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Epidemiology of respiratory viral infections in children enrolled in a study of influenza vaccine effectiveness

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Influenza-like illness (ILI) confers a high annual morbidity in young children. We report the epidemiology of ILIs in children who participated in an influenza vaccine effectiveness study during the 2010 Southern Hemisphere influenza season in Sydney, Australia. Children aged 0·5-3 years were prospectively recruited from child care centres (CCCs). We classified them as fully vaccinated, partially vaccinated and unvaccinated according to their receipt of unadjuvanted vaccines containing influenza A (H1N1)pdm09. For 13 weeks commencing 30 July 2010, parents reported when their children developed an ILI (fever ≥37·8°C/feverishness plus ≥1 respiratory symptom) and collected nose and/or throat swabs for multiplex respiratory virus polymerase chain reaction (PCR) testing. Health impacts were assessed by telephone interview at enrolment and two weeks after each ILI. There were 124 ILIs reported in 105 of 381 enrolled children. Swabs were taken in 117 ILIs: 175 viruses were identified from 103 swabs. Adeno- and rhinoviruses were most frequently identified; 44% of swabs yielded multiple viruses. No virus was associated with more severe symptoms, although rhinovirus-related ILIs lasted longer. Nose swabs had a higher virus detection rate than throat swabs. Influenza-vaccinated children were 1·6 times (P = 0·001) more likely than unvaccinated children to have a non-influenza ILI. Adeno- and rhinoviruses were the most common viruses causing ILI. Swabs taken by parents are an effective method for sample collection. Influenza-like illness was more common in children vaccinated against influenza in this observational study, but prior health-seeking behaviour may have contributed to this difference.
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Epidemiology of respiratory viral infections in children enrolled in
a study of influenza vaccine effectiveness
Alexa Dierig, a,b Leon G. Heron, a,c,d Stephen B. Lambert, e,f Jiehui Kevin Yin, a,c Julie Leask, a,c,d Maria Yui Kwan Chow, a,c
Theo P. Sloots, e Michael D. Nissen, e Iman Ridda, c Robert Booy a,c,d
a National Centre for Immunisation Research and Surveillan ce, T he Children’s Hospital at West mead, Westmead, NSW, Australia.
b University Children’s Hospit al bot h Basel, Basel, Switzerland.
c Sydney Medical School, The Universit y of Sydney, Sydney, NSW, Australia.
d Marie Bashir Instit ute, Sydney, NSW, Australia.
e Queensland P aediatric Infectious Disease Laborat ory , Queensland Children’s Medical Research Inst itute, Queensland Children’s Health
Service, Brisbane, Qld, Australia.
f Clinical and Stat ewide Services, P athology Queensland Cent ral, Herston, Qld, Australia.
Correspondence: Alexa Dierig, University Children′s Hospital Basel, Spitalstr. 33 , 4031 Basel, Switzerland. E-mail: alexadierig@web.de
Introduction
Acute respiratory infection (ARI) is among the major causes of death in young children worldwide. 1 In Australia, ARI is
the main cause for short-term illness in children aged 0–14 years. 2 The number of newly identified viruses in respiratory
tract specimens, including the recently discovered polyomaviruses WUV and KIV, 3,4 is increas ing. Influenza causes a
substantial health burden with direct and indirect costs, including hospitalisations and loss of productivity. 5–8
Inactivated and live-attenuated influenza vaccines offer both direct and herd benefits to vaccinated children, their
contacts and the broader community. 9–11 Several studies have shown that children attending child care centres (CCCs)
are at greater risk of ARI including influenza. 12–15 In 2008, formal child care was undertaken by 9% of Australian children
aged <1 year, 35% aged 1 year and 47% aged 2–3 years. 16 In order to determine the health, s ocial and economic effects
of influenza vaccination in young children, we planned a randomised controlled trial (RCT) of an unadjuvanted trivalent
influenza vaccine in children aged 6–35 months who attended a CCC in metropolitan Sydney during 2010. However,
because of the 2009 pandemic, the Australian government recommended and funded universal use of inactivated
pandemic influenza A(H1N1)pdm09 vaccination for those aged >6 months in 2010. Hence, a RCT design became
unethical. The study was restructured to a prospective cohort design addres sing the epidemiology of ILIs among young
children.
Methods
Study cohorts
Children were recruited through 90 CCCs and one general practitioner with a s pecial interest in paediatrics. Informed cons ent was
obtained from a parent or legal guardian. To meet inclusion criteria, children needed to be aged ≥6– 35 months on 1 March 2010.
Exclusions were for known allergy to any component of the influenza vaccine, a history of Guillain–Barre s yndrome, a bleeding
disorder, an unstable chronic illness or enrolment in another trial. Parents reported influenza vaccinations their children had
received and, where possible, the influenza vaccination status was validated from vaccination records . The children were divided
into three cohorts: fully vaccinated (usually two doses in 2010), partially vaccinated (usually one dose in 2010) and unvaccinated
according to their receipt of vaccines that contained influenza A (H1N1)pdm09 – full definitions are in the footnotes to Table 1.
ILI case reporting
We planned to commence ILI case reporting as soon as an upswing in influenza cases in Sydney was recognised through
laboratory surveillance. During the ILI follow-up period, parents were asked to report to us whenever a subject child developed an
ILI, defined as fever ≥37Á8°C or feeling feverishness according to the carer’s assessment, plus at least one of the following
symptoms: cough, rhinorrhoea/nasal congestion, sore throat. During the ILI-reporting period, each family received a weekly e-mail,
text message or telephone call to remind them to contact the study team immediately if a child developed an ILI. Before the ILI-
reporting period, e-mail addresses and mobile telephone numbers of all parents/guardians were confirmed with parents/guardians to
ensure that they received messages. In addition, during the 1 week of the ILI-reporting period, all parents/guardians were
contacted/recontacted until they indicated that they had received the message that the ILI- reporting period had commenced.
Parents/guardians were provided with plastic shaft rayon-budded swabs and plastic trans port tubes with a foam pad reservoir
soaked in viral trans port medium (Virocult MW950; Medical Wire & Equipment, Wiltshire, UK). They were given verbal and written
instructions on how to collect a nose swab and a throat swab from the subject whenever an ILI occurred. We as ked for a nos e swab
to be done first and did not ins ist on a throat swab if the parents felt uncomfortable to collect one. Parents mailed swabs to the
Queens land Paediatric Infectious Diseases Laboratory (QPID), where they were stored at 80°C until tested.
Laboratory methods
Swabs were tes ted for 19 respiratory viruses by qualitative real-time PCR, 17–19 including influenza viruses A and B (Flu A, Flu B),
adenovirus (AV), human rhinovirus (HRV), polyomaviruses (JCV, BKV, WUV, KIV), parainfluenza viruses 1, 2, 3 (PIV1, PIV2, PIV3),
coronaviruses (HCoV- OC43, HCoV-NL63, HCoV-229E, HCoV-HKU1), human metapneumovirus (HMPV), bocavirus (BV) and
human respiratory s yncytial viruses A and B (hRSV A, hRSV B). All RNA virus assays used Qiagen One-Step RT-PCR, Qiagen
(Melbourne, Victoria, Australia), and all DNA virus assays used Qiagen Quantitect Probe PCR Mix, Qiagen, Australia. In order to
asses s extraction quality, specimens were spiked with equine herpes virus-1 (EHV-1) and tes ted for EHV-1 using a duplex real-time
PCR as say. Any samples that failed the EHV- 1 quality control were re-extracted. In order to monitor quality of s pecimen collection,
specimens were tested for human endogenous retrovirus 3 (ERV3) using a duplex real-time PCR assay. In addition, the positive
controls included in each PCR run were monitored for any shift in cycle thres hold values to detect problems within individual runs.
ILI outcome assessment
In order to determine health impacts of the ILI event upon the child and the household, study staff interviewed the child’s
parent/guardian by telephone 2 weeks after the onset of each ILI in subject children, and if, at that time, the subject child still had
ILI symptoms other than a dry cough, another telephone interview was arranged and conducted 2 weeks later. Data collected
included the nature and duration of symptoms, severity of illness , intrahousehold spread, visits to healthcare providers and
medication usage. Severe ILIs were defined as having at least one of the following features: fever ≥5 days, any s ymptom other than
dry cough persisting more than 14 days, otitis media, suspected bacterial respiratory infection or admiss ion to hos pital.
