of
death among vaccinated compared with unvaccinated
hospitalised adults.11 Although the existing literature
supports the hypothesis that vaccination can attenuate
the course of illness among those with breakthrough
infections, heterogeneity has been shown in the results
of previous studies11 as well as our own. Although
several hypotheses have been put forward, including
heterogeneity in outcome definitions and measurement,
our findings might suggest that population and infectionrelated factors influence the ability of influenza
vaccination to modify influenza severity. Our study
indicated that on average, between 2013 and 2019,
influenza vaccination was associated with lower odds of
severe influenza A(H1N1) virus illness among all target
groups, but not lower odds of severe illness with
influenza A(H3N2) virus. Previous studies have
documented lower severity for influenza A(H1N1) virus
but not influenza A(H3N2) virus associated with
influenza vaccination.13 A number of studies conducted
during the 2009 influenza A(H1N1) pandemic showed
that vaccination was associated with a lower odds of
severe influenza A(H1N1) virus illness.24–26 Furthermore,
with the exception of a shorter length of stay, we observed
www.thelancet.com/infection Vol 23 February 2023
Articles
indications of less severe disease in vaccinated young
children and older adults, but not among vaccinated
adults aged 18–64 years with pre-existing medical
conditions. This could suggest that attenuation of disease
severity could be specific to certain target groups,
potentially explaining the heterogeneity in previously
published results. However, further research is needed to
investigate these associations.
This study provides additional evidence in support of
influenza illness attenuation among vaccinated,
previously healthy, young children aged 6–24 months.
Although previous studies have documented disease
attenuation following influenza vaccination in adults,
fewer studies have evaluated this in young children with
breakthrough infection. Most previous paediatric studies
have focused on estimating the effectiveness of vaccines
for preventing admission to hospital, admission to ICU,
or death.17,18,22,23 A US case-cohort analysis showed that
influenza vaccination was associated with a 65% reduction
in the odds of paediatric death.27 One randomised
controlled trial of a quadrivalent inactivated influenza
vaccine among children aged 6–35 months across
13 countries showed that paediatric influenza vaccination
resulted in lower odds of fever and moderate-to-severe
illness.28 A 2013 US study indicated that influenza
vaccination was associated with a 75% reduction the odds
of in-hospital death or invasive ventilation among
children younger than 18 years admitted to ICU.23
However, these studies did not explicitly evaluate
breakthrough infections in children. We observed a
36–48% reduction in the odds of ICU admission among
partially or fully vaccinated, influenza-infected children
aged 6–24 months, most of whom did not have diagnosed
pre-existing medical conditions, indicating that influenza
vaccination might attenuate the severity of influenza
among previously healthy young children.
We drew from health and medical information collected
through a large, pre-existing sentinel sur­
veillance
network, which allowed us to gather information from a
large, 7 year cohort of hospitalised patients with PCRconfirmed influenza virus infection across 41 sites
from four South American countries. Data collection
conformed to a common protocol, reducing heterogeneity
in measurements. As a result, we were able to evaluate
the health effects associated with influenza vaccination in
a large sample of three priority groups, including children
aged 6–24 months. Our large sample size also enabled
analyses by influenza virus subtype and by number of
pre-existing health conditions. Second, we applied
propensity score analyses to reduce the potential
confounding influence of vaccine-seeking behaviour (a
common concern in observational studies of influenza
vaccination) and achieve covariate balance between
vaccinated and unvaccinated groups (similar to a
randomised controlled trial). Despite these strengths,
however, this study relied on observational data that were
collected for surveillance purposes, and although we
www.thelancet.com/infection Vol 23 February 2023
applied robust techniques to account for confounding, we
cannot exclude the possibility of residual confounding,
particularly due to differential health-seeking behaviour
between vaccination groups (the so-called healthy
vaccinee effect). Furthermore, we did not have consistently
collected information about influenza symptoms or
discharge diagnoses, which made it impractical to
evaluate these outcomes. These data limitations highlight
the importance of complete, high-quality surveillance
data for research and surveillance. Future research should
also consider a wider spectrum of outcomes and the
potential influence of residual confounding on findings.
Furthermore, although these results help to extend the
evidence documenting benefits of influenza vaccine
programmes to South America, the findings might not be
generalisable to other continents with different circulating
types or subtypes of influenza viruses and different health
systems. Finally, we did not have adequate information to
identify individual hospitals for study records, which
precluded us from adjusting for possible variations in
standard of care or hospital practices across sites. We do
not believe this would strongly influence our results,
because there is no reason to believe an inverse
association exists between a clinician’s likelihood of
admitting patients to ICU and vaccination status.
