Abstract and Figures

Few data are available about the effectiveness of nonpharmaceutical interventions for preventing influenza virus transmission. To investigate whether hand hygiene and use of facemasks prevents household transmission of influenza. Cluster randomized, controlled trial. Randomization was computer generated; allocation was concealed from treating physicians and clinics and implemented by study nurses at the time of the initial household visit. Participants and personnel administering the interventions were not blinded to group assignment. (ClinicalTrials.gov registration number: NCT00425893) Households in Hong Kong. 407 people presenting to outpatient clinics with influenza-like illness who were positive for influenza A or B virus by rapid testing (index patients) and 794 household members (contacts) in 259 households. Lifestyle education (control) (134 households), hand hygiene (136 households), or surgical facemasks plus hand hygiene (137 households) for all household members. Influenza virus infection in contacts, as confirmed by reverse-transcription polymerase chain reaction (RT-PCR) or diagnosed clinically after 7 days. Sixty (8%) contacts in the 259 households had RT-PCR-confirmed influenza virus infection in the 7 days after intervention. Hand hygiene with or without facemasks seemed to reduce influenza transmission, but the differences compared with the control group were not significant. In 154 households in which interventions were implemented within 36 hours of symptom onset in the index patient, transmission of RT-PCR-confirmed infection seemed reduced, an effect attributable to fewer infections among participants using facemasks plus hand hygiene (adjusted odds ratio, 0.33 [95% CI, 0.13 to 0.87]). Adherence to interventions varied. The delay from index patient symptom onset to intervention and variable adherence may have mitigated intervention effectiveness. Hand hygiene and facemasks seemed to prevent household transmission of influenza virus when implemented within 36 hours of index patient symptom onset. These findings suggest that nonpharmaceutical interventions are important for mitigation of pandemic and interpandemic influenza. Centers for Disease Control and Prevention.
Content may be subject to copyright.
Facemasks and Hand Hygiene to Prevent Influenza Transmission
in Households
A Cluster Randomized Trial
Benjamin J. Cowling, BSc, PhD; Kwok-Hung Chan, BSc, PhD; Vicky J. Fang, BSc, MPhil; Calvin K.Y. Cheng, BSc, MMedSci;
Rita O.P. Fung, BNS; Winnie Wai, BNS; Joey Sin, BNS; Wing Hong Seto, MBBS; Raymond Yung, MBBS, MPH; Daniel W.S. Chu, MBBS;
Billy C.F. Chiu, MBBS; Paco W.Y. Lee, MBBS; Ming Chi Chiu, MBBS; Hoi Che Lee, MBBS; Timothy M. Uyeki, MD, MPH;
Peter M. Houck, MD; J.S. Malik Peiris, MBBS, DPhil; and Gabriel M. Leung, MD, MPH
Background: Few data are available about the effectiveness of
nonpharmaceutical interventions for preventing influenza virus
transmission.
Objective: To investigate whether hand hygiene and use of face-
masks prevents household transmission of influenza.
Design: Cluster randomized, controlled trial. Randomization was
computer generated; allocation was concealed from treating physi-
cians and clinics and implemented by study nurses at the time of
the initial household visit. Participants and personnel administering
the interventions were not blinded to group assignment. (Clinical-
Trials.gov registration number: NCT00425893)
Setting: Households in Hong Kong.
Patients: 407 people presenting to outpatient clinics with influenza-
like illness who were positive for influenza A or B virus by rapid
testing (index patients) and 794 household members (contacts) in
259 households.
Intervention: Lifestyle education (control) (134 households), hand
hygiene (136 households), or surgical facemasks plus hand hygiene
(137 households) for all household members.
Measurements: Influenza virus infection in contacts, as confirmed
by reverse-transcription polymerase chain reaction (RT-PCR) or di-
agnosed clinically after 7 days.
Results: Sixty (8%) contacts in the 259 households had RT-PCR–
confirmed influenza virus infection in the 7 days after intervention.
Hand hygiene with or without facemasks seemed to reduce influ-
enza transmission, but the differences compared with the control
group were not significant. In 154 households in which interven-
tions were implemented within 36 hours of symptom onset in the
index patient, transmission of RT-PCR–confirmed infection seemed
reduced, an effect attributable to fewer infections among partici-
pants using facemasks plus hand hygiene (adjusted odds ratio, 0.33
[95% CI, 0.13 to 0.87]). Adherence to interventions varied.
Limitation: The delay from index patient symptom onset to inter-
vention and variable adherence may have mitigated intervention
effectiveness.
Conclusion: Hand hygiene and facemasks seemed to prevent
household transmission of influenza virus when implemented within
36 hours of index patient symptom onset. These findings suggest
that nonpharmaceutical interventions are important for mitigation
of pandemic and interpandemic influenza.
Primary Funding Source: Centers for Disease Control and
Prevention.
Ann Intern Med. 2009;151:437-446. www.annals.org
For author affiliations, see end of text.
This article was published at www.annals.org on 4 August 2009.
Interpandemic human influenza virus infects millions of
people every year. Some infections are mild, but others—
especially in young or elderly persons—can result in more
severe illness requiring hospitalization. Influenza is associ-
ated with hundreds of thousands of deaths worldwide an-
nually (1, 2). The 2009 swine-origin influenza A (H1N1)
pandemic highlighted the importance of identifying public
health measures to mitigate influenza virus transmission.
Many countries would use nonpharmaceutical inter-
ventions, including facemasks, improved hand hygiene,
cough etiquette, isolation of sick and quarantine of exposed
individuals, social distancing measures, and travel restric-
tions, as their primary means to mitigate an influenza pan-
demic, particularly at its beginning (3–10). However, data
are scarce on the effectiveness of simple personal protective
measures, such as facemasks and hand hygiene, against
pandemic or interpandemic influenza and on the modes of
influenza virus transmission among people (5, 11). After a
pilot study in 2007 (12), we conducted a prospective clus-
ter randomized trial to test whether improved hand hy-
giene or surgical facemasks reduce the transmission of in-
terpandemic influenza in households. We used a cluster
design with randomization to interventions at the house-
hold level to avoid difficulties in blinding and potential
contamination of interventions.
See also:
Print
Editors’ Notes .............................438
Related article.............................464
Summary for Patients.......................I-18
Web-Only
Appendix
Appendix Tables
Appendix Figures
Conversion of graphics into slides
Annals of Internal Medicine Article
© 2009 American College of Physicians 437
METHODS
Design
From 45 outpatient clinics in the private and public
sectors across Hong Kong, we enrolled persons who re-
ported at least 2 symptoms of acute respiratory illness
(temperature 37.8 °C, cough, headache, sore throat, or
myalgia); had symptom onset within 48 hours; and lived in
a household with at least 2 other people, none of whom
had reported acute respiratory illness in the preceding 14
days. After participants gave informed consent, they pro-
vided nasal and throat swab specimens, which were com-
bined and tested with the QuickVue Influenza AB rapid
diagnostic test (Quidel, San Diego, California). Partici-
pants with a positive rapid test result and their household
contacts were randomly assigned to 1 of 3 study groups:
control (lifestyle measures), control plus enhanced hand
hygiene only, and control plus facemasks and enhanced
hand hygiene. Table 1 provides detailed descriptions of the
interventions. Data on clinical signs and symptoms were
collected for all participants. An additional nasal and throat
swab specimen was collected for laboratory confirmation of
influenza virus infection by reverse-transcription polymer-
ase chain reaction (RT-PCR).
Randomization lists were prepared by a biostatistician.
The households of eligible study index patients were allo-
cated to 3 groups in a 1:1:1 ratio under a block random-
ization structure with randomly permuted block sizes of
18, 24, and 30 by using a random-number generator (R
software, R Development Core Team, Vienna, Austria).
Interventions were assigned to households by the study
manager on the basis of the randomization sequence. The
allocation to specific intervention groups was concealed to
recruiting physicians and clinics throughout the study. Par-
ticipants and people who administered the interventions
were not blinded to the interventions, but participants
were not informed of the specific nature of the interven-
tions applied to other participating households.
After randomization, a home visit was scheduled
within 2 days (ideally within 12 hours) to implement the
intervention and to collect informed consent, baseline de-
mographic data, and nasal and throat swab specimens from
all household members 2 years of age or older. During the
home visit, index patients and household contacts were
instructed in the proper use of a tympanic thermometer.
During the 6 days after the initial home visit, all household
contacts were asked to keep daily symptom diaries. Further
home visits were scheduled around 3 and 6 days after the
Context
Hand hygiene and use of facemasks are key elements of
influenza pandemic preparedness plans, but their effects
on preventing transmission of infection have not been
demonstrated.
Contribution
In this cluster randomized trial, hand washing and face-
masks seemed to prevent influenza transmission when
healthy family members started using these measures
within 36 hours of symptom onset in an infected family
member.
Caution
Adherence to the interventions was low.
Implication
Hand hygiene and facemasks seem to reduce influenza
virus transmission when implemented early after symptom
onset.
—The Editors
Table 1. Study Interventions
Control intervention
Education about the importance of a healthy diet and lifestyle, both in terms of illness prevention (for household contacts) and symptom alleviation (for the
index case).
Hand hygiene intervention
All household members (including the index patient) received education about the potential efficacy of proper hand hygiene in reducing transmission. All
household members (including the index patient) were instructed to use the liquid soap provided instead of their usual soap after every washroom visit,
after sneezing or coughing, and in general when their hands were soiled. They were instructed to use the alcohol hand rub when first retuning home and
immediately after touching any potentially contaminated surfaces.
1. Provision of liquid hand soap for each kitchen and each bathroom (221 mL Ivory liquid hand soap [Proctor & Gamble, Cincinnati, Ohio]).
2. Provision of individual small bottles of alcohol hand rub to each participant (100 mL World Health Organization Recommended Formulation I, liquid
content with 80% ethanol, 1.45% glycerol, and 0.125% hydrogen peroxide [Vickmans Laboratories, Hong Kong, China]).
3. Demonstration of proper hand washing and antisepsis.
Facemask intervention
Index cases and all household contacts received education about the potential efficacy of surgical facemasks in reducing disease spread to household contacts if
all parties wear masks. Index patients and all household contacts were requested to wear masks as often as possible at home during the 7-day follow-up
period (except when eating or sleeping) and also when the index patient was with the household members outside of the household.
1. Provision of a box of 50 surgical facemasks (Tecnol–The Lite One [Kimberly-Clark, Roswell, Georgia]) to each household member or a box of 75 pediatric
masks for children aged 3 to 7 years.
2. Demonstration of proper facemask wearing and hygienic disposal.
Article Nonpharmaceutical Interventions to Prevent Influenza
438 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
baseline household visit to monitor adherence to interven-
tions and to collect further nasal and throat swab speci-
mens from all household members regardless of illness.
During the final home visit, study nurses collected and
reviewed symptom diaries, and they evaluated adherence to
interventions by interview and by counting the number of
surgical masks remaining and weighing the amount of soap
and alcohol left in bottles and dispensers. Households were
reimbursed for their participation with a supermarket cou-
pon worth approximately U.S. $25.
All participants 18 years or older gave written in-
formed consent. Proxy written consent from parents or
legal guardians was obtained for persons 17 years or
younger, with additional written assent from those 8 to 17
years of age. The study protocol was approved by the in-
stitutional review board of The University of Hong Kong
and the Hospital Authority Hong Kong West Cluster.
Outcome Measures
The primary outcome measure was the secondary at-
tack ratio at the individual level: the proportion of house-
hold contacts infected with influenza virus. We evaluated
the secondary attack ratio by using a laboratory definition
(a household contact with a nasal and throat swab speci-
men positive for influenza by RT-PCR) as the primary
analysis and 2 clinical definitions of influenza based on
self-reported data from the symptom diaries as secondary
analyses (12). The first definition of clinical influenza was
at least 2 of the following signs and symptoms: tempera-
ture 37.8 °C or greater, cough, headache, sore throat, and
myalgia (13); the second was temperature 37.8 °C or
greater plus cough or sore throat (14). An additional sec-
ondary outcome measure was the secondary attack ratio at
the household (cluster) level: the proportion of households
with 1 or more secondary case.