ILIs in household members
During ILI outcome as sess ment interviews, parents were as ked to report ILIs in household members in the week before and the
week after the onset of an ILI in the subject children. ILI attack rates in hous ehold members were calculated for the week following
ILI onset in subject children.
Statistical analysis
Statistical tests used were one-way ANOVA for continuous variables, chi-square tests for categorical data (SPSS 19, Chicago, IL,
USA) and t-tes ts for normally distributed data to compare means. Poisson regression (STATA/SE 120, StataCorp LP, TX, USA) was
used to compare incidence rates. We used person-year in the calculation.
2
3
For children who became (fully) vaccinated in the few days after the formal start date of follow-up (30 July 2010), we deducted the
number of days until the children became (fully) vaccinated from the surveillance time. Meta-Analyst 3Á13 (Tufts Medical Centre,
Boston, MA, USA) was used to calculate the probability of a virus being the sole agent identified from nose/throat s wabs during
an ILI episode (binary analysis with model type Random (D/L) and random method Der-Simonian Laird).
Ethical approval
The study was approved by the Human Research Ethics Committee at The Children’s Hospital at Westmead and was registered
with the Australian New Zealand Clinical Trials Registry (ANZCTR, ACTRN12610000319077).
Results
The cohorts
Between March and August 2010, we enrolled 399 children, of which 95Á6% completed follow-up (exclusions: 9 were of incorrect
age and nine others withdrew without contributing to the ILI-reporting period); therefore, 381 children (208 males) from 358
households participated. The ILI-reporting period was 30 July to 31 October 2010. There were just four subjects who were enrolled
slightly late during the first week of the ILI-reporting period – their person-year contribution to the ILI follow-up period was
adjusted to be from the time of joining the cohorts (one was fully vaccinated, one partially vaccinated and two unvaccinated). The
majority (89%) of enrolled children attended CCCs. On commencement of ILI surveillance, the mean age of enrolled children was
2Á3 years (0Á9–3Á4 years). At that time, 83 (22%) children fulfilled the criteria for ‘fully vaccinated’ against influenza
A/California/7/ 2009 (H1N1) (A(H1N1)pdm09); 60 (16%) were ‘partially vaccinated’, and 238 (62%) were unvaccinated (see Table 1).
The great majority given influenza vaccine (94Á4%) com- pleted vaccination by the beginning of the formal ILI follow-up period;
eight subjects received their s econd dose of influenza vaccine after follow-up began (between 1 August and 3 September). These
subjects were primarily assigned to the fully vaccinated cohort, and for incidence rate calculations, their person-time contributions
to the partially and fully vaccinated cohorts were determined using 1 week after the date of receipt of the second dose of vaccine
as the time-point at which they changed s tatus. All vaccines given were licensed unadjuvanted inactivated split virion vaccines.
There were no demographic differences between the vaccinated children, partially vaccinated children and unvaccinated children
(Table 1).
ILI episodes
During the 13 weeks 30 July to 31 October 2010, parents/ guardians reported a total of 124 ILI episodes in 105 children (13 had two
ILIs, three had three). Symptomatic ILIs were reported significantly more commonly in recipients of influenza vaccination (Table 1).
Non-influenza ILIs were more common among fully vaccinated subjects (33 non-influenza ILIs, 1Á59/person-year of observation)
and partially vaccinated subjects (20 non-influenza ILIs, 1Á54/ person-year) than among unvaccinated subjects (59 non- influenza
ILIs, 0Á99/person-year, P = 0Á001, rate ratio 1Á6, vaccinated versus unvaccinated, Table 1). Excluding ILIs from which no virus
was identified made no significant difference to this finding. No particular res piratory virus, with the exception of AV, was found
less frequently in ILI episodes among unvaccinated subjects compared to fully or partially vaccinated subjects (P = 0Á04, data not
shown). The vaccination s tatus of subjects was not correlated with the mean number of doctor (GP, emergency department or
specialist) visits made in response to non-influenza ILIs (P = 0Á45, data not shown). Nor were there significant differences in the
mean duration of ILIs (P = 0Á95) or use of antibiotics (P = 0Á92) for non-influenza ILIs between fully or partially vaccinated
subjects and unvaccinated subjects (data not shown). However, before enrolment in the study, there was evidence for an
increased use of healthcare services in both the partially and fully vaccinated groups with significantly higher rates of prior
hos pitalisation, hearing tests and grommet insertion, whereas the incidence of past otitis media was not significantly different
between the groups (Table 1).
4
Increased use of thes e healthcare services did not, however, prove significant when added to a multivariate model to predict non-
influenza ILI in study subjects (data not shown). The apparent greater risk of non-influenza ILI in influenza-vaccinated s ubjects did not
vary significantly over time, compared with non-vaccinated participants. For example, the rates of non-influenza ILI between the two
groups (vaccinated versus non-vaccinated) were 1Á88/person-year and 1Á09/person-year, respectively (rate ratio = 1Á72, P < 0Á001) in
the first half of follow-up period, while the rates in the second half were 1Á40/person-year and 0Á97/ person-year, respectively (rate ratio
= 1Á45, P = 0Á02).
Follow-up of ILIs
Telephone follow-up 2 weeks after ILI ons et was conducted for all 124 ILIs. Symptoms other than dry cough persisted in 29 ILIs at that
time. At the 4-week telephone interview, symptoms other than dry cough still persisted in eight ILIs. Data on ILI duration were not
available for five ILIs. The most commonly reported s ymptoms (data available for 121 of the 124 episodes ) were rhinorrhoea 92% (111),
cough 63% (76), decreased activity 27% (33), gas trointestinal symptoms 22% (abdominal pain, diarrhoea, vomiting; 27) and s ore throat
20% (24). Fever was documented in 84 ILIs (68%). The mean temperature was 38Á7°C. The frequency of documented fevers was similar
in each of the three cohorts – see Table 1. Managing the ILIs required 134 GP visits (for 70 ILIs, 35 of which required more than one GP
visit), 106 pharmacy visits (64 ILIs), five emergency department visits and three specialist visits – evenly distributed between the cohorts
(data not shown). No hospitalisations were reported. Antibiotics were used for 52 ILIs and 73 were treated with analgesic/antipyretics
evenly distributed between the cohorts (data not shown). The median duration of ILIs was 8 days , but 16 (13%) lasted more than 28
days. Forty-four ILI episodes (35%) met our definition of ‘severe ILI’: 15 had otitis media, 31 had symptoms other than post-ILI dry
cough persisting >14 days, and 9 had fever persisting ≥5 days (some overlap).
Virus identification
Swab samples were available for 117 (94%) of the 124 ILI episodes, both nose and throat (69 ILIs) or nose only (48 ILIs). The quality of
samples was high in terms of extraction and cell collection; only one sample failed EHV testing and ERV3 was detected in all but one
specimen, and this s pecimen was negative of all other viruses. A total of 175 viruses were identified from 103 ILIs (see Figure 1). Multiple
viruses were detected in 52 (44%) of the swabbed ILIs 38 ILIs yielded two viruses each, nine yielded three viruses , four yielded four,
and one yielded five. The probability of a virus being the sole agent identified from nose/throat swabs during an ILI episode is s hown in
Figure 2. Influenza A(H1N1)pdm09, which was the sole virus causing 5 ILIs, was the only virus consistently identified as the sole agent
from all ILIs with which it was associated. Although coronavirus NL63 (3 of 5 ILIs in which they were identified) and rhinovirus (15 of 39
ILIs in which they were identified) were frequently identified as sole agents of ILIs, that tendency was not statistically different to the
probabilities of the other non-influenza viruses being solely identified. No particular virus or virus combination or multiplicity of virus
infection was associated with any particular symptom or combination of symptoms or with greater frequency of antibiotic or
analges ic/antipyretic use, GP visits or other healthcare service usage. One or more of the polyomaviruses WUV and KIV were more
commonly identified in children aged <2 years (P = 0Á05), and adenoviruses were more common in females (P = 0Á03) – data not shown.