However, we cannot discount potential confounding by
individual hospital clinical practices.
In summary, these results from the surveillance of
young children and adults hospitalised with laboratoryconfirmed influenza virus infection at 41 sentinel sites
across Argentina, Brazil, Chile, and Paraguay suggest
that influenza vaccination is associated with illness
attenuation among this population. These results could
be used to inform the global health benefits of annual
influenza vaccination among individuals with risk factors
for severe influenza.
Contributors
AKR and CSA conceived the study. AKR did the formal analysis, wrote
the original draft of the manuscript, and was responsible for data
visualisation. CSA supervised the study. CSA, EA, and AMR acquired
funding for the study. CSA, LD, and EA contributed to reviewing and
editing the manuscript. AKR, CSA, LD, EA, PC, SL, FN, WAFdA, JA,
SA, MAAV, SB, IB, PB, MEF, RF, CMG, CIGC, MvH, MVJ, NK, MFO,
DAdS, ETdS, VS, and NV contributed to methodology. PC, SL, FN,
WAFdA, JA, SA, MAAV, SB, IB, PB, MEF, RF, CMG, CIGC, MvH,
MVJ, NK, MFO, DAdS, ETdS, VS, AMR, and NV contributed to data
curation and reviewing editing the manuscript. AKR and CSA had
access to the data. AKR was responsible for the decision to submit the
manuscript.
Declaration of interests
We declare no competing interests.
Data sharing
Surveillance data collected for the study are not publicly available and the
research team does not have permission to make these data available to
others. The protocol used for this project is publicly available and can be
downloaded from the PAHO website.
Acknowledgments
This work was supported by a grant from the US CDC through
cooperative agreements with PAHO and WHO. The findings and
conclusions in this report are those of the authors and do not necessarily
For the study protocol on the
PAHO website see https://www.
paho.org/en/documents/
multicenter-evaluationeffectiveness-seasonal-influenza
231
Articles
232
represent the views of the US CDC. We thank the national
epidemiological and virological influenza surveillance and
immunisation teams in participating countries including, among others,
Teresa Varela (Ministry of Health, Argentina); Ernesto Issac Montenegro
Renoiner, Ana Carolina de Lacerda Sousa, Carla Domingues, Felipe
Cotrim de Carvalho, and Swamy Lima Palmeira (Ministry of Health,
Brazil); Leticia Garay Martins (Health Department of Rio Grande do Sul,
Brazil); Janaina Almeida (Health Department of Minas Gerais, Brazil);
Patricia Marques Ferreira (Health Department of São Paulo, Brazil);
Fernanda Crosewski and Laurina Tanabe (Health Department of Paraná,
Brazil); Eduardo Marques Macario (Health Department of Santa
Catarina, Brazil); Alice Rodovalho (Health Department of Pernambuco,
Brazil); Mirleide Santos (Evandro Chagas Institute, National Influenza
Center (NIC), Brazil; Terezinha Paiva (Adolfo Lutz Institute, National
Influenza Center (NIC), Brazil; Marilda Agudo Mendonça Teixeira de
Siqueira (Oswaldo Cruz Foundation, National Influenza Center (NIC),
Brazil); Sonia Arza Fernández, and José Sánchez (Ministry of Health,
Paraguay); María Fernanda Olivares Barraza, and Reinaldo Rosas
(Ministry of Health, Chile); Olga López Muñoz (Hospital Iquique, Chile);
Alberto Fica (Hospital Militar, Chile); Claudia Aguayo (Hospital
G G Benavente, Chile); Tania Campos (Hospital Temuco, Chile);
Carolina Nuñez (Hospital de Puerto Montt, Chile);
Camila Bolados Zumelzu (Hospital Dr. Eduardo Shutz Schroeder, Chile);
Marta Werne Canales (Hospital Guillermo Grant Benavnete Concepcion,
Chile); Jeannette Dabanch Peña (Hospital Clinico Universidad de Chile,
Chile); Juliana Leite and Angel Rodriguez (PAHO influenza team,
Washington, DC, USA); and the PAHO immunisation focal points for
their support in the implementation of the REVELAC-i network
(Mirta Magariños and Tamara Mancero [Argentina],
Claudio Marcelo Canales and Mario Cruz-Penate [Chile], Maria Almiron,
Priscila Leal e Leite, and Lely Guzman [Brazil],
and Fabiana Michel Romeo Montoya [Paraguay]). We also thank
Nathalie El Omeiri (PAHO) for assistance in implementing the
REVELAC-i network; the US CDC for their technical and financial
support; and Sara Mirza and Victor Veguilla for their management of the
cooperative agreement.
10
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