Laboratory Methods
Specimens collected from index patients at recruit-
ment were stored in a refrigerator at 2 to 8 °C. Specimens
collected during home visits were stored in an ice chest
with at least 2 ice packs immediately after collection. Be-
fore the end of the day of a home visit, study nurses ob-
tained samples to the nearest collection point for storage in
a refrigerator at 2 to 8 °C. Samples stored at 2 to 8 °C in
ice chests were delivered to the central testing laboratory at
Queen Mary Hospital by courier. Samples were eluted and
cryopreserved at 70 °C immediately after receipt. All
specimens were tested by RT-PCR for influenza A and B
viruses using standard methods (15–17). The Appendix
(available at www.annals.org) provides additional details of
the laboratory procedures that we used.
Statistical Analysis
On the basis of data collected in our pilot study (12)
and other studies with similar design (18, 19), we assumed
that 10% to 15% of household contacts in the control
group would develop RT-PCR–confirmed influenza, with
an average household size of 3.8 and an intracluster corre-
lation coefficient of 0.29. Specifying 80% power and a
significance level of 5%, we aimed to follow 300 house-
holds in each intervention group to allow us to detect dif-
ferences in secondary attack ratios of 35% to 45%, de-
pending on the actual secondary attack ratios in the control
group (15% or 10%, respectively). Recruiting 100 or 200
households to each group would allow 80% power to de-
tect 55% to 70% and 45% to 55% differences in second-
ary attack ratios, assuming a secondary attack ratio of 10%
to 15% in the control group.
To evaluate and compare secondary attack ratios by in-
tervention group, we estimated 95% CIs by using a cluster
bootstrap technique with 1000 resamples (20) and chi-square
tests and multivariable logistic regression models adjusting for
potential within-household correlation (21, 22). We esti-
mated the intracluster correlation coefficient from the mean
squared errors in the secondary attack ratio between and
within households (21). For the multivariable logistic regres-
sion models, we used forced-entry methods to include plausi-
ble confounders, including the intervention allocated, the age
and sex of the household contacts and their corresponding
index patients, vaccination status of the household contacts,
and antiviral use in corresponding index patients, whereas
missing data on the exact age of 14 household contacts were
imputed by comparison with their relationship with the index
patient or occupation. Participants were analyzed in the group
to which they were randomly assigned, regardless of adherence
to the intervention or use of hand washing or facemasks in
groups not assigned that intervention.
Our protocol specified that households with more than 1
member with RT-PCR–confirmed influenza virus infection
at baseline (co–index patients) or index patients in whom in-
fluenza virus infection could not be confirmed by RT-PCR
would be excluded from analyses. We excluded from analyses
participants who dropped out before receiving the interven-
tion and the few participants who dropped out after the in-
tervention but before data on the primary outcome measure
were collected (23). In sensitivity analyses, we analyzed all
households in which the intervention was applied, using mul-
tiple imputation for unobserved outcomes (24) and including
an additional explanatory variable for households with more
than 1 index patient. Statistical analyses were conducted in R,
version 2.7.1 (R Development Core Team).
Role of the Funding Source
The study was funded by the Centers for Disease Con-
trol and Prevention; the Research Fund for the Control of
Infectious Disease, Food and Health Bureau, Government
of the Hong Kong SAR; and the Area of Excellence
Scheme of the Hong Kong University Grants Committee.
The sponsors had no role in data collection and analysis, or
the decision to publish, but the Centers for Disease Con-
trol and Prevention were involved in study design and
preparation of the manuscript.
ArticleNonpharmaceutical Interventions to Prevent Influenza
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 439
RESULTS
We recruited 2750 potential index patients from 2
January through 30 September 2008; recruitment in-
creased during periods of peak influenza activity in Febru-
ary and March and July and August (Appendix Figure 1,
available at www.annals.org).
The Figure shows the study flow. Of the 2750 poten-
tial index patients, 407 (14.8%) had influenza A or B virus
infection according to the rapid test; these persons and
their households were randomly allocated. In an uninten-
tional deviation from that protocol, 49 of the 407 persons
had a household contact with influenza symptoms at re-
cruitment (a potential co–index patient). We also ran-
domly assigned 6 of 407 persons who had symptoms for
slightly more than 48 hours.
After random assignment, 76 (19%) of the households
declined home visits or could not be contacted after nu-
merous repeated attempts. We implemented the interven-
tions in 331 households. After initial home visits, 9 house-
holds declined further participation and were excluded
from analyses. Thus, 322 (97%) households completed
follow-up. Influenza could not be confirmed by RT-PCR
in 16 of 322 index patients in these households at baseline,
and those 16 households were excluded (Figure 1). A fur-
ther 47 households were excluded because 1 or more con-
tacts had RT-PCR–confirmed influenza virus infection at
baseline. Three household contacts declined to participate
and were excluded from analyses. We evaluated and com-
pared secondary attack ratios in the remaining 259 (64%)
households, which included 794 household contacts. One
hundred sixty (62%) index patients had influenza A virus
infection, and 99 (38%) had influenza B virus infection.
Participants
Table 2 shows the characteristics of all randomly as-
signed index patients and of the index patients and house-
Figure. Study flow diagram.
Assessed for eligibility
(2750 index patients)
Randomly allocated (407 index patients)
QuickVue* positive for influenza: 245 patients with influenza A, 162 patients with influenza B
Control intervention (134 households)
Received allocated intervention: 112
households (median household size [IQR],
4 [3–5]) with 346 household contacts
Did not receive allocated intervention
Declined to participate: 22 households
Hand hygiene intervention (136 households)
Received allocated intervention: 106
households (median household size [IQR],
4 [3–5]) with 329 household contacts
Did not receive allocated intervention
Declined to participate: 30 households
Facemask + hand hygiene intervention
(137 households)
Received allocated intervention: 104
households (median household size [IQR],
4 [4–5]) with 340 household contacts
Did not receive allocated intervention
Declined to participate: 33 households
Excluded: QuickVue* negative or
inconclusive for influenza (2343 index
patients)
Analyzed: 91 households (median household
size [IQR], 4 [3–5]) with 279 (81%) household
contacts
Excluded from analysis
21 households (median household size [IQR],
5 [3–5])
4 households where index patient did not
have RT-PCR–confirmed influenza virus
infection at baseline
17 households where 1 contact had
RT-PCR–confirmed influenza virus infection
at baseline
Analyzed: 85 households (median household
size [IQR], 4 [3–5]) with 257 (78%) household
contacts
Excluded from analysis
21 households (median household size [IQR],
4 [4–5])
5 households where index patient did not
have RT-PCR–confirmed influenza virus
infection at baseline
16 households where 1 contact had
RT-PCR–confirmed influenza virus infection
at baseline
Analyzed: 83 households (median household
size [IQR], 4 [3–5]) with 258 (76%) household
contacts
Excluded from analysis
21 households (median household size [IQR],
5 [4–6])
7 households where index patient did not
have RT-PCR–confirmed influenza virus
infection at baseline
14 households where 1 contact had
RT-PCR–confirmed influenza virus infection
at baseline
IQR interquartile range; RT-PCR reverse-transcription polymerase chain reaction.
*QuickVue Influenza AB rapid diagnostic test (Quidel, San Diego, California).
Article Nonpharmaceutical Interventions to Prevent Influenza
440 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
hold members that were retained in the main analysis. In
general, the groups were similar. Around two thirds of
index patients were children.
The median household size was 4 persons (inter-
quartile range, 3 to 5 persons). A median of 1 child
(interquartile range, 1 to 2 children) lived in the ana-
lyzed households in each intervention group. The me-
dian size of a household’s apartment was 700 square feet
(interquartile range, 581 to 1000 square feet), and the
mean residential density index, defined as the number of
household members divided by the household size, was
0.6 (SD, 0.3) persons per 100 square feet; this did not
differ substantially or significantly between intervention
groups.
Table 2. Participant Characteristics*
Characteristic Control Group Hand Hygiene Group Facemask Plus Hand Hygiene Group
Randomly Assigned
(
n
134)
Analyzed
(
n
91)
Randomly Assigned
(
n
136)
Analyzed
(
n
85)
Randomly Assigned
(
n
137)
Analyzed
(
n
83)
Index patients
Age group
5 y 26 (19) 20 (22) 19 (14) 10 (12) 25 (18) 14 (17)
6–15 y 70 (52) 54 (59) 66 (49) 46 (54) 67 (49) 45 (54)
16–30 y 17 (13) 5 (5) 24 (18) 12 (14) 22 (16) 11 (13)
31–50 y 15 (11) 11 (12) 23 (17) 15 (18) 18 (13) 9 (11)
50 y 6 (4) 1 (1) 4 (3) 2 (2) 5 (4) 4 (5)
Median age (IQR), y 10 (6–18) 9 (6–12) 12 (7–28) 11 (8–28) 10 (6–22) 10 (6–20)
Men 63 (47) 44 (48) 76 (56) 41 (48) 62 (45) 33 (40)
Symptoms
Temperature 37.8 °C 111 (83) 75 (82) 110 (81) 75 (88) 104 (76) 66 (80)
Headache 75 (56) 48 (53) 74 (54) 46 (54) 66 (48) 38 (46)
Sore throat 73 (54) 50 (55) 82 (60) 51 (60) 95 (69) 56 (67)
Cough 112 (84) 75 (82) 108 (79) 67 (79) 119 (87) 71 (86)
Myalgia 68 (51) 46 (51) 59 (43) 40 (47) 63 (46) 36 (43)
Runny nose 122 (91) 82 (90) 116 (85) 73 (86) 121 (88) 76 (92)
Phlegm 85 (63) 56 (62) 85 (62) 55 (65) 92 (67) 56 (67)
Symptom onset to
randomization interval
0–12 h 22 (16) 16 (18) 31 (23) 15 (18) 29 (21) 20 (24)
12–24 h 72 (54) 54 (59) 60 (44) 44 (52) 61 (45) 38 (46)
24–36 h 12 (9) 8 (9) 15 (11) 9 (11) 10 (7) 3 (4)
36–48 h 27 (20) 13 (14) 28 (21) 16 (19) 34 (25) 21 (25)
48–60 h 1 (1) 0 (0) 2 (1) 1 (1) 3 (2) 1 (1)
Randomization to intervention
interval
0–12 h 74 (81) 65 (76) 74 (89)
12–24 h 8 (9) 7 (8) 3 (4)
24–36 h 8 (9) 12 (14) 6 (7)
36–48 h 1 (1) 1 (1) 0 (0)
Prescribed antiviral
Oseltamivir 22 (24) 19 (22) 23 (28)
Amantadine 0 (0) 0 (0) 0 (0)
Zanamivir 1 (1) 0 (0) 1 (1)
Ribavirin 1 (1) 0 (0) 0 (0)
Median household size, n444
Household contacts†
Age group
5 y 20 (7) 9 (4) 15 (6)
6–15 y 29 (10) 32 (12) 25 (10)
16–30 y 37 (13) 27 (11) 36 (14)
31–50 y 157 (56) 125 (49) 131 (51)
50 y 34 (12) 53 (21) 50 (19)
Unknown 2 (1) 11 (4) 1 (0)
Median age (IQR) 38 (26–45) 40 (28–49) 38 (27–48)
Men 105 (38) 103 (40) 98 (38)
Received influenza vaccination in
the previous 12 mo
30 (11) 32 (12) 44 (17)
IQR interquartile range.
*Data are the number (percentage) of participants, unless otherwise indicated. We excluded 85 households that dropped out, 16 households in which the index patients did
not have reverse-transcription polymerase chain reaction–confirmed influenza virus infection at baseline, and 47 households in which 1 household contacts had reverse
transcription polymerase chain reaction–confirmed influenza virus infection at baseline (a co–index patient).
279 patients in the control group, 257 in the hand hygiene group, and 258 in the facemask plus hand hygiene group.
ArticleNonpharmaceutical Interventions to Prevent Influenza
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 441
Most of the initial home visits were completed within
12 hours of recruitment (Appendix Table 1, available at
www.annals.org). The interval between symptom onset
and intervention did not significantly differ between the
intervention groups (data not shown).
Influenza Transmission
Overall, 60 (8%) household contacts in 49 (19%)
households developed RT-PCR–confirmed influenza virus
infection during the follow-up period, including 7 house-
holds with 2 secondary cases and 2 households with 3
secondary cases; 150 (19%) and 41 (5%) contacts met the
2 definitions of clinical influenza. There were no signifi-
cant differences between intervention groups in contact in-
fections when any of the influenza definitions were used
(Table 3). Among 597 household contacts of 188 index
patients who were children 15 years or younger, there were
54 (9%) secondary cases (17 siblings [secondary attack ra-
tio, 15%], 26 parents (8%), 10 live-in domestic helpers
(9%), and 1 aunt (2%).Among 197 household contacts of
71 adult index patients, there were 6 (3%) secondary cases
(2 children [secondary attack ratio, 4%]) and 1 spouse
[4%]). Secondary attack ratios did not significantly differ
at the household level (24% in the control group, 14% in
the hand hygiene group, and 18% in the facemask plus
hand hygiene group; P0.37).