Rhinovirus alone or in combination with other viruses was as sociated with longer duration of ILI than other viruses (P = 0Á02). None of
these values were corrected for multiple testing. Of the five children who had influenza A(H1N1)pdm09 infection, one was fully
vaccinated, one was partially vaccinated (1 dose of Panvax, CSL, in October 2009), and three were not vaccinated against influenza. The
management of the A(H1N1) pdm09 infections required GP visits for four of the children; three received antipyretic/analgesic
medications, and two received antibiotics.
Yield of viruses by swabbing site
Nose swabs were collected from 117 swabbed ILIs, while throat swabs were collected from 69. The use of neither nose nor throat swabs
was not s ignificantly differently distributed acros s the three cohorts. Furthermore, there was no statistical difference in the number of
throat s wabs collected from the three study groups (P = 0Á20). Swabs were not combined prior to tes ting. One or more viruses were
detected in 88% of swabbed ILIs. Nos e swabs more often yielded viruses 102/117 (87%) – than did throat swabs 45/69 (65%), P <
0Á001.
5
Nose swabs yielded more viruses per swab than did
throat swabs (161 virus identities from 117 nose s wabs
= 1Á38 viruses/swab compared to 59 virus identities
from 69 throat swabs = 0Á86 viruses/swab, P < 0Á001).
Limiting the comparison of virus yields from nos e
versus throat swabs to ILIs from which both nose and
throat swabs were taken (n = 69) gave the same rates of
virus identification (1Á37 viruses per swab for nose
swabs, 0Á86 viruses per swab for throat swabs, P =
0Á001) with 61 (88%) of 69 nose swabs yielding a virus
and 45 (65%) of 69 throat swabs yielding a virus, P =
0Á002.
ILI transmission within households
In the week before onset of their ILIs, only nine subjects were exposed to one or more household members with ILIs (three other
children and eight adults). In the week after onset of the subject’s ILI, eight other children (154 exposed, 5% attack rate) and 38
adults (244 exposed, 16% attack rate) in the ill subjects’ household reported ILIs. Adult household members more often developed
an ILI in the week after ILI onset in subject children than did child members of the households, P = 0Á001 (asymptomatic carriage
and trans miss ion were not taken into account as it could not be identified). No virus was more likely than any other to be
transmitted from the ill subject to members of the household.
Discussion
In the 2010 Southern Hemisphere influenza season in Sydney, Australia, we found that young children suffered relatively often
from ILIs, but less than in previous studies. 20 The ILIs were caus ed by many different viruses, most commonly rhinoviruses and
adenoviruses. Adenovirus was more commonly found in females, an association which has not been reported previously 21,22 and
may be due to chance as no correction for multiple testing was performed. In contrast to others, we detected few RSV infections
14,20,23,24 probably because RSV infections peaked in Sydney during June and July 2010 and had declined significantly in frequency
by the time we commenced obs ervations for ILIs in the study participants (from 30 July 2010). We found only 5 ILIs caused by
influenza viruses – all A (H1N1) pdm09. Their illnesses were little different to the ILIs experienced by the children from whom other
viruses were identified (data not shown). However, the small number of influenza infections is consistent with the low degree of
influenza activity during 2010, 25 limiting the power of this study to detect differences in influenza infection rates. We did, however,
unexpectedly find that non-influenza ILI occurred about 1Á6 times more commonly in children vaccinated with one or two doses of
the influenza vaccine than in unvaccinated children.
6
These results support the findings of a recent RCT reported by Cowling et al. 26 Cowling’s study in Hong Kong concluded that non-
influenza ARI may be detected at a higher rate in children for a short period after they received influenza vaccine. The non- influenza
virus incident rate ratio (IRR) was higher in the Hong Kong s tudy (4Á4 versus 1Á6), but there are some key differences to our study,
including age of subjects, follow-up period, proportion of illnesses swabbed and proportion of swabs yielding viruses. As with all
obs ervational studies, bias must be cons idered. Vaccinated and unvaccinated cohorts in Sydney were demographically s imilar (Table 1);
however, lack of blinding by vaccination status makes it difficult to rule out selection or measurement bias. We could find no evidence of
different parental responses to ILIs in vaccinated and unvaccinated children: parents of vaccinated children were no more likely to seek
medical care during an ILI. However, we did find that health-seeking behaviours, recorded on enrolment (before the ILI observation
period), s uch as hospitalis ation (any cause), hearing tests and grommet insertion were significantly more common in the vaccinated
groups, suggesting that families that vaccinate children have a prior preference for greater healthcare service usage. This may be a
partial explanation for the obs erved difference in ILI frequency between the groups; however, prior access to any of these healthcare
services did not predict the frequency of reported ILI. Cowling et al. proposed pos sible explanations ranging from an unknown biological
mechanism by which vaccine-induced immunity to influenza was accompanied by decreased immunity to other respiratory virus to a
temporary non-specific immunity (interferon- and/or cell-mediated related) to other respiratory viruses after wild influenza infection. A
formal biological explanation is lacking. A recent US obs ervational (case–control) study has not found an association between influenza
vaccination and detection of non-influenza respiratory viruses 27 . Re-analysis of observational studies or preferably new RCTs with high
parent-collected specimen availability is required to further examine this phenomenon. It should be a priority to determine whether a
caus al as sociation exists, whether it is consistent across vaccines and populations and whether any observed increase in the rate of
non-influenza respiratory virus identification outweighs the benefit of seasonal TIVs in children. In nearly half (44%) of the nose/throat
swabs, multiple viruses were detected. Other studies in different s ettings, us ing a variety of definitions for ILI, have reported diverse
virus aetiologies for ILIs, but, in general, with lower frequencies of virus co-infection than we report. 14,20,23,24,28 Our finding may be
explained by the large number of viruses for which we tested and also by our high rate of swabbed ILIs being positive (88%).
While we found no increased severity or number of symptoms with multiple virus compared with single virus infection, this study lacked
power to tease apart the relative significance of each virus, virus combinations and multiplicity of infection. A simultaneously sampled
asymptomatic control group would have been us eful to explore further the meaning of multiple virus identification. Interestingly,
influenza A(H1N1)pdm09 was the only virus constantly identified as the sole virus from ILIs. However, there were too few cas es (five
only) to permit a firm conclusion about this. We found that nose swabs were more effective than throat s wabs for detecting respiratory
viruses in young children with ILIs. Also, parents more frequently collected nose swabs than throat swabs from their children,
suggesting that they may be more acceptable. In our study, we detected the polyomaviruses WUV and KIV at higher frequencies
(mainly as co-infections) than other investigators. 29–38 Children aged <2 years were more often infected than older children, but this
barely reached a statistical significance. To date, the pathogenicity and clinical significance of WUV and KIV (discovered in 2007) 3,4
remain unclear and studies, conducted in a variety of settings and with a variety of respiratory disease definitions, have yielded
inconsistent results. Key strengths of our study include the high rate of specimen collection (94% of ILIs were swabbed) and the high
rate of virus detection in swabbed ILIs (88% of all cas es swabbed yielded at least one virus). We believe that parent-collected specimens
combined with mail return of the specimens to the laboratory can be cons idered a reliable means of virus detection for studies s uch as
ours, partly because children are sampled earlier when viral loads may be higher.
Limitations
The participant characteristics are somewhat different to the general Australian population. Participating households had a higher
income (83% of the studies households compared to 30% of Australians had income of $ 2000/week or more), 39 the mothers were slightly
older (33Á1 years compared to 30Á1 years in the general population) 40 and were more likely to live with a partner (married or de facto
97% compared to 88%) 41 and, because we recruited in CCCs, 89% of the study population were in formal child care compared to 35% of
Aus tralian children aged 0–4 years. 42 At the start of the ILI follow-up period, we established that all parents/guardians were receiving
reminder messages, and during the course of the ILI follow-up period, we s poke to parents/guardians of 52% of the enrolled children
(evenly distributed across the cohorts data not shown). However, we did not contact all parents/guardians after the ILI follow-up
period in order to determine whether they had not reported ILIs. We did
record at enrolment data on prior healthcare service usage (e.g. hospitalisation) and this was higher in vaccinated children; all this might
have biased the research to show a higher frequency of ILI in influenza vaccinees . The open-
label cohort design is also open to unmeasured confounding.
7
Conclusion
Influenza-like illness is common in children, and the burden on their families may be considerable. Many different respiratory
viruses are responsible for ILIs in children. In this study, conducted after the RSV season, adeno- and rhinoviruses were the most
commonly detected viruses . Symptom profiles were similar among the different viruses, and the rate of virus co-infection was high.
Recipients of influenza vaccines had about 1Á6 times more ILI episodes than did unvaccinated children, and although this may be
at least partly explained a healthcare service-seeking bias, further investigations are warranted into whether influenza vaccine
increases the risk of non-influenza ILI, as healthcare-seeking behaviour did not predict ILI in a regression model. Nose swabs
collected by parents had a high yield of respiratory viruses when using multiplex PCR methods and had s ignificantly more viruses
compared to throat swabs . In addition, parents appeared to feel more comfortable in performing nose than throat s wabs. This is of
relevance to future studies requiring parent-collected samples for PCR analysis.
Addendum – List of Authors
Dr. Alexa Dierig contributed substantially to the design of the study, helped with analysis and interpretation of data and wrote and
revised the intellectual content. She was also the study coordinator. Dr. Leon Heron contributed s ubstantially to the concept and
design of the study, helped with analys is and interpretation of data and wrote and revised the intellectual content. A/Prof Stephen
Lambert contributed substantially to the concept and des ign of the study, helped with analysis and interpretation of data and wrote
and revised the intellectual content. Dr. Jiehui Kevin Yin analysed the data, helped with their interpretation and revised the
intellectual content. A/Prof Julie Leask contributed substantially to concept and design of the study and revised the intellectual
content. Maria Yui Kwan Chow helped with analysis of data and revised the intellectual content. Prof Theo Sloots contributed
substantially to the concept and design of the study and helped with the analysis of data. Prof. Michael Nissen contributed
substantially to the concept and design of the study and helped with the analysis of the data. Dr Iman Ridda helped with the
interpretation of data and wrote and revised the clinical content. Prof Robert Booy contributed substantially to concept and design
of the study, helped with analysis and interpretation of data and also with writing and revising of the intellectual content. He was
the supervisor of the whole project. All authors approved the final version.
Funding
This work was supported by a grant from the Australian Research Council and Sanofi Pasteur (industry partner) with kind
assistance from KU Children’s Services.
Acknowledgements
We thank all participating families, the research nurses and the staff at the Queens land Paediatric Infectious Diseases Laboratory.
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http://www.ausstats.abs.gov.au/Ausstats/subscriber.nsf/ 0/573FA1277E2378E3CA25765700162238/$File/44020_June% 202008%20(reissue).pdf. (Accessed 30 July 2012). 17 Lu
X, Holloway B, Dare RK et al. Real-time reverse transcription-PCR assay for comprehensive detection of human rhinoviruses. J Clin Microbiol 2008; 46:533–539. 18 O’Grady
KA, T orzillo PJ, Rockett RJ et al. Successful application of a simple specimen transport method for the conduct of respiratory virus surveillance in remote Indigenous communities
in Australia. T rop Med Int Health 2011; 16:766–772. 19 Maunula L, Klemola P, Kauppinen A et al. Enteric Viruses in a Large Waterborne Outbreak of Acute Gastroenteritis in
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... [9][10][11][12][13] While much literature exists regarding influenza burden, we know that children are also are more at risk than adults for a wide swath of respiratory pathogens including rhinovirus, parainfluenza virus, and adenovirus. 8,[14][15][16][17] Children are also recognized as important sources of respiratory illness within households. 18 Retrospective analyses of both vaccination campaigns and outbreak dynamics similarly attest to the importance of children in disease transmission. ...
... A number of papers, including several from childcare-specific populations, have found no association between codetection and illness severity. 17,120,121 Others have found an increased risk of codetectionassociated severity, though most of these conclusions are based on hospitalized populations (which skew towards severe compared to the more benign illness of community-based surveillance). 16,104,122,123 Our results suggest no association between codetection and illness severity; there was no statistically significant difference between single virus and codetection illnesses in terms of subjective worst day of illness, duration of illness, contact with healthcare providers, or hospitalization. ...
... While previous studies have specifically focused on childcare illness they lacked a non-childcare comparison group. 17,44,45,117 Analysis in this Aim provides a direct comparison of children who do and do not attend childcare. Moreover, the systematic case detection strategy of HIVE helped to identify many cases of mild respiratory disease that would have remained undetected in more common hospital-based studies, which skew towards more severe ARI cases. ...
Thesis
Young children experience high rates of morbidity and mortality associated with acute respiratory illness (ARI) and are noted contributors of ARI risk to their households as well. It is also well established that ARI risk is higher in children who attend out-of-home childcare, compared to children cared for at home. Using prospective illness surveillance data collected regionally in southeast Michigan, the four Aims of this Dissertation add pertinent information to better quantify, characterize, and mitigate childcare-associated ARIs in both children and their families. Aim 1 investigates the association between household childcare use and illness risk for family members. Adjusted mixed-effects Poisson regression models reveal no association between whether or not a young child concurrently attends childcare and the incidence rate of reported ARI in family members. Likewise, we find no evidence for any relevant effect modification of the association by household or individual characteristics. Contrary to our original hypothesis, out-of-home childcare does not appear to be linked to higher illness incidence in associated families; several reasons are offered to explain these null findings. In Aim 2, we shift our focus to the children themselves. Previous research has shown that childcare attendees are ill more often than their counterparts cared for at home—we were interested in whether childcare-associated ARI was also characteristically different in terms of illness etiology and severity. In this analysis, we compare molecular test results from ARI episodes of children who do and do not attend childcare. Adjusted mixed-effects logistic regression models reveal higher odds of both adenovirus and human metapneumovirus infection in childcare attendees, yet lower odds of rhinovirus infection; we found no evidence for a difference in illness severity. Furthermore, we statistically show that the pool of viruses causing childcare illness is significantly more diverse than that of homecare illnesses. Our results support the idea that childcare children are sick more than homecare children because they are exposed to a wider array of viruses early in life. Aim 3 steps back to assess surveillance data in the context of the larger community. Three prospective illness surveillance networks of southeast Michigan operate in distinct population subgroups; we wanted to determine how different surveillance settings influenced observed epidemic patterns. Using influenza as our outcome of interest, we find that a household, ambulatory clinic, and hospital network all capture similar epidemic trends across six surveillance seasons. Annually, all three systems report comparable distributions of influenza A and B and record similar timing in epidemic activity start and peak activity. Broad agreement between network epidemic curves should be reassuring for local public health departments that may only rely on one system of active influenza surveillance. Aim 4 focuses on the role of illness surveillance in childcare programs. Epidemiologic data serve as an important tool in timely outbreak intervention; we wanted to understand how illness surveillance in childcare could be more effectively leveraged to mitigate childcare disease outbreaks. Using results from a series of semi-structured focus groups among childcare providers, we find that providers are eager to use epidemiologic data in their programs to corroborate their subjective experiences and policy decisions. Our findings offer a framework by which surveillance data could be collected and packaged in a more beneficial way for providers and parents, and—ideally—help to prevent childcare associated illness outbreaks.
... Additionally, immunologic interference related to vaccination may modify the risk of ARI in potentially different ways. For example, lack of viral interference has been hypothesized to increase the risk of ARI after influenza vaccination while temporary nonspecific immunity has been hypothesized to decrease the risk of ARI after influenza vaccination [8][9][10]. ...
... Previous studies have investigated the risk of ARI after influenza vaccination with conflicting results which may reflect variations in study design [9][10][11][12]. For example, some studies included study populations recruited from cases of medically attended illness which may not reliably estimate the population incidence of ARI [11]. ...
... For example, some studies included study populations recruited from cases of medically attended illness which may not reliably estimate the population incidence of ARI [11]. Use of a cohort study design comparing vaccinated to unvaccinated individuals may be better, but can also be prone to bias if groups are not well-matched groups and/or unmeasured confounders exist [10]. Additionally, previous investigations of ARI risk after vaccination, lacking a biologically plausible temporal relationship to the vaccine may not accurately estimate risk of ARI attributed to the vaccine itself [9]. ...