Table 4 shows the adjusted odds ratios of RT-PCR–
confirmed influenza virus infection or clinical influenza
in household contacts by intervention group, allowing
for within-household correlation. The risk of RT-PCR–
confirmed influenza virus infection did not differ signifi-
cantly between intervention groups, but it was significantly
higher for children 6 to 15 years of age, and there was a
nonsignificant higher risk for influenza virus infection for
contacts in households in which the index patient was a
child.
In a subgroup analysis planned before study imple-
mentation (12), we found a significant reduction in RT-
PCR–confirmed influenza virus infections in the house-
hold contacts in 154 households in which the intervention
was applied within 36 hours of symptom onset in the in-
dex patient (Table 3). The significant difference between
the treatment groups was also observed for the first defini-
tion of clinical influenza and seemed to be attributable to
fewer infections in the facemask plus hand hygiene group
(adjusted odds ratio, 0.33 [95% CI 0.13 to 0.87]) (Table
5). No significant difference was found between the face-
mask plus hand hygiene group and the hand hygiene group
in RT-PCR–confirmed influenza virus infections in house-
hold contacts (odds ratio, 0.72 [CI, 0.21 to 2.48]). In an
exploratory analysis, we found a borderline nonsignificant
difference between intervention groups in RT-PCR–con-
firmed influenza virus infections among household con-
tacts in which the intervention was applied within 48
hours of symptom onset in the index patient (Appendix
Table 2, available at www.annals.org).
Consistent results were found in separate analyses of
household contacts of index patients with influenza A or B
virus infection (Appendix Tables 3 and 4, available at
www.annals.org). The reductions were not statistically sig-
nificant in the smaller number of household contacts of
index patients with influenza B virus infection.
In sensitivity analyses, we compared secondary attack
ratios by using combinations of RT-PCR or clinical influ-
enza outcomes in household contacts, by intervention
group (Appendix Tables 5,6, and 7, available at www
.annals.org). When the intervention was applied within 36
hours of symptom onset of the index patient, we found
significant differences between groups in influenza infec-
tions that were both RT-PCR confirmed and met the first
clinical definition. We also found significant differences in
influenza virus infections that were either RT-PCR con-
firmed or met the first clinical definition, or both. In ad-
ditional sensitivity analyses on all 331 households in which
the intervention was applied, results were similar to the
Table 3. Secondary Attack Ratios of RT-PCR–Confirmed Influenza Virus Infection and Clinical Influenza
Interval Between
Symptom Onset
and Intervention
Determination of
Influenza*
Control Group (
n
279) Hand Hygiene Group
(
n
257)
Facemask Plus Hand
Hygiene (
n
258)
P
Value†
Cases,
n
SAR (95% CI),
%
Cases,
n
SAR (95% CI),
%
Cases,
n
SAR (95% CI),
%
Any RT-PCR confirmed 28 10 (6–14) 14 5 (3–9) 18 7 (4–11) 0.22
Clinical definition 1 53 19 (14–24) 42 16 (12–21) 55 21 (16–27) 0.40
Clinical definition 2 14 5 (2–8) 9 4 (2–6) 18 7 (4–11) 0.28
36 h§ RT-PCR confirmed 22 12 (7–18) 7 5 (1–11) 6 4 (1–7) 0.040
Clinical definition 1 42 23 (16–30) 14 11 (5–17) 27 18 (12–24) 0.032
Clinical definition 2 12 7 (3–11) 5 4 (1–7) 11 7 (3–12) 0.52
RT-PCR reverse-transcription polymerase chain reaction; SAR secondary attack ratio.
*“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
For difference among the 3 groups by the Pearson chi-square test, adjusted for within-household correlations of 0.12 for the RT-PCR–confirmed secondary attack ratios
and 0.04 and 0.07 for the clinical influenza secondary attack ratios.
The secondary attack ratio at the individual level was defined as the proportion of household contacts of an index case that subsequently became infected with influenza.
The CIs were calculated by using a cluster bootstrap method (20).
§Based on 183 patients in the control group, 130 in the hand hygiene group, and 149 in the facemask plus hand hygiene group.
Article Nonpharmaceutical Interventions to Prevent Influenza
442 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
main findings (Appendix Tables 8 and 9, available at www
.annals.org).
Adherence
At the final home visit, the intervention groups re-
ported higher adherence to the interventions than the
control group. Self-reported data were consistent with
measurements of the amount of soap, alcohol hand rub,
and facemasks used (Table 6). As part of their symptom
diaries, participants in the intervention groups reported
daily adherence to the respective interventions; im-
proved hand hygiene was maintained throughout
follow-up and was similar among index patients and
contacts (Appendix Figure 2, available at www.annals
.org). Adherence to the hand hygiene intervention was
slightly higher in the hand hygiene group than the face-
mask plus hand hygiene group (Appendix Table 10,
available at www.annals.org). Index patients reported
greater use of facemasks than household contacts, par-
ticularly during the first few days of follow-up (Appen-
dix Figure 2, available at www.annals.org). Adherence
was similar in the subgroup of households in which the
intervention was applied within 36 hours of symptom
onset in the index patient (Appendix Table 10, avail-
able at www.annals.org).
DISCUSSION
We report the largest study to date of the efficacy of
facemasks and hand hygiene to prevent influenza virus
transmission in households. Overall, the interventions
did not lead to statistically significant reductions in
household transmission, although we did observe statis-
tically significant reductions where interventions were
applied early after symptom onset in the index patient.
The strengths of our study include laboratory confirma-
tion of secondary influenza virus infections and the
community setting with outpatient-based recruitment,
which allows broad generalizability.
Our study design resulted in delays between symp-
tom onset in the index patient and application of the
interventions; thus, although adherence was incomplete,
we have probably underestimated the true effectiveness
of these simple interventions. Our results suggest that
substantial clinically significant reductions in household
infections could result if the interventions are applied
Table 4. Risk for Influenza Virus Infection in Included Households*
Characteristic Participants,
n
Odds Ratio (95% CI)†
RT-PCR–Confirmed
Influenza
Clinical Influenza‡
Definition 1 Definition 2
Study group
Control 279 1.00 (reference) 1.00 (reference) 1.00 (reference)
Hand hygiene 257 0.57 (0.26–1.22) 0.92 (0.57–1.48) 0.81 (0.33–2.00)
Facemask plus hand hygiene 258 0.77 (0.38–1.55) 1.25 (0.79–1.98) 1.68 (0.68–4.15)
Contact characteristics
Age
Adult (16 y) 662 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 88 2.87 (1.42–5.78) 1.71 (0.99–2.96) 6.64 (3.01–14.7)
Child (5 y) 44 1.91 (0.69–5.30) 1.27 (0.59–2.72) 6.75 (2.45–18.6)
Sex
Female 488 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 306 0.71 (0.41–1.24) 0.69 (0.47–1.01) 0.46 (0.21–1.02)
Vaccination status
No influenza vaccination in the past 12 mo 688 1.00 (reference) 1.00 (reference) 1.00 (reference)
Influenza vaccination in the past 12 mo 106 0.33 (0.12–0.91) 1.19 (0.71–2.01) 1.50 (0.57–3.93)
Index patient characteristics
Age
Adult (16 y) 71 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 144 2.74 (0.95–7.90) 1.75 (1.01–3.01) 1.85 (0.55–6.17)
Child (5 y) 44 2.82 (0.87–9.14) 2.22 (1.19–4.14) 3.89 (0.98–15.4)
Sex
Female 140 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 119 1.11 (0.61–2.04) 0.99 (0.67–1.44) 0.47 (0.23–0.99)
Antiviral status
Not prescribed antiviral 191 1.00 (reference) 1.00 (reference) 1.00 (reference)
Prescribed antiviral 68 0.70 (0.33–1.45) 0.71 (0.45–1.12) 0.70 (0.28–1.78)
RT-PCR reverse-transcription polymerase chain reaction.
*Based on 794 household contacts in 259 analyzed households.
Adjusted for intervention group; age, sex, and vaccination history of the contact; and age, sex, and antiviral use of the index patient.
“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
ArticleNonpharmaceutical Interventions to Prevent Influenza
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 443
soon after symptom onset (Tables 3 and 5), which is
plausible given that infectiousness may be highest soon
after symptom onset (25–27). Although our results sug-
gest a benefit of hand hygiene and facemasks in combi-
nation if applied early, our study cannot precisely
distinguish the relative contributions of the 2 interven-
tions. A recent prospective trial of 143 households re-
ported a protective effect of facemasks against a clinical
outcome measure in the per-protocol (as-treated) analy-
sis, although no evidence of efficacy was found by
intention-to-treat analysis or in laboratory-confirmed re-
spiratory virus infections (28).
In addition to statistically significant differences be-
tween the intervention groups in the primary outcome
measure of RT-PCR–confirmed infections, we observed
statistically significant differences between groups when
we used the first definition of clinical influenza but not
the second definition (Table 3). Symptom-based out-
comes can lack specificity for influenza virus infections
(12, 29), and the interventions in our study aimed to
reduce influenza virus transmission within households
and may not have been effective in preventing other
respiratory infections outside the home. Another possi-
ble explanation is that our study lacked statistical power
to identify differences in the second clinical definition,
with few patients meeting the stricter criteria of fever
plus cough or sore throat.
As in our pilot study (12), adherence to the inter-
ventions varied. We observed contamination between
groups, because both interventions were practiced to
some degree in the control group. Only half of the index
patients in the facemask plus hand hygiene group re-
ported regular use of a surgical mask during follow-up.
Facemask adherence among household contacts was
lower. Adherence to the hand hygiene intervention
seemed low compared with rates recommended in
health care settings but was similar to rates in previous
community studies (30–32). In addition, effects in our
study may tend toward a lower bound on the effects that
might be observed in a pandemic with heightened pub-
lic awareness (28). It is important to find ways of im-
proving adherence for future studies.
Limitations of our study design include the poten-
tial bias from recruiting symptomatic persons, which
Table 5. Risk for Influenza Virus Infection When the Intervention Was Applied Within 36 Hours of Symptom Onset in the
Index Patient*
Characteristic Participants,
n
Odds Ratio (95% CI)†
RT-PCR–Confirmed
Influenza
Clinical Influenza‡
Definition 1 Definition 2
Study group
Control 183 1.00 (reference) 1.00 (reference) 1.00 (reference)
Hand hygiene 130 0.46 (0.15–1.43) 0.46 (0.22–0.96) 0.64 (0.20–2.02)
Facemask plus hand hygiene 149 0.33 (0.13–0.87) 0.86 (0.48–1.53) 1.45 (0.49–4.24)
Contact characteristics
Age
Adult (16 y) 386 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 51 3.02 (1.16–7.85) 2.09 (1.01–4.32) 7.57 (2.79–20.6)
Child (5 y) 25 2.45 (0.75–8.01) 2.16 (0.87–5.34) 7.20 (1.92–27.0)
Sex
Female 283 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 179 0.68 (0.30–1.53) 0.40 (0.23–0.70) 0.36 (0.12–1.06)
Vaccination status
No influenza vaccination in the past 12 mo 401 1.00 (reference) 1.00 (reference) 1.00 (reference)
Influenza vaccination in the past 12 mo 61 0.40 (0.12–1.33) 1.33 (0.71–2.49) 1.10 (0.31–3.91)
Index patient characteristics
Age
Adult (16 y) 39 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 85 1.17 (0.33–4.23) 1.57 (0.66–3.74) 0.79 (0.20–3.19)
Child (5 y) 30 1.55 (0.37–6.45) 2.26 (0.86–5.95) 2.36 (0.46–12.3)
Sex
Female 82 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 72 0.97 (0.44–2.14) 1.18 (0.71–1.98) 0.56 (0.24–1.30)
Antiviral status
Not prescribed antiviral 109 1.00 (reference) 1.00 (reference) 1.00 (reference)
Prescribed antiviral 45 0.81 (0.32–2.04) 0.76 (0.42–1.38) 0.66 (0.21–2.06)
RT-PCR reverse-transcription polymerase chain reaction.