Article
Background: A barrier to influenza vaccination is the misperception that the inactivated vaccine can cause influenza. Previous studies have investigated the risk of acute respiratory illness (ARI) after influenza vaccination with conflicting results. We assessed whether there is an increased rate of laboratory-confirmed ARI in post-influenza vaccination periods. Methods: We conducted a cohort sub-analysis of children and adults in the MoSAIC community surveillance study from 2013 to 2016. Influenza vaccination was confirmed through city or hospital registries. Cases of ARI were ascertained by twice-weekly text messages to household to identify members with ARI symptoms. Nasal swabs were obtained from ill participants and analyzed for respiratory pathogens using multiplex PCR. The primary outcome measure was the hazard ratio of laboratory-confirmed ARI in individuals post-vaccination compared to other time periods during three influenza seasons. Results: Of the 999 participants, 68.8% were children, 30.2% were adults. Each study season, approximately half received influenza vaccine and one third experienced ≥1 ARI. The hazard of influenza in individuals during the 14-day post-vaccination period was similar to unvaccinated individuals during the same period (HR 0.96, 95% CI [0.60, 1.52]). The hazard of non-influenza respiratory pathogens was higher during the same period (HR 1.65, 95% CI [1.14, 2.38]); when stratified by age the hazard remained higher for children (HR 1·71, 95% CI [1.16, 2.53]) but not for adults (HR 0.88, 95% CI [0.21, 3.69]). Conclusion: Among children there was an increase in the hazard of ARI caused by non-influenza respiratory pathogens post-influenza vaccination compared to unvaccinated children during the same period. Potential mechanisms for this association warrant further investigation. Future research could investigate whether medical decision-making surrounding influenza vaccination may be improved by acknowledging patient experiences, counseling regarding different types of ARI, and correcting the misperception that all ARI occurring after vaccination are caused by influenza.
... 13 In another prospective Australian study in children aged 6 months to 3 years reporting ILI, rhinovirus was again the most commonly detected. 15 However, in contrast to our results, adenovirus was detected at the same frequency as rhinovirus, followed by parainfluenza 3, polyomavirus, hMPV and HBov. 15 Influenza (A/H1N1) and RSV were relatively uncommon; approximately 40% of children were fully or partially vaccinated against influenza. ...
... 15 However, in contrast to our results, adenovirus was detected at the same frequency as rhinovirus, followed by parainfluenza 3, polyomavirus, hMPV and HBov. 15 Influenza (A/H1N1) and RSV were relatively uncommon; approximately 40% of children were fully or partially vaccinated against influenza. Rhinovirus is not always the most commonly detected virus in children with respiratory disease. ...
Article
Background: Better population data on respiratory viruses in children in tropical and southern hemisphere countries is needed. Methods: The epidemiology of respiratory viruses among healthy children (6 months to <10 years) with influenza-like illness (ILI) was determined in a population sample derived from an influenza vaccine trial (NCT01051661) in 17 centers in eight countries (Australia, South East Asia and Latin America). Active surveillance for ILI was conducted for approximately 1 year (between February 2010 and August 2011), with PCR analysis of nasal and throat swabs. Results: 6266 children were included, of whom 2421 experienced 3717 ILI episodes. Rhino- virus/enterovirus had the highest prevalence (41.5%), followed by influenza (15.8%), adeno- virus (9.8%), parainfluenza and respiratory syncytial virus (RSV) (both 9.7%), coronavirus (5.6%), human metapneumovirus (5.5%) and human bocavirus (HBov) (2.0%). Corresponding incidence per 100 person-years was 29.78, 11.34, 7.03, 6.96, 6.94, 4.00, 3.98 and 1.41. Except for influenza, respiratory virus prevalence declined with age. The incidence of medically- attended ILI associated with viral infection ranged from 1.03 (HBov) to 23.69 (rhinovirus/ enterovirus). The percentage of children missing school or daycare ranged from 21.4% (HBov) to 52.1% (influenza). Conclusions: Active surveillance of healthy children provided evidence of respiratory illness burden associated with several viruses, with a substantial burden in older children.
... Regarding influenza-like illness (ILI) one study identified that in addition to influenza(s) there are at least eight common viruses causing ILI (Taylor et al 2017). In another study, 44% of ILI respiratory swabs yielded multiple viruses (Dierig et al 2014). ILI can also be caused by bacteria, fungi, and parasites. ...
Article
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The weighted population density for 349 English local government areas, and the raw population density for a further 58 areas from Northern Ireland and Scotland, were used to demonstrate the role of high population density in the volatility associated with year-to-year total deaths and of excess winter mortality (EWM). Volatility in EWM was measured as the standard deviation over a 20-year period while for total deaths looked at the absolute value of the year-to-year difference expressed as standard deviation equivalents. The volatility in EWM for the most densely populated areas was almost double that of least populated areas. This reached a plateau when weighted population density exceeded 8,000 persons per square Km. For total deaths, the year-to-year average difference was around 35% higher when population density exceeded 7,000 persons per square Km. Death culminates a six-month period of increasing admission to acute hospital which can account for 55% of a person's lifetime use of a hospital bed. Hence the volatility in death is a good measure of volatile costs and capacity pressures. Volatility in costs will follow the year-to-year pattern while hospital capacity pressures will tend to follow the EWM pattern, although with time lags. Population density acts to facilitate the spread of infectious agents, which increasingly arrive via international air travel. Population density is also associated with air pollution which acts to increase systemic inflammation in the population, thereby rendering them more susceptible to infection and adverse outcomes. Dysregulation of the inflammatory response to infection in the elderly implies that infection(s) with otherwise seemingly 'trivial' pathogens can then lead to surges in admissions and deaths which are then reported as a variety of (secondary) diagnoses. Unexplained patterns in average length of stay and the gender ratio for admissions for common conditions, which have previously been ignored, support this explanation. Similar unusual trends in the volatility associated with sickness absence among health care workers are also observed. Key Points • Population density is a proxy for air pollution and person-to-person contact, both of which enhance the transmission of infectious diseases • Highest population density was associated with the highest volatility in year-to-year deaths and of Excess Winter Mortality (EWM) • Transmissible infections work via the inflammatory immune response to promote acute illness and death in a variety of respiratory and pre-existing conditions, i.e., they often act as the trigger for final demise • Human pathogens are now known to interact in complex ways • Multiple infections are far more common than realized • Unexplained trends and spikes in hospital average length of stay and the ratio of male to female admissions seemingly arise from the network of such infectious outbreaks • Unusual volatility in sickness absence rates among health care workers is also related to population density • The higher volatility associated with population density implies that costs associated with the population of large cities will be more volatile than for least populated areas, i.e., there is higher financial risk and greater opportunity for insurance revenue to be out of sync with insurance costs • The foundations for the health insurance underwriting cycle appear to lie in the time patterns arising from this complex and ever-changing infectious landscape • For the hospitals situated in large cities, this will manifest in more volatility in winter capacity pressures. However, this will be partly mitigated by larger hospital size necessitated in the more densely populated areas. A 14-minute interview regarding the series is available, https://jjunland.egnyte.com/dl/CPdNnjCVle/?
... One study [44] demonstrated an increased hazard of acute respiratory infection caused by noninfluenza respiratory pathogens in the 14 days post-vaccination compared to children who had not yet received influenza vaccination. Other studies have also identified a statistically significant increased risk of non-influenza respiratory pathogens among influenza vaccine recipients in children [45] and a higher occurrence of non-influenza ILI in vaccinated children over their unvaccinated peers [46]. Our findings show that despite accounting for less than 6% of vaccinated individuals, children aged under 5 ranked the highest for overall respiratory consultations, resulting in a crude consultation rate over seven times higher than the elderly, who accounted for 55.5% of total vaccinations. ...