*Based on 462 household contacts in 154 analyzed households.
Adjusted for intervention group; age, sex, and vaccination history of the contact; and age, sex, and antiviral use of the index patient.
“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
Article Nonpharmaceutical Interventions to Prevent Influenza
444 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
has 3 effects. First, by using a point-of-care rapid test to
detect influenza virus infection, we might preferentially
have included index patients with higher viral shedding
(33). However, statistical power would generally be in-
creased if index patients were more infectious, because
we might observe more household transmission; the
limitation thus relates more to generalizability. Second,
our study design resulted in an unavoidable delay be-
tween onset of symptoms in the index patient and the
application of interventions; this may have led to under-
estimation of their true effects, as suggested by our sta-
tistically significant finding of reduced infection when
interventions were implemented within 36 hours. Our
household sample may have been biased toward includ-
ing household contacts with preexisting immunity, be-
cause in households in which all contacts were suscep-
tible, there might have been more possibility of
secondary cases being observed before the index patient
presented to a primary care provider (12). Our primary
outcome measure is based on laboratory confirmation of
influenza by RT-PCR, with specimens collected from
home visits at 3-day intervals, and some infections may
have been missed if peak viral shedding in the respira-
tory tract occurred between home visits. We may have
missed secondary infections that occurred 7 days or
more after illness onset in the index patient. In addition,
collection of poor-quality specimens or degeneration
during transport or freezing could have reduced RT-
PCR sensitivity. Finally, we did not evaluate other face-
masks or respirators, such as P2 or N95 masks; these
might be more effective than surgical facemasks, al-
though fit testing is usually required and adherence
could be difficult to maintain (28).
Several issues should be considered when planning
further studies of nonpharmaceutical interventions. We
recruited index patients from outpatient clinics, and re-
cruitment was therefore driven by influenza incidence
(Appendix Figure 1, available at www.annals.org). This
could be problematic in temperate locations with
shorter and more intense influenza seasons, where delays
between recruitment and intervention may dilute ef-
fects. An alternative approach would be to recruit a co-
hort of uninfected households before an influenza sea-
son. However, a much larger sample would be needed,
given the low attack rate of influenza. Studies over mul-
tiple influenza seasons are useful to allow for variability
in incidence rates from year to year. It is challenging to
obtain longitudinal laboratory specimens from partici-
pants with repeated home visits, but relying on clinical
symptoms to guide testing may not yield results specific
for influenza. Paired serology could be compared to de-
termine influenza infections during follow-up; this was
not feasible in our study.
In conclusion, our results suggest that hand hygiene
and facemasks can reduce influenza virus transmission if
implemented early after symptom onset in an index pa-
tient. During a pandemic, resources may not be available
to isolate all infected individuals, and home isolation of
some patients may be required. Our results directly inform
the personal protective measures that should be taken in
such a scenario and support the use of these nonpharma-
ceutical interventions in public health control measures
against interpandemic influenza in annual epidemics.
From School of Public Health and University of Hong Kong; Hospital
Authority and Centre for Health Protection, Department of Health,
Government of the Hong Kong SAR; Hong Kong Sanatorium and Hos-
pital; St Paul’s Hospital; St Teresa’s Hospital; and Hong Kong Baptist
Hospital, Hong Kong; National Center for Immunization and Respira-
tory Diseases, Centers for Disease Control and Prevention, Atlanta,
Georgia; and Seattle Quarantine Station, Division of Global Migration
and Quarantine, Centers for Disease Control and Prevention and Na-
tional Center for Preparedness, Detection and Control of Infectious Dis-
eases, Seattle, Washington.
Table 6. Summary Measures of Adherence to Interventions During the 7-Day Follow-up Period
Characteristic Control Group Hand Hygiene Group Facemask Plus Hand Hygiene
Group
Index Patient Contact Index Patient Contact Index Patient Contact
Using liquid soap, %* 7077687177 78
Using alcohol hand rub, %*7636283324
Practicing good hand hygiene, %4446625461 56
Median amount of liquid hand soap used by
household (IQR), g
85.7 (42.9–155.2) 78.9 (37.9–120.1)
Median amount of alcohol hand rub used by
individuals (IQR), g
2.7 (0.6–6.0) 1.4 (0.3–5.3) 1.6 (0.5–5.4) 1.4 (0.3–4.7)
Wearing surgical mask, % 15 7 31 5 49 26
Median number of masks used (IQR) 9 (3.0–16.3) 4 (0–9)
IQR interquartile range.
*Proportion of individuals who reported washing their hands with liquid hand soap or using alcohol hand rub often or always (rather than sometimes or never) during the
follow-up period.
Proportion of individuals who reported washing their hands often or always (rather than sometimes or never) after sneezing, coughing, or blowing their nose during the
follow-up period.
Proportion of individuals who reported wearing a surgical facemask often or always (rather than sometimes or never) during the follow-up period.
ArticleNonpharmaceutical Interventions to Prevent Influenza
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 445
Disclaimer: This work represents the views of the authors and not their
institutions, including the Centers for Disease Control and Prevention.
Acknowledgment: The authors thank the physicians, nurses and staff of
participating centers for facilitating recruitment and our dedicated team
of health care workers who conducted the home visits.
Grant Support: By the Centers for Disease Control and Prevention,
Atlanta, Georgia (grant 1 U01 CI000439-02). The Research Fund for
the Control of Infectious Disease, Food and Health Bureau, Govern-
ment of the Hong Kong SAR (grant 08070632); and the Area of Excel-
lence Scheme of the Hong Kong University Grants Committee (grant
AoE/M-12/06).
Potential Conflicts of Interest: None disclosed.
Reproducible Research Statement: Study protocol and data set: Available
at www.hku.hk/bcowling/influenza/HK_NPI_study.htm. Statistical code:
The R syntax to permit reproducible statistical analyses is available at
www.hku.hk/bcowling/influenza/HK_NPI_study.htm.
Requests for Single Reprints: Benjamin J. Cowling, BSc, PhD, School
of Public Health, The University of Hong Kong, Units 624-7, Core F,
Cyberport 3, Pokfulam, Hong Kong; e-mail, bcowling@hku.hk.
Current author addresses and author contributions are available at www
.annals.org.
References
1. Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wort-
ley PM, Weintraub E, et al. The annual impact of seasonal influenza in the US:
measuring disease burden and costs. Vaccine. 2007;25:5086-96. [PMID:
17544181]
2. Monto AS. Individual and community impact of influenza. Pharmacoeco-
nomics. 1999;16 Suppl 1:1-6. [PMID: 10623371]
3. Aledort JE, Lurie N, Wasserman J, Bozzette SA. Non-pharmaceutical public
health interventions for pandemic influenza: an evaluation of the evidence base.
BMC Public Health. 2007;7:208. [PMID: 17697389]
4. Epstein JM, Goedecke DM, Yu F, Morris RJ, Wagener DK, Bobashev GV.
Controlling pandemic flu: the value of international air travel restrictions. PLoS
One. 2007;2:e401. [PMID: 17476323]
5. Jefferson T, Foxlee R, Del Mar C, Dooley L, Ferroni E, Hewak B, et al.
Physical interventions to interrupt or reduce the spread of respiratory viruses:
systematic review. BMJ. 2008;336:77-80. [PMID: 18042961]
6. World Health Organization Writing Group. Non-pharmaceutical interven-
tions for pandemic influenza, international measures. Emerg Infect Dis. 2006;12:
81-7. [PMID: 16494722]
7. World Health Organization Writing Group. Non-pharmaceutical interven-
tions for pandemic influenza, national and community measures. Emerg Infect
Dis. 2006;12:88-94. [PMID: 16494723]
8. Markel H, Lipman HB, Navarro JA, Sloan A, Michalsen JR, Stern AM, et al.
Nonpharmaceutical interventions implemented by US cities during the 1918-
1919 influenza pandemic. JAMA. 2007;298:644-54. [PMID: 17684187]
9. Hatchett RJ, Mecher CE, Lipsitch M. Public health interventions and epi-
demic intensity during the 1918 influenza pandemic. Proc Natl Acad SciUSA.
2007;104:7582-7. [PMID: 17416679]
10. Oshitani H, Kamigaki T, Suzuki A. Major issues and challenges of influenza
pandemic preparedness in developing countries. Emerg Infect Dis. 2008;14:875-
80. [PMID: 18507896]
11. Aiello AE, Coulborn RM, Perez V, Larson EL. Effect of hand hygiene on
infectious disease risk in the community setting: a meta-analysis. Am J Public
Health. 2008;98:1372-81. [PMID: 18556606]
12. Cowling BJ, Fung RO, Cheng CK, Fang VJ, Chan KH, Seto WH, et al.
Preliminary findings of a randomized trial of non-pharmaceutical interventions to
prevent influenza transmission in households. PLoS One. 2008;3:e2101. [PMID:
18461182]
13. Monto AS, Pichichero ME, Blanckenberg SJ, Ruuskanen O, Cooper C,
Fleming DM, et al. Zanamivir prophylaxis: an effective strategy for the preven-
tion of influenza types A and B within households. J Infect Dis. 2002;186:
1582-8. [PMID: 12447733]
14. Babcock HM, Merz LR, Fraser VJ. Is influenza an influenza-like illness?
Clinical presentation of influenza in hospitalized patients. Infect Control Hosp
Epidemiol. 2006;27:266-70. [PMID: 16532414]
15. Chan KH, Peiris JS, Lim W, Nicholls JM, Chiu SS. Comparison of naso-
pharyngeal flocked swabs and aspirates for rapid diagnosis of respiratory viruses in
children. J Clin Virol. 2008;42:65-9. [PMID: 18242124]
16. Peiris JS, Tang WH, Chan KH, Khong PL, Guan Y, Lau YL, et al.
Children with respiratory disease associated with metapneumovirus in Hong
Kong. Emerg Infect Dis. 2003;9:628-33. [PMID: 12781000]
17. Lambert SB, Whiley DM, O’Neill NT, Andrews EC, Canavan FM,
Bletchly C, et al. Comparing nose-throat swabs and nasopharyngeal aspirates
collected from children with symptoms for respiratory virus identification using
real-time polymerase chain reaction. Pediatrics. 2008;122:e615-20. [PMID:
18725388]
18. Viboud C, Boe¨lle PY, Cauchemez S, Lavenu A, Valleron AJ, Flahault A,
et al. Risk factors of influenza transmission in households. Br J Gen Pract. 2004;
54:684-9. [PMID: 15353055]
19. Hayden FG, Belshe R, Villanueva C, Lanno R, Hughes C, Small I, et al.
Management of influenza in households: a prospective, randomized comparison
of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis.
2004;189:440-9. [PMID: 14745701]
20. Field CA, Welsh AH. Bootstrapping clustered data. J R Stat Soc Series B Stat
Methodol. 2007;69:369-90.
21. Donner A, Klar N. Design and Analysis of Cluster Randomization Trials in
Health Research. London: Arnold; 2000:90.
22. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear
models. Biometrika. 1986;73:13-22.
23. Hollis S, Campbell F. What is meant by intention to treat analysis? Survey
of published randomised controlled trials. BMJ. 1999;319:670-4. [PMID:
10480822]
24. Schafer JL. Multiple imputation: a primer. Stat Methods Med Res. 1999;8:
3-15. [PMID: 10347857]
25. Cowling BJ, Fang VJ, Riley S, Malik Peiris JS, Leung GM. Estimation of
the serial interval of influenza. Epidemiology. 2009;20:344-7. [PMID:
19279492]
26. Ferguson NM, Cummings DA, Cauchemez S, Fraser C, Riley S, Meeyai A,
et al. Strategies for containing an emerging influenza pandemic in Southeast Asia.
Nature. 2005;437:209-14. [PMID: 16079797]
27. Carrat F, Vergu E, Ferguson NM, Lemaitre M, Cauchemez S, Leach
S, et al. Time lines of infection and disease in human influenza: a review
of volunteer challenge studies. Am J Epidemiol. 2008;167:775-85.
[PMID: 18230677]
28. MacIntyre CR, Cauchemez S, Dwyer DE, Seale H, Cheung P, Browne G,
et al. Face mask use and control of respiratory virus transmission in households.