Article
Full-text available
Influenza, a vaccine preventable disease, is a serious global public health concern which results in a considerable burden on the healthcare system. However, vaccine hesitancy is increasingly becoming a global problem. One prevalent misconception is that influenza vaccinations can cause the flu. We carried out this study to determine whether people undertaking influenza vaccination presented less with acute respiratory tract infection (ARTI) and influenza-like-illness (ILI) following vaccination. We utilised the Oxford Royal College of General Practitioners Research and Surveillance Centre sentinel database to examine English patients who received vaccination between 2014/2015 and 2018/2019. Of the 3,841,700 influenza vaccinations identified, vaccination details and primary care respiratory consultation counts were extracted to calculate the relative incidence (RI) per exposure risk period using the self-controlled case series methodology. Results showed a significant increase in the RI of respiratory consultation rates within fourteen days of vaccination across all five years. Less than 6.2% of vaccinations led to consultations for ARTI or ILI in primary care (crude consultation rate 6196 per 100,000). These findings, particularly if confirmed in further research, may reduce the risk of cross-infection between waiting patients and increase uptake of influenza vaccine. Keywords: influenza vaccine; general practice; vaccine hesitancy; primary care
... In line with this, several recent studies suggested a potential beneficial effect of influenza vaccination 68 on susceptibility to COVID-19 [12,13]. Despite earlier reports that have shown little or opposite effects 69 of influenza vaccines on heterologous infections in children [14][15][16][17][18][19]. With the flu season on its way and 70 influenza vaccination campaigns starting off soon, it is paramount to clarify the exact effects of influenza 71 vaccination on the incidence and the disease course of COVID- 19. ...
Preprint
Full-text available
Every year, influenza causes 290.000 to 650.000 deaths worldwide and vaccination is encouraged to prevent infection in high-risk individuals. Interestingly, cross-protective effects of vaccination against heterologous infections have been reported, and long-term boosting of innate immunity (also termed trained immunity ) has been proposed as the underlying mechanism. Several epidemiological studies also suggested cross-protection between influenza vaccination and COVID-19 during the current pandemic. However, the mechanism behind such an effect is unknown. Using an established in-vitro model of trained immunity, we demonstrate that the quadrivalent inactivated influenza vaccine used in the Netherlands in the 2019-2020 influenza season can induce a trained immunity response, including an improvement of cytokine responses after stimulation of human immune cells with SARS-CoV-2. In addition, we found that SARS-CoV-2 infection was less common among Dutch hospital employees who had received influenza vaccination during the 2019/2020 winter season (RR = 0,61 (95% CI, 0.4585 - 0.8195, P = 0.001). In conclusion, a quadrivalent inactivated influenza vaccine can induce trained immunity responses against SARS-CoV-2, which may result in relative protection against COVID-19. These data, coupled with similar recent independent reports, argue for a beneficial effect of influenza vaccination against influenza as well as COVID-19, and suggests its effective deployment in the 2020-2021 influenza season to protect against both infections.
... The virus detection rate was higher among symptomatic children (20.1%). Recent investigations from distinct countries have shown viral detection rates of 25.7-80% in respiratory samples obtained from children with acute respiratory infection symptoms [14][15][16]. Positivity rates from previous Brazilian studies ranged from 31 to 85% [17][18][19]. These rates are relatively higher than those found in this study. ...
Article
Acute respiratory infection (ARI) is a major cause of morbidity and mortality worldwide. Most of these infections are caused by viruses. Infections pose as important triggers of acute episodes of chronic respiratory diseases (CRD). This study sought to evaluate the frequency and circulation profile of respiratory viruses among ARI symptomatic patients and completely asymptomatic children in Midwest Brazil. The study enrolled symptomatic children with and without ARI symptoms. During 1 year, 225 nasal respiratory samples were obtained from patients aged 4–14 years old. The samples were screened by multiplex nested-PCR for 16 common respiratory viruses. From 225 samples, 42 had at least one virus detected. Samples from four different patients had multiple viruses detected. The viral detection rate in symptomatic (20.1%) and asymptomatic patients (14.8%) showed no significant difference. The most frequent viruses detected were rhinovirus (28.6%), FLUA (11.9%), adenovirus (11.9%), human bocavirus (HBoV) (11.9%), and respiratory syncytial virus (RSV) antigenic group A (9.5%). Monthly detection rate was higher during the rainy season. RSVs were detected during the months with higher rainfall indexes and higher air humidity, while FLU and HBoV were detected during the winter months. The obtained results reinforce the importance of viral pathogens in pediatric population, emphasizing similar viral occurrence in symptomatic and asymptomatic children.
... Среди бактериальных возбудителей наибольшее значение имеет β-гемолитический стрептококк группы А (БГСА), золотистый стафилококк (S. aureus), кото-рый часто формирует микст-инфекции с респираторными вирусами или в 20% является моновозбудителем воспалительного процесса задней стенки глотки или/и небных миндалин [1]. При этом вне зависимости от природы возбудителя почти 100% больных при острых респираторных заболеваниях жалуются на чувство инородного тела, жжения, першения, сухости в ротоглотке и боль при глотании, различающихся разной степенью выраженности [2]. К другим инфекционным агентам относят Arcanobacterium haemolyticum, где клинические проявления фарингита возникают одновременно со скарлатиноподобной сыпью, Neisseria gonorrhoeae, Staphylococcus aureus, Streptococcus pneumonia, Mycoplasma pneumonia и Chlamydia pneumonia [3, 4]. ...
Article
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Acute inflammatory diseases of the oropharynx dominate the medical aid appealability among all age categories. Such diseases are characterized by poly-ethiology and may form a mixed infection with bacteria and respiratory viruses. Components of bacterial cell walls, toxins, decay products of tissues during cytolysis or apoptosis of cells as a result of massive output of mature virions induce epithelial cells and macrophages for active synthesis of chemokines MCP-1, MCP-3, RANTES, IL-8, which leads to increased inflow of polymorphonuclear leukocytesin to the flammatory focus and a mass release of biogenic amines, lysosomal enzymes, cationic proteins, the release of arachidonic acid, which gradually turns into eicosanoids. Systemic use of NSAIDs can cause NSAID-associated gastropathies. Good accessibility of the target organ in diseases of the oropharynx allows target organspecific delivery of local treatment. Benzidamine hydrochloride (Tantum® Verde) refers to the group of anti-inflammatory suppressor of cytokines and also has a pronounced analgesic effect. The article provides data of the follow-up study of the efficacy of Tantum Verde® in the treatment of acute tonsillopharyngitis in outpatient settings.
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Aykaç K, Karadağ-Öncel E, Bayhan C, Tanır-Başaranoğlu S, Akın MŞ, Özsürekci Y, Alp A, Cengiz AB, Kara A, Ceyhan M. Prevalence and seasonal distribution of viral etiology of respiratory tract infections in inpatients and outpatients of the pediatric population: 10 year follow-up. Turk J Pediatr 2018; 60: 642-652. The aim of this study was to investigate the prevalence and seasonal distribution of respiratory viruses in pediatric patients. Nasopharyngeal swab specimens, demographic and clinical information were collected from 1240 pediatric patients aged < 18 years between 2006 and 2015 in Hacettepe University Children`s Hospital. Multiplex RT-PCR (multiplex reverse transcriptase polymerase chain reaction) was performed to detect viral pathogens. A total of 1240 pediatric outpatients and inpatients who had been admitted to the hospital with symptoms of upper and lower respiratory tract infections (RTIs) were enrolled. Viruses were identified in 339 (27.3%) of cases, with the leading three viruses being respiratory syncytial virus (RSV, 74/339; 21.8%), human rhinovirus (62/339; 18.3%), and multiple viruses (56/339; 16.5%). Most of the patients were diagnosed with lower RTI (264/339; 77.8%) and antibiotics were administered to three quarters of positive patients (254/339; 74.9%). With an overall viral agent detection rate of 27.3%, the findings of the present study suggest that other respiratory pathogens, whether viral or bacterial, may also lead to hospital visits due to respiratory tract symptoms in children.