Emerg Infect Dis. 2009;15:233-41. [PMID: 19193267]
29. Call SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP. Does
this patient have influenza? JAMA. 2005;293:987-97. [PMID: 15728170]
30. Sandora TJ, Taveras EM, Shih MC, Resnick EA, Lee GM, Ross-Degnan
D, et al. A randomized, controlled trial of a multifaceted intervention including
alcohol-based hand sanitizer and hand-hygiene education to reduce illness trans-
mission in the home. Pediatrics. 2005;116:587-94. [PMID: 16140697]
31. Luby SP, Agboatwalla M, Feikin DR, Painter J, Billhimer W, Altaf A, et al.
Effect of handwashing on child health: a randomised controlled trial. Lancet.
2005;366:225-33. [PMID: 16023513]
32. Luby SP, Agboatwalla M, Painter J, Altaf A, Billhimer W, Keswick B, et al.
Combining drinking water treatment and hand washing for diarrhoea preven-
tion, a cluster randomised controlled trial. Trop Med Int Health. 2006;11:479-
89. [PMID: 16553931]
33. Cheng KY, Cowling BJ, Chan KH, Fang VJ, Seto WH, Yung R, et
al. Factors affecting QuickVue Influenza AB rapid test performance in
the community setting. Diagn Microbiol Infect Dis. 2009;65:35-41.
[PMID: 19679233]
Article Nonpharmaceutical Interventions to Prevent Influenza
446 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
Current Author Addresses: Drs. Cowling, Cheng, and Leung; Ms.
Fang; Ms. Fung; Ms. Wai; and Mr. Sin: School of Public Health, The
University of Hong Kong, Units 624-7, Core F, Cyberport 3, Pokfulam,
Hong Kong.
Drs. Chan, Peiris, and Seto: Department of Microbiology, Queen Mary
Hospital, Pokfulam, Hong Kong.
Drs. Yung and B.C.F. Chiu: Hong Kong Sanatorium and Hospital,
Happy Valley, Hong Kong.
Dr. Chu: Sai Ying Pun General Outpatient Clinic, 134 Queen’s Road
West, Sai Ying Pun, Hong Kong.
Dr. P.W.Y. Lee: General Outpatient Clinic, St Paul’s Hospital, 2 Eastern
Hospital Road, Causeway Bay, Hong Kong.
Dr. M.C. Chiu: General Outpatient Clinic, St Teresa’s Hospital, 327-
Prince Edward Road, Kowloon, Hong Kong.
Dr. H.C. Lee: Out Patient Department, Hong Kong Baptist Hospital,
222 Waterloo Road, Kowloon, Hong Kong.
Dr. Uyeki: Influenza Division, National Center for Immunization and
Respiratory Diseases, Centers for Disease Control and Prevention, 1600
Clifton Road, Atlanta, GA 30333.
Dr. Houck: Seattle Quarantine Station, Division of Global Migration
and Quarantine, Centers for Disease Control and Prevention, National
Center for Preparedness, Detection and Control of Infectious Diseases,
c/o U.S. Customs & Border Protection, 2580 South 156th Street, Build-
ing A, Room 101, Seattle, WA 98158.
Author Contributions: Conception and design: B.J. Cowling, C.K.Y.
Cheng, W.H. Seto, R. Yung, D.W.S. Chu, T.M. Uyeki, P.M. Houck,
J.S.M. Peiris, G.M. Leung.
Analysis and interpretation of the data: B.J. Cowling, K.H. Chan, V.J.
Fang, C.K.Y. Cheng, R.O.P. Fung, T.M. Uyeki, J.S.M. Peiris, G.M.
Leung.
Drafting of the article: B.J. Cowling, V.J. Fang, C.K.Y. Cheng, P.M.
Houck, G.M. Leung.
Critical revision of the article for important intellectual content: V.J.
Fang, C.K.Y. Cheng, W.H. Seto, R. Yung, B.C.F. Chiu, T.M. Uyeki,
P.M. Houck, J.S.M. Peiris, G.M. Leung.
Final approval of the article: B.J. Cowling, V.J. Fang, C.K.Y. Cheng,
D.W.S. Chu, B.C.F. Chiu, T.M. Uyeki, J.S.M. Peiris, G.M. Leung.
Provision of study materials or patients: C.K.Y. Cheng, R.O.P. Fung, W.
Wai, D.W.S. Chu, P.W.Y. Lee, M.C. Chiu, G.M. Leung.
Statistical expertise: B.J. Cowling, V.J. Fang.
Obtaining of funding: B.J. Cowling, P.M. Houck, G.M. Leung.
Administrative, technical, or logistic support: K.H. Chan, V.J. Fang,
C.K.Y. Cheng, R.O.P. Fung, W. Wai, J. Sin, P.W.Y. Lee, M.C. Chiu,
H.C. Lee, T.M. Uyeki, P.M. Houck, G.M. Leung.
Collection and assembly of data: K.H. Chan, V.J. Fang, C.K.Y. Cheng,
R.O.P. Fung, W. Wai, J. Sin, D.W.S. Chu, P.W.Y. Lee, G.M. Leung.
APPENDIX:ADDITIONAL DETAILS OF RT-PCR
METHODS
Total nucleic acid was extracted from specimens by using
the NucliSens easyMAG extraction system (bioMe´rieux, Boxtel,
the Netherlands) according to the manufacturer’s instructions.
Twelve microliters of extracted nucleic acid was used to prepare
complementary DNA (cDNA) by using an Invitrogen Super-
script III kit (Invitrogen, San Diego, California) with random,
primer, as described elsewhere (16).
For detection of influenza A virus, 2
L of cDNA was
amplified in a LightCycler 2.0 (Roche Diagnostics, Penzberg,
Germany) with a total reaction-mix volume of 20
L reaction
containing FastStart DNA Master SYBR Green I Mix reagent kit
(Roche Diagnostics), 4.0 mM MgCl
2
and 0.5mM of each
primer. The forward primer (5-CTTCTAACCGAGGTC-
GAAACG-3) and the reverse primer (5-GGCATTTTGG-
ACAAAKCGTCTA-3) were used for amplification of the ma-
trix gene of influenza A virus [15]. Cycling conditions were as
follows: initial denaturation at 95 °C for 10 minutes, followed by
40 cycles of 95 °C for 10 seconds, 60 °C for 3 seconds, and
72 °C for 12 seconds, with ramp rates of 20 °C/s. At the end of
the assay, PCR products were subjected to a melting-curve anal-
ysis to determine the specificity of the assay.
For detection of influenza B virus, forward (5-GCA-
TCTTTTGTTTTTTATCCATTCC) and reverse (5-CACAAT-
TGCCTACCTGCTTTCA) primers and 5nuclease probe (Fam-
TGCTAGTTCTGCTTTGCCTTCTCCATCTTCT-TAMRA)
were used for amplification of the matrix gene [17]. Testing was
performed by using the TagMan EZ RT-PCR Core reagent kit
(Applied Biosystems, Hammonton, New Jersey), with 0.8
mol/L of forward and reverse primers and 0.2
mol/L of probe
in a total reaction volume of 25
L, comprising 4
L of nucleic
acid extract. Amplification and detection was performed on an
ABI StepOneTM Real-Time PCR System (Applied Biosystems)
under the following conditions: initial hold at 50 °C for 20 min-
utes and 95 °C for 15 minutes, followed by 45 cycles at 95 °C for
15 seconds and 60 °C for 1 minute.
Annals of Internal Medicine
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 W-135
Appendix Figure 1. Study recruitment and local influenza activity.
Participants Recruited, n
Month
0
40
80
120
160
200
ILI Rate, n per 1000 consultations
0
20
40
60
80
Isolation Rate, %
0Jan Feb Mar Apr May Jun Jul Aug Sep
20
10
QV –ve
QV Flu B +ve
QV Flu A +ve
Flu B +ve
Flu A +ve
ILI influenza-like illness; QV ve negative result by QuickVue Influenza AB test; QV Flu A ve positive result for influenza A by QuickVue
Influenza AB test; QV Flu B ve positive result for influenza B by QuickVue Influenza AB test.
Top. Weekly recruitment rates, stratified by rapid test result. Middle. Local surveillance data on the weekly rate of ILI consultations per 1000
consultations among sentinel general practitioners reporting to the Centre for Health Protection. Bottom. Weekly rate of positive influenza A and B virus
isolations among specimens submitted to the World Health Organization reference laboratory of Queen Mary Hospital, Hong Kong.
W-136 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
Appendix Table 1. Interval Between Symptom Onset in Index
Patients, Random Assignment, and Application of the
Intervention*
Delay Symptom Onset to
Random Assignment,
n (%)
Random Assignment
to Intervention,
n
(%)
Symptom Onset
to Intervention,
n (%)
0–12 h 51 (20) 213 (82) 0 (0)
12–24 h 136 (53) 18 (7) 44 (17)
24–36 h 20 (8) 26 (10) 110 (42)
36–48 h 50 (19) 2 (1) 30 (12)
48–60 h 2 (1) 0 (0) 65 (25)
60–72 h 6 (2)
72–84 h 3 (1)
84–96 h 1 (0)
*Based on 259 index patients.
Appendix Table 2. Secondary Attack Ratios for RT-PCR–Confirmed and Clinical Influenza When the Intervention Was Applied
Within 48 Hours of Symptom Onset in the Index Patient*
Interval Between
Symptom Onset
and Intervention
Determination of
Influenza†
Secondary Attack Ratio (95% CI),
%
P
Value§
Control Group
(
n
214)
Hand Hygiene
Group (
n
167)
Facemask Plus Hand
Hygiene Group (
n
171)
48 h RT-PCR confirmed 11 (6–16) 6 (2–10) 4 (2–7) 0.077
Clinical definition 1 20 (14–26) 13 (7–18) 19 (13–25) 0.182
Clinical definition 2 6 (2–10) 3 (1–6) 8 (4–12) 0.24
RT-PCR reverse-transcription polymerase chain reaction.
*Based on 552 household contacts in 184 analyzed households.
“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
The CIs were calculated by using a cluster bootstrap method (20).
§For the difference among the 3 groups by the Pearson chi-square test, adjusted for within-household correlation.
Appendix Table 3. Secondary Attack Ratios for RT-PCR–Confirmed and Clinical Influenza A Virus Infection
Interval Between
Symptom Onset
and Intervention
Determination of
Influenza*
Secondary Attack Ratio (95% CI),
%
P
Value‡
Control Group Hand Hygiene
Group
Facemask Plus
Hand Hygiene
Group
Any§ RT-PCR confirmed 10 (5–16) 4 (1–7) 5 (2–9) 0.117
Clinical definition 1 20 (13–27) 13 (8–18) 21 (14–28) 0.162
Clinical definition 2 5 (2–9) 3 (1–6) 8 (3–14) 0.173
36 hRT-PCR confirmed 12 (5–20) 3 (0–10) 4 (1–8) 0.083
Clinical definition 1 23 (15–31) 8 (3–14) 20 (12–29) 0.031
Clinical definition 2 7 (2–12) 3 (0–8) 9 (4–15) 0.30
RT-PCR reverse-transcription polymerase chain reaction.
*“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
The CIs were calculated by using a cluster bootstrap method (20).
For the difference among the 3 groups by the Pearson chi-square test, adjusted for within-household correlation.
§Based on 175 persons in the control group, 158 in the hand hygiene group, and 154 in the facemask plus hand hygiene group.
Based on 123 persons in the control group, 87 in the hand hygiene group, and 99 in the facemask plus hand hygiene group.
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 W-137
Appendix Table 4. Secondary Attack Ratios for RT-PCR–Confirmed and Clinical Influenza B Virus Infection
Interval Between
Symptom Onset
and Intervention
Determination of
Influenza*
Secondary Attack Ratio (95% CI),
%
P
Value‡
Control Group Hand Hygiene
Group
Facemask Plus
Hand Hygiene
Group
Any§ RT-PCR confirmed 10 (5–16) 8 (3–15) 10 (4–17) 0.93
Clinical definition 1 17 (10–25) 22 (14–30) 22 (15–30) 0.62
Clinical definition 2 5 (0–11) 4 (1–8) 5 (1–8) 0.97
36 hRT-PCR confirmed 12 (5–20) 09 (2–20) 4 (0–11) 0.32
Clinical definition 1 23 (12–34) 16 (5–28) 14 (6–22) 0.42
Clinical definition 2 7 (0–16) 5 (0–11) 4 (0–11) 0.90
RT-PCR reverse-transcription polymerase chain reaction.
*“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
The CIs were calculated by using a cluster bootstrap method (20).