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Background Respiratory viral infections are a leading cause of mortality worldwide. As many as 40% of patients hospitalized with influenza-like illness are reported to be infected with more than one type of virus. However, it is not clear whether these infections are more severe than single viral infections. Mathematical models can be used to help us understand the dynamics of respiratory viral coinfections and their impact on the severity of the illness. Most models of viral infections use ordinary differential equations (ODE) that reproduce the average behavior of the infection, however, they might be inaccurate in predicting certain events because of the stochastic nature of viral replication cycle. Stochastic simulations of single virus infections have shown that there is an extinction probability that depends on the size of the initial viral inoculum and parameters that describe virus-cell interactions. Thus the coinfection dynamics predicted by the ODE might be difficult to observe in reality. Results In this work, a continuous-time Markov chain (CTMC) model is formulated to investigate probabilistic outcomes of coinfections. This CTMC model is based on our previous coinfection model, expressed in terms of a system of ordinary differential equations. Using the Gillespie method for stochastic simulation, we examine whether stochastic effects early in the infection can alter which virus dominates the infection. Conclusions We derive extinction probabilities for each virus individually as well as for the infection as a whole. We find that unlike the prediction of the ODE model, for similar initial growth rates stochasticity allows for a slower growing virus to out-compete a faster growing virus. Electronic supplementary material The online version of this article (10.1186/s12859-019-2793-6) contains supplementary material, which is available to authorized users.
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In 2010, 65 diseases and conditions were nationally notifiable in Australia. States and territories reported a total of 209,079 notifications of communicable diseases to the National Notifiable Diseases Surveillance System, a decrease of 12% on the number of notifications in 2009. This decrease was largely due to a reduction of influenza compared with the influenza A(H1N1) pandemic 2009. In 2010, the most frequently notified diseases were sexually transmissible infections (86,620 notifications, 41.4% of total notifications), vaccine preventable diseases (61,964 notifications, 29.6% of total notifications), and gastrointestinal diseases (31,548 notifications, 15.1% of total notifications). There were 18,302 notifications of bloodborne diseases; 8,244 notifications of vectorborne diseases; 1,866 notifications of other bacterial infections; 532 notifications of zoonoses and 3 notifications of quarantinable diseases.
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In Nokia city about 450,000l of treated sewage water was for 2days allowed to run into the drinking water supplies of the city due to a personal error of one employee. Within the next 5weeks about 1,000 people sought care at the municipal health centre or regional hospital because of gastroenteritis. Here we report the results of viral analyses performed by gene amplification assays from the earliest water and sewage samples as well as from close to 300 patient samples. The contaminating treated sewage was shown to harbour several enteric viruses known to cause acute gastroenteritis. Likewise, the drinking water sample was positive for noro-, astro-, rota-, entero- and adenoviruses. Noroviruses were also found in 29.8% of stool samples from affected patients, while astro-, adeno-, rota- and enteroviruses were detected in 19.7, 18.2, 7.5 and 3.7% of the specimens, respectively.
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The efficacy of inactivated influenza vaccines is known to be poor in infants and young children. We studied the effect of the adjuvant MF59, an oil-in-water emulsion, on the efficacy of trivalent inactivated influenza vaccine (TIV) in 4707 healthy children 6 to less than 72 months of age who had not previously been vaccinated against influenza. The children were randomly assigned to three study groups, each of which received the assigned vaccines in two doses, 28 days apart, during two consecutive influenza seasons. Two of the groups were given age-appropriate doses of TIV either with or without the MF59 adjuvant, and the third group was given control (noninfluenza) vaccines to assess their absolute and relative efficacy against influenza-like illness, as confirmed by means of polymerase-chain-reaction (PCR) assay. Attack rates of influenza-like illness across both influenza seasons were 0.7%, 2.8%, and 4.7% in the adjuvant, nonadjuvant, and control vaccine groups, respectively. The absolute vaccine efficacy rates against all influenza strains (94 of 110 cases were due to vaccine-matched H3N2 viruses) were 86% (95% confidence interval [CI], 74 to 93) for the MF59-adjuvant vaccine (ATIV) and 43% (95% CI, 15 to 61) for the vaccine without the adjuvant (TIV); the relative vaccine efficacy rate for ATIV versus TIV was 75% (95% CI, 55 to 87). The efficacy rates for ATIV were 79% (95% CI, 55 to 90) in children 6 to less than 36 months of age and 92% (95% CI, 77 to 97) in those 36 to less than 72 months of age, as compared with 40% (95% CI, -6 to 66) and 45% (95% CI, 6 to 68), respectively, for TIV. Antibody responses were higher with ATIV and remained so through day 181. The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group (relative risk, 1.04; 95% CI, 0.98 to 1.09), but systemic events in the older age group were more frequent after administration of ATIV (63%) than after administration of TIV (44%) or the control vaccine (50%). Serious adverse events were distributed evenly across the three vaccine groups. Influenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children. (Funded by Novartis Vaccines and Diagnostics; ClinicalTrials.gov number, NCT00644059.).
Article
In this study, we aimed to determine the prevalance of Respiratory Syncytial Virus, Parainfluenza and Adenovirus leading to infection and influenza in upper respiratory tract by means of cell culture method. In the study, samples belonging to total 171 patients, 97 of whom are adults (56.7%) and 74 of whom are children (43.3%) were used. While 49 of adult sampling group were male (50.5%), 48 of them were female (49.5%), and children sampling group consisted of 33 male (44.6%) and 41 female (55.4%). In the conclusion of the study, while parainfluenza virus couldnt be observed, there was Influenza A in 27 samples (10 children, 17 adults; 15.8%), and there was Adenovirus (ADV) in 11 samples (10 children and 1 adult; 6.4%), and there was Respiratory Syncytial Virus (RSV) in seen 7 samples (6 children and 1 adult; 4.1%) and there was Influenza B virus in 5 samples (4 children and 1 adult; 2.9%) and H5N1 Bird Flu Virus was detected in a patient by means of Real Time PCR method. By means of Roboscreen RoboGene H5N1 Ready-Commercial Kit, RNA investigation was carried out i{dotless}n one sample (a children) H5N1 virus was detected. After planting for MDCK and Hep-2 cells, and by using direct immunoflourescence (IFA) method in order for cytopotic effects to be devided, virus agents were detected. By means of cell culture, Influenza A and B were produced in MDCK cells, and RSV and ADV were produced in Hep-2 cells. Among viral agents, while Influenza A was detected the most, Influenza B was found the least. In our study, we couldnt find a distinction in the rates of viral agents prevalence according to age and genders of the patients by means of chi-square method.
Article
Background: The test-negative control study design is the basis for observational studies of influenza vaccine effectiveness (VE). Recent studies have suggested that influenza vaccination increases the risk of noninfluenza respiratory virus infection. Such an effect could create bias in VE studies using influenza-negative controls. We investigated the association between influenza infection, vaccination, and detection of other respiratory viruses among children <5 years old and adults ≥50 years old with acute respiratory illness who participated in seasonal studies of influenza vaccine effectiveness. Methods: Nasal/nasopharyngeal samples collected from 2004–2005 through 2009–2010 were tested for 19 respiratory virus targets using a multiplex reverse-transcription polymerase chain reaction (RT-PCR) platform. Vaccination status was determined using a validated registry. Adjusted odds ratios for influenza and vaccination status were calculated using three different control groups: influenza-negative, other respiratory virus positive, and pan-negative. Results: Influenza was detected in 12% of 2010 children and 20% of 1738 adults. Noninfluenza respiratory viruses were detected in 70% of children and 38% of adults without influenza. The proportion vaccinated did not vary between virus-positive controls and pan-negative controls in children (P = .62) or adults (P = .33). Influenza infection was associated with reduced odds of vaccination, but adjusted odds ratios differed by no more than 0.02 when the analysis used influenza-negative or virus-positive controls. Conclusions: Influenza vaccination was not associated with detection of noninfluenza respiratory viruses. Use of influenza-negative controls did not generate a biased estimate of vaccine effectiveness due to an effect of vaccination on other respiratory virus infections.