For the difference among the 3 groups by the Pearson chi-square test, adjusted for within-household correlation.
§Based on 104 persons in the control group, 99 in the hand hygiene group, and 104 in the facemask plus hand hygiene group.
Based on 60 persons in the control group, 43 in the hand hygiene group, and 50 in the facemask plus hand hygiene group.
Appendix Table 5. Secondary Attack Ratios for RT-PCR–Confirmed and Clinical Influenza Virus Infection When Composite
Definitions Are Used*
Interval Between
Symptom Onset
and Intervention
Determination of Influenza† Secondary Attack Ratio (95% CI),
%
P
Value§
Control Group Hand Hygiene
Group
Facemask Plus
Hand Hygiene
Group
AnyRT-PCR confirmed or clinical definition 1 22 (17–28) 19 (14–24) 23 (18–28) 0.55
RT-PCR confirmed and clinical definition 1 7 (4–10) 3 (1–6) 5 (3–9) 0.178
RT-PCR confirmed or clinical definition 2 11 (8–16) 7 (4–10) 11 (7–15) 0.23
RT-PCR confirmed and clinical definition 2 4 (2–6) 2 (1–5) 3 (1–6) 0.71
36 hours¶ RT-PCR confirmed or clinical definition 1 26 (20–33) 13 (8–20) 19 (13–26) 0.040
RT-PCR confirmed and clinical definition 1 9 (5–14) 3 (1–8) 3 (1–8) 0.051
RT-PCR confirmed or clinical definition 2 13 (9–19) 7 (3–13) 9 (5–14) 0.31
RT-PCR confirmed and clinical definition 2 5 (3–10) 2 (0–7) 3 (1–7) 0.26
RT-PCR reverse-transcription polymerase chain reaction.
*Based on 794 household contacts in 259 analyzed households.
“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
The CIs were calculated by using a cluster bootstrap method (20).
§For the difference among the 3 groups by the Pearson chi-square test, adjusted for within-household correlation.
Based on 279 persons in the control group, 257 in the hand hygiene group, and 258 in the facemask plus hand hygiene group.
Based on 183 persons in the control group, 130 in the hand hygiene group, and 149 in the facemask plus hand hygiene group.
W-138 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
Appendix Table 6. Risk for Influenza Virus Infection in the Overall Sample, Using a Composite Definition of Infection*
Characteristic Participants,
n
Odds Ratio (95% CI)†
RT-PCR–Confirmed
Influenza or Clinical
Influenza (Definition 1)‡
RT-PCR–Confirmed
Influenza and
Clinical Influenza
(Definition 1)‡
RT-PCR–Confirmed
Influenza or
Clinical Influenza
(Definition 2)‡
RT-PCR–Confirmed
Influenza and
Clinical Influenza
(Definition 2)‡
Study group
Control 279 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Hand hygiene 257 0.90 (0.56–1.45) 0.46 (0.17–1.21) 0.60 (0.30–1.22) 0.75 (0.26–2.15)
Facemask plus hand hygiene 258 1.14 (0.72–1.79) 0.91 (0.41–1.99) 1.03 (0.55–1.95) 1.09 (0.37–3.25)
Contact characteristics
Age
Adult (16 y) 662 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 88 1.59 (0.95–2.68) 4.46 (1.93–10.3) 3.01 (1.60–5.66) 9.72 (3.70–25.5)
Child (5 y) 44 1.05 (0.50–2.23) 3.34 (1.09–10.3) 2.29 (0.94–5.55) 8.74 (2.57–29.8)
Sex
Female 488 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 306 0.72 (0.51–1.03) 0.56 (0.29–1.10) 0.60 (0.36–1.01) 0.59 (0.23–1.51)
Vaccination status
No influenza vaccination in the past 12 mo 688 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Influenza vaccination in the past 12 mo 106 1.00 (0.59–1.68) 0.56 (0.19–1.60) 0.69 (0.30–1.60) 0.86 (0.22–3.39)
Index patient characteristics
Age
Adult (16 y) 71 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 144 2.06 (1.22–3.48) 1.83 (0.51–6.50) 2.50 (0.97–6.42) 1.79 (0.41–7.78)
Child (5 y) 44 2.24 (1.20–4.18) 2.86 (0.72–11.4) 2.93 (1.03–8.37) 4.03 (0.78–20.7)
Sex
Female 140 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 119 1.05 (0.72–1.53) 0.92 (0.44–1.95) 0.83 (0.48–1.44) 0.72 (0.28–1.83)
Antiviral status
Not prescribed antiviral 191 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Prescribed antiviral 68 0.79 (0.52–1.21) 0.41 (0.13–1.30) 0.77 (0.40–1.48) 0.46 (0.13–1.69)
RT-PCR reverse-transcription polymerase chain reaction.
*Based on 794 household contacts in 259 households.
Adjusted for intervention group; age, sex, and vaccination history of the contact; and age, sex, and antiviral use of the index patient.
“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 W-139
Appendix Table 7. Risk for Influenza Virus Infection When the Intervention Was Applied Within 36 Hours of Symptom Onset in
the Index Patient, Using a Composite Definition of Infection*
Characteristic Participants,
n
Odds Ratio (95% CI)†
RT-PCR–Confirmed
Influenza or
Clinical Influenza
(Definition 1)‡
RT-PCR–Confirmed
Influenza and
Clinical Influenza
(Definition 1)‡
RT-PCR–Confirmed
Influenza or
Clinical Influenza
(Definition 2)‡
RT-PCR–Confirmed
Influenza and
Clinical Influenza
(Definition 2)‡
Study group
Control 183 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Hand hygiene 130 0.50 (0.25–1.01) 0.34 (0.08–1.34) 0.54 (0.20–1.51) 0.43 (0.11–1.65)
Facemask plus hand hygiene 149 0.75 (0.43–1.34) 0.40 (0.13–1.24) 0.70 (0.31–1.57) 0.64 (0.17–2.40)
Contact characteristics
Age
Adult (16 y) 386 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 51 1.65 (0.82–3.34) 6.31 (2.13–18.8) 3.18 (1.38–7.36) 11.1 (3.08–40.1)
Child (5 y) 25 1.62 (0.68–3.87) 5.19 (1.44–18.8) 2.64 (0.85–8.13) 9.44 (2.29–39.0)
Sex
Female 283 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 179 0.50 (0.30–0.84) 0.37 (0.13–1.03) 0.54 (0.26–1.11) 0.48 (0.13–1.74)
Vaccination status
No influenza vaccination in the past 12 mo 401 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Influenza vaccination in the past 12 mo 61 1.10 (0.58–2.06) 0.65 (0.19–2.26) 0.72 (0.27–1.89) 0.46 (0.05–4.15)
Index patient characteristics
Age
Adult (16 y) 39 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 85 1.76 (0.78–3.96) 0.79 (0.16–3.83) 1.19 (0.36–3.87) 0.58 (0.12–2.81)
Child (5 y) 30 2.12 (0.84–5.35) 1.73 (0.29–10.4) 1.81 (0.48–6.77) 1.92 (0.31–11.9)
Sex
Female 82 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 72 1.26 (0.76–2.10) 0.72 (0.29–1.81) 0.73 (0.36–1.51) 0.88 (0.31–2.46)
Antiviral status
Not prescribed antiviral 109 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference)
Prescribed antiviral 45 0.82 (0.47–1.41) 0.69 (0.20–2.32) 0.75 (0.32–1.75) 0.65 (0.16–2.59)
RT-PCR reverse-transcription polymerase chain reaction.
*Based on 462 household contacts in 154 households.
Adjusted for intervention group; age, sex, and vaccination history of the contact; and age, sex, and antiviral use of the index patient.
“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
W-140 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
Appendix Table 8. Risk for Influenza Virus Infection in All Households That Received the Intervention*
Characteristic Participants,
n
Odds Ratio (95% CI)†
RT-PCR–Confirmed
Influenza
Clinical Influenza‡
Definition 1 Definition 2
Study group
Control 331 1.00 (reference) 1.00 (reference) 1.00 (reference)
Hand hygiene 317 0.73 (0.38–1.38) 1.43 (0.91–2.22) 1.60 (0.73–3.49)
Facemask plus hand hygiene 336 0.89 (0.46–1.73) 1.47 (0.94–2.29) 1.89 (0.85–4.18)
Contact characteristics
Age
Adult (16 y) 820 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 109 3.20 (1.74–5.89) 2.16 (1.34–3.46) 4.64 (2.36–9.12)
Child (5 y) 56 1.81 (0.78–4.19) 1.72 (0.95–3.11) 8.37 (3.85–18.2)
Sex
Female 609 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 375 0.81 (0.52–1.28) 0.78 (0.57–1.08) 0.68 (0.38–1.23)
Vaccination status
No influenza vaccination in the past 12 mo 848 1.00 (reference) 1.00 (reference) 1.00 (reference)
Influenza vaccination in the past 12 mo 136 0.50 (0.24–1.05) 1.03 (0.65–1.64) 1.16 (0.53–2.55)
Index patient characteristics
Age
Adult (16 y) 93 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 177 3.71 (1.41–9.77) 2.02 (1.26–3.24) 3.10 (1.07–8.99)
Child (5 y) 61 3.76 (1.25–11.3) 2.48 (1.41–4.36) 4.23 (1.27–14.1)
Sex
Female 171 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 160 1.20 (0.71–2.05) 1.02 (0.72–1.44) 0.69 (0.38–1.26)
Antiviral status
Not prescribed antiviral 246 1.00 (reference) 1.00 (reference) 1.00 (reference)
Prescribed antiviral 85 0.73 (0.39–1.37) 0.78 (0.53–1.14) 0.87 (0.43–1.77)
Household characteristics
No co–index patients 282 1.00 (reference) 1.00 (reference) 1.00 (reference)
Co–index patients 49 1.99 (0.98–4.05) 1.33 (0.83–2.12) 2.28 (1.12–4.63)
RT-PCR reverse-transcription polymerase chain reaction.
*Based on 984 household contacts in 331 households.
Adjusted for intervention group; age, sex, and vaccination history of the contact; and age, sex, and antiviral use of the index patient.
“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 W-141
Appendix Table 9. Risk for Influenza Virus Infection When the Intervention Was Applied Within 36 Hours of Symptom Onset in
the Index Patient*
Characteristic Participants,
n
Odds Ratio (95% CI)†
RT-PCR–Confirmed
Influenza
Clinical Influenza‡
Definition 1 Definition 2
Study group
Control 212 1.00 (reference) 1.00 (reference) 1.00 (reference)
Hand hygiene 158 0.54 (0.22–1.33) 0.97 (0.53–1.78) 1.43 (0.52–3.95)
Facemask plus hand hygiene 191 0.46 (0.19–1.08) 1.14 (0.67–1.96) 1.83 (0.70–4.78)
Contact characteristics
Age
Adult (16 y) 469 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 60 4.30 (1.94–9.55) 3.11 (1.68–5.74) 6.19 (2.63–14.6)
Child (5 y) 32 2.16 (0.86–5.39) 2.24 (1.10–4.58) 6.92 (2.52–19.0)
Sex
Female 349 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 212 0.89 (0.47–1.68) 0.56 (0.36–0.86) 0.64 (0.28–1.44)
Vaccination status
No influenza vaccination in the past 12 mo 490 1.00 (reference) 1.00 (reference) 1.00 (reference)
Influenza vaccination in the past 12 mo 71 0.43 (0.16–1.15) 1.03 (0.57–1.87) 0.63 (0.18–2.24)
Index patient characteristics
Age
Adult (16 y) 49 1.00 (reference) 1.00 (reference) 1.00 (reference)
Child (6–15 y) 104 2.13 (0.61–7.44) 1.93 (0.94–3.96) 1.88 (0.48–7.45)
Child (5 y) 39 2.36 (0.59–9.48) 2.74 (1.18–6.38) 4.10 (0.84–19.9)
Sex
Female 101 1.00 (reference) 1.00 (reference) 1.00 (reference)
Male 91 0.92 (0.44–1.89) 1.02 (0.64–1.62) 0.68 (0.32–1.45)
Antiviral status
Not prescribed antiviral 136 1.00 (reference) 1.00 (reference) 1.00 (reference)
Prescribed antiviral 56 0.76 (0.35–1.66) 0.84 (0.51–1.37) 0.85 (0.36–1.98)
Household characteristics
No co–index patients 162 1.00 (reference) 1.00 (reference) 1.00 (reference)
Co–index patients 30 1.51 (0.61–3.78) 1.40 (0.77–2.56) 1.76 (0.71–4.33)
RT-PCR reverse-transcription polymerase chain reaction.
*Based on 561 household contacts in 192 households.
Adjusted for intervention group; age, sex, and vaccination history of the contact; and age, sex, and antiviral use of the index patient.
“Clinical definition 1” is at least 2 of the following: temperature 37.8 °C, cough, headache, sore throat, and myalgia. “Clinical definition 2” is temperature 37.8 °C,
plus cough or sore throat.
W-142 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
Appendix Figure 2. Daily reported adherence to hand hygiene
and facemask interventions.
Data are presented as means (95% CIs).
www.annals.org 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 W-143
Appendix Table 10. Summary Measures of Adherence to Interventions During the 7-Day Follow-up Period in Households in Which
the Intervention Was Applied Within 36 Hours of Symptom Onset in the Index Patient
Characteristic Control Group Hand Hygiene Group Facemask Plus Hand Hygiene
Group
Index
Patient
Contact Index
Patient
Contact Index
Patient
Contact
Using liquid soap, %* 697966726974
Using alcohol hand rub, %*7741302930
Practicing good hand hygiene, %424868606355
Median amount of liquid hand soap
used by household (IQR), g
77.6 (42.4–162.6) 78.9 (35.2–114.2)
Median amount of alcohol hand rub
used by individuals (IQR), g
3.2 (1.1–9.7) 1.5 (0.3–5.3) 1.6 (0.7–5.1) 1.5 (0.3–3.8)
Wearing surgical mask, % 19 8 32 8 47 27
Median number of masks used
(IQR)
10 (2–16) 3 (0–9)
IQR interquartile range.
*Proportion of individuals who reported washing their hands with liquid hand soap or using alcohol hand rub often or always (rather than sometimes or never) during the
follow-up period.
Proportion of individuals who reported washing their hands often or always (rather than sometimes or never) after sneezing, coughing, or blowing their nose during the
follow-up period.
Proportion of individuals who reported wearing a surgical facemask often or always (rather than sometimes or never) during the follow-up period.
W-144 6 October 2009 Annals of Internal Medicine Volume 151 • Number 7 www.annals.org
... The outcome assessment was different between articles. Although the educational interventions were highly variable and often multimodal, all but three studies (8,14,15) addressed and emphasized that educational interventions are successful in influenza prevention in terms of respiratory tract infection incidence (16-22), vaccination rate (7,9,(23)(24)(25), and improvement of knowledge or preventive behaviors (9,(26)(27)(28)(29)(30) (Tables 1-3). ...
... The setting of these studies varied from the household setting (n = 4) (14,16,23,27), over the hospital and healthcare facilities (n = 7) (7,9,10,(24)(25)(26)28), schools (n = 6) (15,17,18,(29)(30)(31), and University setting (n = 2) (20,22), to the corporation worksites (n = 2) (8, 21) and one study was performed on Hajj pilgrims (19). ...
... The educational sessions were characterized by education of the target group through either verbally communicated hand and respiratory hygiene lessons (e.g., instructions by telephone, on the internet, or face-to-face), with training or instructions on how and how frequent to practice hand hygiene and to use face masks or in combination with written or visual media (e.g., information leaflets, posters, video/live demonstration) (7,9,15,(17)(18)(19)(20)31). In addition to that, some studies consisted of the provision of hand hygiene materials, either soap (14,19), alcohol-based hand sanitizers (14,15,(18)(19)(20)31), face masks (14,19,20), provided by the researchers to every participating individual (14,19,20) or to be shared within their cluster or with others in case of provision at a common place (e.g., common courtyards or school toilets) (15,18,31). ...
Article
Full-text available
Introduction Seasonal influenza, a contagious viral disease affecting the upper respiratory tract, circulates annually, causing considerable morbidity and mortality. The present study investigates the effectiveness of educational interventions to prevent influenza. Methods We searched PubMed/Medline, Embase, and Cochrane Controlled Register of Trials (CENTRAL) for relevant clinical studies up to March 1 2022. The following terms were used: “influenza,” “flu,” “respiratory infection,” “prevent,” “intervention,” and “education.” Results Out of 255 studies, 21 articles satisfied the inclusion criteria and were included in our study: 13 parallel randomized controlled trials (RCT) studies, two cross-over RCT studies, two cohort studies, and four quasi-experimental studies. A total of approximately 12,500 adults (18 years old or above) and 11,000 children were evaluated. Educational sessions and reminders were the most common interventions. The measured outcomes were vaccination rates, the incidence of respiratory tract infection (RTI), and preventive behaviors among participants. Eighteen out of 21 articles showed a significant association between educational interventions and the outcomes. Conclusions The included studies in the current systematic review reported the efficacy of health promotion educational interventions in improving knowledge about influenza, influenza prevention behaviors, vaccination rates, and decreased RTI incidence regardless of the type of intervention and the age of cases.
... 16,21 were performed exclusively with children. The other productions, which dealt exclusively with children, 4,5,8,23-30 did not carry out field research, as they were articles or documents that presented opinions or recommendations from experts, being classified by the JBI as level of evidence 5. 31 Six (31.5%) studies analyzed the use of masks concomitantly with other preventive measures, such as hand hygiene, 15,16,18,22 use of hand sanitizer/alcohol 17 , and staying in an airy environment 19 (Table 3). ...
... Eight productions identified do not recommend the use of masks by children under 2 years of age, with the justification that there is an increased risk of suffocation. 5,[23][24][25] Three original studies 15,17,22 included children aged between 2 and 5 years in their samples, and identified that adherence to the regular use of masks in the school environment was reduced as the days went by, with disuse factors being distraction, physical discomfort, and difficulty in communication between the child and the teachers. 17 In addition, in the home environment, two of these studies showed that, together with the habit of frequent hand hygiene, the use of a mask by children with Influenza did not reduce significantly the risk of infection in the family. ...
... 17 In addition, in the home environment, two of these studies showed that, together with the habit of frequent hand hygiene, the use of a mask by children with Influenza did not reduce significantly the risk of infection in the family. 15,22 In preschool children, efficient mask use can only be achieved through a thorough work with parents or guardians. 23 Due to the low understanding of the need for mask use, child adherence is sometimes so poor that it is better to stop wearing a mask and just adopt other preventive measures, such as social distancing and frequent hand hygiene. ...
Article
Objective: To identify and synthesize scientific evidence that the use of face protection masks by children, in the community and at home, is a way of preventing communicable diseases. Data source: A scoping review was made using the Joana Briggs Institute method and PRISMA-ScR. A research was carried out in five electronic databases, at the Cochrane Library and on seven websites of governmental and non-governmental institutions. The data were organized in a spreadsheet and submitted to narrative analysis. Data synthesis: Initially, 658 productions were identified, of which 19 made up the final sample. Studies with higher levels of evidence are scarce. The types of masks identified were professional (surgical and facial respirators with filtration) and non-professional (homemade). The transmissible agents studied were influenza and SARS-CoV-2 viruses, and the evaluated environments were schools, homes and community spaces. The main discomforts reported were heat, shortness of breath, headache and maladjustment to the face. The indication and acceptability of masks change according to the age group and clinical conditions. There is no consensus on the reduction in the transmissibility of infections. Conclusions: Children older than five can benefit from the correct use of masks, as long as they are supervised, taught and educated to do so and the masks should be well adjusted to the face. The use of masks show better results when associated with other measures such as physical distancing, keeping places ventilated and frequent hand hygiene.
... In Hong Kong, the overall vaccine coverage is low. Based on previous studies [34][35][36], the vaccine coverage for children, adults, and the elderly was 18%, 12% and 27% respectively. Therefore, our results should be interpreted as the indirect protection in the household level only. ...
... When exposed to a household member with influenza A virus infection, we estimated that the transmission probability was 10% and 14% for children aged <12 and, with a pre-season titer <10. These estimates were similar to those from a case-ascertained study [25,34,37]. The probability of transmission within households with smaller number of household members was higher, which was consistent with other studies [20,[38][39][40]. ...
Article
Full-text available
Influenza vaccination is an important intervention to prevent influenza virus infection. Our previous analysis suggested that indirect protection is limited in an influenza B epidemic in Hong Kong. We further analyzed six influenza A epidemics to determine such potential. We applied a statistical model to estimate household transmission dynamics in the 3 influenza A(H3N2) and 3 pandemic influenza A(H1N1) epidemics. Then, we estimated the reduction in infection risk among unvaccinated household members when all children in households are vaccinated, with different assumptions on vaccine efficacy (VE). In the optimal scenario that VE was 70%, the reduction to the total probability of infection was only marginal, with relative probabilities ranged from 0.91–0.94 when all children in households were vaccinated because community was by far the main source of infection during the six epidemics in our study. The proportion of cases attributed to household transmission was 10% (95% CrI: 7%, 13%). Individual influenza vaccination is important even when other household members are vaccinated, given the degree of indirect protection is small.
... If used by a susceptible person, the mask proposes effectiveness against the acquirement of disease. Additionally, if worn by a diseased individual (but mildly-symptomatic or asymptomatic and unaware that he/she is sick), the face mask shows effectiveness against their capacity to spread the disease to susceptible persons [2,3,24,48,52]. ...
... μ 1 , μ 2 = 0, μ 3 = 0). The optimal trajectory of the total number of infectious people for the controlled system (19) when strategy-C is applied and trajectory of that for system (24) when no control is implemented, are illustrated in Figure 13(a). It has been observed whenever this preventive technique is used, the overall number of infected individuals decreases. ...
Article
In this paper we assess the effectiveness of different non-pharmaceutical interventions (NPIs) against COVID-19 utilizing a compartmental model. The local asymptotic stability of equilibria (disease-free and endemic) in terms of the basic reproduction number have been determined. We find that the system undergoes a backward bifurcation in the case of imperfect quarantine. The parameters of the model have been estimated from the total confirmed cases of COVID-19 in India. Sensitivity analysis of the basic reproduction number has been performed. The findings also suggest that effectiveness of face masks plays a significant role in reducing the COVID-19 prevalence in India. Optimal control problem with several control strategies has been investigated. We find that the intervention strategies including implementation of lockdown, social distancing, and awareness only, has the highest cost-effectiveness in controlling the infection. This combined strategy also has the least value of average cost-effectiveness ratio (ACER) and associated cost.
... Cluster-randomized trials with hand hygiene and facemask interventions found mild reductions in risk among intervention users (effect for hand hygiene and facemask groups, separately) that did not reach statistical significance [42]. This finding was consistent with those from studies performed in Hong Kong and Bangkok that showed the effect of hand hygiene plus facemask to be small at best [1,43,44]. A similar result was observed for crowded, urban households in upper Manhattan after 19 months of follow-up in 509 households [45]. ...
Chapter
Full-text available
Despite uncertainty about the specific transmission risk posed by airborne, spray-borne, and contact modes for influenza, SARS-CoV-2, and other respiratory viruses, there is evidence that airborne transmission via inhalation is important and often predominates. An early study of influenza transmission via airborne challenge quantified infectious doses as low as one influenza virion leading to illness characterized by cough and sore throat. Other studies that challenged via intranasal mucosal exposure observed high doses required for similarly symptomatic respiratory illnesses. Analysis of the Evaluating Modes of Influenza Transmission (EMIT) influenza human-challenge transmission trial-of 52 H3N2 inoculated viral donors and 75 sero-susceptible exposed individuals-quantifies airborne transmission and provides context and insight into methodology related to airborne transmission. Advances in aerosol sampling and epidemiologic studies examining the role of masking, and engineering-based air hygiene strategies provide a foundation for understanding risk and directions for new work.
... For their safety, they should be provided with hand sanitizers, hand gloves, masks and other PPEs (personal protective equipments). Suspected people should be sent to a private room or negative pressure room if available Radonovich et al., 2019;Cowling et al., 2009). ...