Article
Background: The consequences of influenza in children and adults are mainly absenteeism from school and work. However, the risk of complications is greatest in children and people over 65 years of age. Objectives: To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children, assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness (ILI)) and document adverse events associated with influenza vaccines. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3) which includes the Acute Respiratory Infections Group's Specialised Register, OLD MEDLINE (1950 to 1965), MEDLINE (1966 to November 2011), EMBASE (1974 to November 2011), Biological Abstracts (1969 to September 2007), and Science Citation Index (1974 to September 2007). Selection criteria: Randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years of age. Data collection and analysis: Four review authors independently assessed trial quality and extracted data. Main results: We included 75 studies with about 300,000 observations. We included 17 RCTs, 19 cohort studies and 11 case-control studies in the analysis of vaccine efficacy and effectiveness. Evidence from RCTs shows that six children under the age of six need to be vaccinated with live attenuated vaccine to prevent one case of influenza (infection and symptoms). We could find no usable data for those aged two years or younger.Inactivated vaccines in children aged two years or younger are not significantly more efficacious than placebo. Twenty-eight children over the age of six need to be vaccinated to prevent one case of influenza (infection and symptoms). Eight need to be vaccinated to prevent one case of influenza-like-illness (ILI). We could find no evidence of effect on secondary cases, lower respiratory tract disease, drug prescriptions, otitis media and its consequences and socioeconomic impact. We found weak single-study evidence of effect on school absenteeism by children and caring parents from work. Variability in study design and presentation of data was such that a meta-analysis of safety outcome data was not feasible. Extensive evidence of reporting bias of safety outcomes from trials of live attenuated influenza vaccines (LAIVs) impeded meaningful analysis. One specific brand of monovalent pandemic vaccine is associated with cataplexy and narcolepsy in children and there is sparse evidence of serious harms (such as febrile convulsions) in specific situations. Authors' conclusions: Influenza vaccines are efficacious in preventing cases of influenza in children older than two years of age, but little evidence is available for children younger than two years of age. There was a difference between vaccine efficacy and effectiveness, partly due to differing datasets, settings and viral circulation patterns. No safety comparisons could be carried out, emphasising the need for standardisation of methods and presentation of vaccine safety data in future studies. In specific cases, influenza vaccines were associated with serious harms such as narcolepsy and febrile convulsions. It was surprising to find only one study of inactivated vaccine in children under two years, given current recommendations to vaccinate healthy children from six months of age in the USA, Canada, parts of Europe and Australia. If immunisation in children is to be recommended as a public health policy, large-scale studies assessing important outcomes, and directly comparing vaccine types are urgently required. The degree of scrutiny needed to identify all global cases of potential harms is beyond the resources of this review. This review includes trials funded by industry. An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry-funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favourable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in the light of this finding.
Article
Acute respiratory infections (ARI) are the major worldwide health problem due to associated high morbidity and mortality rates. Adenovirus (Adv) is one of the most common causes of viral ARI, and thus calls for specific diagnosis and better understanding of the epidemiology and clinical characteristics. Our aims were to find out the status of Adv infection in children <14 years with ARI, analyze the epidemiology and clinical characteristics among the Adv-infected children in Guangzhou, China, and to provide some basis for the research of Adv. The throat and pharyngeal swabs were collected among the children with acute respiratory tract infections in outpatient department from September 2006 to August 2008. The samples were analyzed by PCR and the sequences were blasted with the sequences of Adv in GenBank. Clinical data were analyzed along with virological data by using appropriate statistical methods. Adv was detected in 25 out of 512 (4.9%) children. The genome types of 23 samples were determined after analysis of the gene sequence. The most prevalent Adv type was species B type 3. Among the patients, 10 were of Ad3 (43.5%), three were of Ad1 (1.3%), five were of species C Ad2 (21.7%), and five were of species E Ad4 (21.7%). A higher incidence of positive results was found during the summer season, thus showing a pattern of seasonality. There exists Adv infection in children with acute respiratory system diseases in Guangzhou area. No significant differences were found among different age groups and gender groups. Co-infections with other respiratory virus were detected in 64% of the Adv positive samples.
Article
Background In children and adults the consequences of influenza are mainly absences from school and work, however the risk of complications is greatest in children and people over 65 years old.Objectives To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children; assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness) and document adverse events associated with receiving influenza vaccines.Search strategyWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005); OLD MEDLINE (1966 to 1969); MEDLINE (1969 to December 2004); EMBASE (1974 to December 2004); Biological Abstracts (1969 to December 2004); and Science Citation Index (1974 to December 2004). We wrote to vaccine manufacturers and a number of corresponding authors of studies in the review.Selection criteriaAny randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years old.Data collection and analysisTwo authors independently assessed trial quality and extracted data.Main resultsFifty-one studies involving 263,987 children were included. Seventeen papers were translated from Russian. Fourteen RCTs and 11 cohort studies were included in the analysis of vaccine efficacy and effectiveness. From RCTs, live vaccines showed an efficacy of 79% (95% confidence interval (CI) 48% to 92%) and an effectiveness of 33% (95% CI 28% to 38%) in children older than two years compared with placebo or no intervention. Inactivated vaccines had a lower efficacy of 59% (95% CI 41% to 71%) than live vaccines but similar effectiveness: 36% (95% CI 24% to 46%). In children under two, the efficacy of inactivated vaccine was similar to placebo. Thirty-four reports containing safety outcomes were included, 22 including live vaccines, 8 inactivated vaccines and 4 both types. The most commonly presented short-term outcomes were temperature and local reactions. The variability in design of studies and presentation of data was such that meta-analysis of safety outcome data was not feasible.Authors' conclusionsInfluenza vaccines are efficacious in children older than two years but little evidence is available for children under two. There was a marked difference between vaccine efficacy and effectiveness. That no safety comparisons could be carried out emphasizes the need for standardisation of methods and presentation of vaccine safety data in future studies. It was surprising to find only one study of inactivated vaccine in children under two years, given recent recommendations to vaccinate healthy children from six months old in the USA and Canada. If immunisation in children is to be recommended as public-health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required.Plain language summaryThis review found nasal spray vaccines are better than injected vaccines at preventing influenza in children; neither were particularly good at preventing influenza-like illnessThis review assessed how good influenza vaccines were in preventing 'flu' in children who are normally healthy. Nasal spray vaccines made from weakened influenza viruses, were better at preventing illness caused by the influenza virus than injected vaccines made from killed virus. Neither type was particularly good at preventing 'flu-like illness' caused by other types of viruses. A large amount of information was collected comparing reactions in children who had received vaccines with those who had not. However, the vaccine types could not be compared because of the different ways the data were collected and presented in the studies. It was not possible to analyse the safety of vaccines from the studies due to the lack of standardisation in the information given. Very little information was found on the safety on inactivated vaccines, the most commonly used, in young children. Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Article
We randomized 115 children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the following 9 months, TIV recipients had an increased risk of virologically-confirmed non-influenza infections (relative risk: 4.40; 95% confidence interval: 1.31-14.8). Being protected against influenza, TIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses.
Article
This study aimed at investigating the prevalence and clinical characteristics of children with respiratory infection by WU polyomavirus (WUPyV) in Southern China. Nasopharyngeal aspirate samples were collected from 771 children with acute respiratory tract infection admitted to hospital and 82 samples from healthy subjects for routine examination at the outpatient service at the Second Affiliated Hospital of Shantou University, Medical College from July 2008 to June 2009. WUPyV was detected by the polymerase chain reaction (PCR) and DNA sequencing. All WUPyV-positive specimens were characterized further for nine viruses causing common respiratory infections, including influenza A and B, respiratory syncytial virus (RSV), parainfluenza virus (PIV) 1 and 3, human metapneumovirus, human bocavirus, adenovirus, and rhinovirus by PCR or real time (RT)-PCR. Fifteen out of 771 specimens from patients with acute respiratory tract infection, but none from healthy subjects, were positive for WUPyV and the positivity rate was 2%. Patients with WUPyV infection were between 2 and 48 months of age, and nine of the patients were male while six female. Four out of 15 patients were co-infected with RSV, one with adenovirus or rhinovirus, respectively. Patients with WUPyV infection displayed predominantly cough, moderate fever, and wheezing, and were diagnosed with pneumonia (n = 8), bronchiolitis (n = 4), upper respiratory tract infections (n = 2) and bronchitis (n = 1). One patient developed encephalitis. Therefore, WUPyV infection can cause acute respiratory tract infection with atypical symptoms, including severe complications, in children.