Article
Full-text available
COVID-19 is a pandemic malady caused by SARS-CoV-2, a novel coronavirus. It is a global threat that has affected 223 countries and territories all over the world. According to the WHO report as of April 06, 2022 coronavirus has affected 492,189,439 people globally with 6,159,474 confirmed deaths. The pandemic of COVID-19 has badly affected Bangladesh likewise many other countries of the world. According to Worldometer report on 06 April 2022 the number of confirmed cases of COVID-19 were 1,951,903 with 29,123 deaths, and 1,886,036 COVID-19 recoveries in Bangladesh. After originating from China, this notorious virus has been spread to almost all the countries of the world. Its spike protein aids in binding with the ACE2 receptors of the cell membrane resulting in cell entry, replication, and induction of inflammatory and pro-inflammatory responses leading to the pathogenic condition. The novel COVID-19 virus has structural and genetic similarity with its predecessors specially SARS-CoV and MERS-CoV. This review presents the existing literature on COVID-19 and discusses different aspects of COVID-19 including virology, etiology, epidemiology, pathogenesis, diagnosis, transmission and susceptibility and preventive measures of COVID-19.
Article
Full-text available
The widespread, and in many countries unprecedented, use of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic has highlighted the need for mathematical models which can estimate the impact of these measures while accounting for the highly heterogeneous risk profile of COVID-19. Models accounting either for age structure or the household structure necessary to explicitly model many NPIs are commonly used in infectious disease modelling, but models incorporating both levels of structure present substantial computational and mathematical challenges due to their high dimensionality. Here we present a modelling framework for the spread of an epidemic that includes explicit representation of age structure and household structure. Our model is formulated in terms of tractable systems of ordinary differential equations for which we provide an open-source Python implementation. Such tractability leads to significant benefits for model calibration, exhaustive evaluation of possible parameter values, and interpretability of results. We demonstrate the flexibility of our model through four policy case studies, where we quantify the likely benefits of the following measures which were either considered or implemented in the UK during the current COVID-19 pandemic: control of within- and between-household mixing through NPIs; formation of support bubbles during lockdown periods; out-of-household isolation (OOHI); and temporary relaxation of NPIs during holiday periods. Our ordinary differential equation formulation and associated analysis demonstrate that multiple dimensions of risk stratification and social structure can be incorporated into infectious disease models without sacrificing mathematical tractability. This model and its software implementation expand the range of tools available to infectious disease policy analysts.
Article
Full-text available
To assess the efficacy of washing cloth masks, we simulated SARS-CoV-2 contamination in tricoline fabric and tested decontaminants to reduce viral particles. Viral suspensions using two variants (B.1.1.28 and P.1) were inoculated in these fabrics, and the inactivation kinetics were evaluated after washing with various household disinfection products (Soap powder, Lysoform®, Hypochlorite sodium and 70% Alcohol), rinse numbers, and exposure times. Afterward, the fabrics were washed in sterile water, and viral RNA was extracted and amplified using RT-qPCR. Finally, viral replication in cell cultures was examined. Our findings show that all biocidal treatments successfully disinfected the tissue tested. Some products showed less reduction in viral loads, such as soap powder (1.60 × 104, 1.04 × 103), soap powder and Lysoform® (1.60 × 104, 1.04 × 103), and alcohol 70% (1.02 × 103, 5.91 × 101), respectively. However, when sodium hypochlorite was used, this reduction was significantly increased (viral inactivation in 100% of the washes). After the first wash, the reduction in the number of viral particles was greater for the P.1 variant than for the B.1.1.28 variant (W = 51,759, p < 0.05). In conclusion, the role of sodium hypochlorite in cloth mask disinfection may also have implications for future health emergencies as well as recommendation by WHO.
Article
Full-text available
Background The coronavirus disease 2019 (COVID-19) pandemic as well as the subsequent prevention and control measures is like a quasi-experiment intervention that might have changed the features of emergency hospitalizations. Mortality is high in patient hospitalization due to emergency respiratory diseases (ERD). Therefore, we compared the characteristics of these patients before and during the pandemic. Exploring this issue might contribute to decision-making of emergency management when most of the resources and attention has been devoted to combat COVID-19. Methods This study was a retrospective observational cohort study. All emergency hospitalizations due to ERD from January 1, 2019 to December 31, 2020 in a tertiary hospital in China were included. Data including patients’ age, sex, and clinical outcomes were extracted. Air quality was collected from the official online platform. Clinical characteristics were compared and odds ratios were calculated. Results The ERD hospitalization rate was lower in 2020 than in 2019 (6.4 vs. 4.3%, χ ² = 55.449, P = 0.000) with a 50.65% reduction; however, the patients were older in 2020 than in 2019 ( P = 0.000) with a higher proportion of admission to the intensive care unit (ICU) (46 vs. 33.5%, χ ² = 20.423, P = 0.000) and a longer ICU stay ( P = 0.000). The overall intubation rate, hospital mortality, and rate of discharge due to ineffective treatment in 2020 were higher than those in 2019 (15.6 vs. 8%, χ ² = 18.578, P = 0.000; 4.2 vs. 1.1%, χ ² = 4.122, P = 0.000; 5.5 vs. 2.4%, χ ² = 8.93, P = 0.000, respectively). The logistic regression analysis indicated hospitalizations due to ERD were mainly associated with PM2.5 and sulfur dioxide on the day, and on the 4th and 5th days before admission ( P = 0.034 and 0.020, 0.021 and 0.000, 0.028, and 0.027, respectively) in 2019. However, in 2020, the relationship between parameters of air quality and hospitalization changed. Conclusion The COVID-19 pandemic has changed the characteristics of emergency hospitalization due to ERD with a larger proportion of severe patients and poorer prognosis. The effect of air quality on emergencies were weakened. During the COVID-19 pandemic, it is necessary to pay more attention to the non-COVID-19 emergency patients.
Article
Full-text available
Many countries are stockpiling face masks for use as a nonpharmaceutical intervention to control virus transmission during an influenza pandemic. We conducted a prospective cluster-randomized trial comparing surgical masks, non–fit-tested P2 masks, and no masks in prevention of influenza-like illness (ILI) in households. Mask use adherence was self-reported. During the 2006 and 2007 winter seasons, 286 exposed adults from 143 households who had been exposed to a child with clinical respiratory illness were recruited. We found that adherence to mask use significantly reduced the risk for ILI-associated infection, but <50% of participants wore masks most of the time. We concluded that household use of face masks is associated with low adherence and is ineffective for controlling seasonal respiratory disease. However, during a severe pandemic when use of face masks might be greater, pandemic transmission in households could be reduced. Many countries are stockpiling face masks for use as nonpharmaceutical interventions to reduce viral transmission during an influenza pandemic. We conducted a prospective cluster-randomized trial comparing surgical masks, non–fit-tested P2 masks, and no masks in prevention of influenza-like illness (ILI) in households. During the 2006 and 2007 winter seasons, 286 exposed adults from 143 households who had been exposed to a child with clinical respiratory illness were recruited. Intent-to-treat analysis showed no significant difference in the relative risk of ILI in the mask use groups compared with the control group; however, <50% of those in the mask use groups reported wearing masks most of the time. Adherence to mask use was associated with a significantly reduced risk of ILI-associated infection. We concluded that household use of masks is associated with low adherence and is ineffective in controlling seasonal ILI. If adherence were greater, mask use might reduce transmission during a severe influenza pandemic.
Article
Full-text available
The objective of this study was to calculate sensitivity values for the detection of major respiratory viruses of childhood by using combined nose-throat swabs and nasopharyngeal aspirates. Children who had symptoms and presented to a pediatric teaching hospital and had a diagnostic respiratory specimen collected were enrolled, and paired nose-throat swab and nasopharyngeal aspirate specimens were collected. Parents were asked to collect the nose-throat swab specimen in the first instance but could defer to a health care worker if unwilling. Nose-throat swab collectors were asked to rate perceived quality of collection. All nasopharyngeal aspirates were collected by a health care worker by using a standard protocol. Real-time polymerase chain reaction for 8 respiratory viruses was performed in our hospital's diagnostic laboratory. Paired nose-throat swab/nasopharyngeal aspirate specimens were collected during 303 illnesses, with at least 1 respiratory virus identified in 186 (61%). For the major pathogens of childhood, influenza A virus and respiratory syncytial virus, collection by using the nose-throat swab had a sensitivity of 91.9% and 93.1%, respectively. A health care worker collected 219 (72%) of the nose-throat swab specimens; concordance with the nasopharyngeal aspirate was not related to health care worker collection or perceived quality of collection. Nose-throat swab specimens, in combination with sensitive molecular testing, are a less invasive diagnostic respiratory specimen with adequate sensitivity for use in the clinic and hospital outpatient settings and large-scale community studies through parent collection. For children who present to a hospital in which an avian or pandemic strain of influenza virus is reasonably part of the differential diagnosis, nasopharyngeal aspirates or a similar collection technique (eg, nasal washes) should continue to be used.
Article
This paper proposes an extension of generalized linear models to the analysis of longitudinal data. We introduce a class of estimating equations that give consistent estimates of the regression parameters and of their variance under mild assumptions about the time dependence. The estimating equations are derived without specifying the joint distribution of a subject's observations yet they reduce to the score equations for niultivariate Gaussian outcomes. Asymptotic theory is presented for the general class of estimators. Specific cases in which we assume independence, m-dependence and exchangeable correlation structures from each subject are discussed. Efficiency of the pioposecl estimators in two simple situations is considered. The approach is closely related to quasi-likelihood.
Article
Trials which randomize intact social groups, or clusters, to different interventions are becoming increasingly widespread. Although statistically less efficient than trials which randomize individuals, such designs are often preferred from a practical or ethical point of view, particularly in the evaluation of health care or educational strategies. We discuss selected issues that arise in the conduct of such trials, including the choice of design, ethical implications, sample size estimation and approaches to the analysis. The discussion is closely tied to methodological issues that have arisen in a recent evaluation trial of a new antenatal care programme, as sponsored by the Special Programme of Research, Development and Research Training in Human Reproduction of the World Health Organization.
Article
Rapid diagnosis of influenza can facilitate timely clinical management. We evaluated the performance of the QuickVue Influenza A + B test (Quidel, San Diego, CA) in a community setting and investigated the factors affecting test sensitivity. We recruited 1008 subjects from 30 outpatient clinics in Hong Kong between February and September 2007. Each subject provided 2 pooled pairs of nose and throat swabs; 1 pair was tested by the QuickVue rapid test on site, and the other pair was sent to a laboratory for reference tests. Among 998 enrolled subjects with valid results, the rapid test had overall sensitivity of 0.68 and specificity of 0.96 compared with viral culture. Sensitivity for both influenza A and B was significantly higher for specimens with viral loads greater than 5 log(10) copies/mL. The QuickVue Influenza A + B test has similar sensitivity in point-of-care community settings to more controlled conditions.
Article
: Estimates of the clinical-onset serial interval of human influenza infection (time between onset of symptoms in an index case and a secondary case) are used to inform public health policy and to construct mathematical models of influenza transmission. We estimate the serial interval of laboratory-confirmed influenza transmission in households. : Index cases were recruited after reporting to a primary healthcare center with symptoms. Members of their households were followed-up with repeated home visits. : Assuming a Weibull model and accounting for selection bias inherent in our field study design, we used symptom-onset times from 14 pairs of infector/infectee to estimate a mean serial interval of 3.6 days (95% confidence interval = 2.9-4.3 days), with standard deviation 1.6 days. : The household serial interval of influenza may be longer than previously estimated. Studies of the complete serial interval, based on transmission in all community contexts, are a priority.
Article
In recent years, multiple imputation has emerged as a convenient and flexible paradigm for analysing data with missing values. Essential features of multiple imputation are reviewed, with answers to frequently asked questions about using the method in practice.
Article
To assess the methodological quality of intention to treat analysis as reported in randomised controlled trials in four large medical journals. Survey of all reports of randomised controlled trials published in 1997 in the BMJ, Lancet, JAMA, and New England Journal of Medicine. Methods of dealing with deviations from random allocation and missing data. 119 (48%) of the reports mentioned intention to treat analysis. Of these, 12 excluded any patients who did not start the allocated intervention and three did not analyse all randomised subjects as allocated. Five reports explicitly stated that there were no deviations from random allocation. The remaining 99 reports seemed to analyse according to random allocation, but only 34 of these explicitly stated this. 89 (75%) trials had some missing data on the primary outcome variable. The methods used to deal with this were generally inadequate, potentially leading to a biased treatment effect. 29 (24%) trials had more than 10% of responses missing for the primary outcome, the methods of handling the missing responses were similar in this subset. The intention to treat approach is often inadequately described and inadequately applied. Authors should explicitly describe the handling of deviations from randomised allocation and missing responses and discuss the potential effect of any missing response. Readers should critically assess the validity of reported intention to treat analyses.