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\begin{document}

\title{Influenza among Children Admitted to the Emergency Department of
Children's Hospital in Vilnius: two seasons, two viruses}



\author[1]{Sigita Petraitiene}%
\author[1]{Daiva Vaičiūniene}%
\author[1]{Barbara Aviženis}%
\author[1]{Audrone Eidukaite}%
\author[1]{Sigita Burokiene}%
\author[1]{Odilija Rudzevičiene}%
\author[1]{Marija Montvydaite}%
\author[1]{Inga Ivaškevičiene}%
\author[1]{Vytautas Usonis}%
\affil[1]{Vilnius University Faculty of Medicine}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background. No specific clinical signs of influenza are defined,
although type A is thought to dominate and be responsible for more
severe cases of influenza diseases. Our study aimed to determine the
value of clinical signs and routine laboratory results on influenza
diagnose among children, reveal possible differences among different
influenza subtypes. Methods. A retrospective study was conducted at
Vilnius University Hospital Santaros Klinikos during two influenza
seasons (2016/2017 and 2017/2018 year). Basic demographic, clinical
data, vaccination for influenza status and results of laboratory
testing, were collected. Results. Data of 655 influenza cases were
analysed. Among them 355 (54.2\%) were boys. Influenza A cases from
2016/2017 season and influenza B cases from 2017/2018 season were
compared. Average age of influenza patients was 6.25\selectlanguage{ngerman}±2.1 years: in
influenza A group - 5.5±4.5 years, and in influenza B - 7.2±4.3 years.
The main symptoms were fever 647 (98.8\%), cough 387 (59.1\%) and
rhinitis 302 (46.1\%). Diarrhoea, stomach ache, muscle pain, headache
were more prominent in the influenza B group. Complications were found
more common in influenza A group (82 (55.4 \%)) and among children above
12 years of age (28/112 (25 \%)). Overall 159 (24.3\%) children were
hospitalized (influenza A dominated (56.6\%)). Conclusions. The
incidence of influenza B is increasing in children under 12 years of age
and the incidence of influenza A is decreasing with increasing age of
children (p =0.00). No significant statistical difference was found in
clinical signs, complications and hospitalisation rate among two
influenza virus types.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


Influenza among Children Admitted to the Emergency Department of
Children's Hospital in Vilnius: two seasons, two viruses

{\label{influenza-among-children-admitted-to-the-emergency-department-of-childrens-hospital-in-vilnius-two-seasons-two-viruses}}

Sigita Petraitien\selectlanguage{polish}ė \selectlanguage{english}\textsuperscript{1}; Daiva
Vai\selectlanguage{polish}č\selectlanguage{english}i\selectlanguage{polish}ū\selectlanguage{english}nien\selectlanguage{polish}ė\selectlanguage{english}\textsuperscript{1}; Barbara Avi\selectlanguage{polish}ž\selectlanguage{english}enis \textsuperscript{1};
Marija Montvydait\selectlanguage{polish}ė \selectlanguage{english}\textsuperscript{1}; Sigita Burokien\selectlanguage{polish}ė
\selectlanguage{english}\textsuperscript{1}; Odilija Rudzevi\selectlanguage{polish}č\selectlanguage{english}ien\selectlanguage{polish}ė \selectlanguage{english}\textsuperscript{1}; Inga
Iva\selectlanguage{polish}š\selectlanguage{english}kevi\selectlanguage{polish}č\selectlanguage{english}ien\selectlanguage{polish}ė\selectlanguage{english}\textsuperscript{1}; Audron\selectlanguage{polish}ė \selectlanguage{english}Eidukait\selectlanguage{polish}ė \selectlanguage{english}\textsuperscript{1};
Vytautas Usonis \textsuperscript{1}

\textsuperscript{1} Institute of Clinical Medicine, Faculty of Medicine,
Vilnius University, Vilnius, Lithuania

\section*{}

{\label{section}}

\subsection*{Abstract}

{\label{abstract}}

Background. No specific clinical signs of influenza are defined,
although type A is thought to dominate

and be responsible for more severe cases of influenza diseases.

Our study aimed to determine the value of clinical signs and routine
laboratory results on influenza diagnose among children, reveal possible
differences among different influenza subtypes.

Methods. A retrospective study was conducted at Vilnius University
Hospital Santaros Klinikos during two influenza seasons (2016/2017 and
2017/2018 year). Basic demographic, clinical data, vaccination for
influenza status and results of laboratory testing, were collected.

Results. Data of 655 influenza cases were analysed. Among them 355
(54.2\%) were boys. Influenza A

cases from 2016/2017 season and influenza B cases from 2017/2018 season
were compared. Average

age of influenza patients was 6.25\selectlanguage{ngerman}±2.1 years: in influenza A group -
5.5±4.5 years, and in influenza B

- 7.2±4.3 years. The main symptoms were fever 647 (98.8\%), cough 387
(59.1\%) and rhinitis 302 (46.1\%). Diarrhoea, stomach ache, muscle
pain, headache were more prominent in influenza B group. Complications
were found more common in influenza A group (82 (55.4 \%)) and among
children above 12 years of age (28/112 (25 \%)). Overall 159 (24.3\%)
children were hospitalized (influenza A dominated (56.6\%)).

Conclusions. The incidence of influenza B is increasing in children
under 12 years of age and the

incidence of influenza A is decreasing with increasing age of children
(p =0.00). No significant statistical

difference was found in clinical signs, complications and
hospitalisation rate among two influenza virus

types.

\subsection*{Keywords}

{\label{keywords}}

Influenza, children, influenza virus types, influenza clinical
manifestation

\subsection*{Background}

{\label{background}}

Influenza virus is one of the most significant causes of acute
respiratory infection worldwide. Every year 5-10\% of adults and 20-30\%
of children are affected by this seasonal infection characterized by
respiratory and gastrointestinal symptoms as well as head, muscle, and
eye pain {[}1, 2{]}. During the 2016-2017 influenza season in Lithuania
- 30 958 cases of influenza were registered and in 13 153 cases patients
were between 0-17 years of age. {[}3{]} According various clinical
studies 1 out of 3 children infected with influenza virus is at risk of
experiencing severe influenza complications. {[}4{]}. This risk is even
higher for children with chronic diseases such as asthma or diabetes,
neurological or neuromuscular pathology and children under the age of 5
years. As per data from the United States, during the past eight years
the number of hospitalisations due to influenza-related illnesses among
children under the age of five has increased from 7,000 to 26,000 cases
per year. {[}5{]} Influenza is a major public health problem worldwide
and its rapid diagnostics is an effective tool in early diagnosing of
this infectious disease. The Polymerase Chain Reaction (PCR) and rapid
antigen detection test are considered to be a gold standard in the
diagnostics of influenza in clinical practice, but due to the limited
availability of PCR in the primary health care, the diagnosis of
influenza is usually based on clinical findings and routine laboratory
parameters. Unfortunately, no specific clinical signs of influenza are
defined, although type A is thought to dominate and be responsible for
more severe cases of influenza disease. {[}6{]}

The aim of our study was to determine the value of clinical signs and
routine laboratory results on influenza diagnose, reveal possible
differences among different influenza subtypes on clinical signs and
outcome of the disease. Importance of the study -- it may be informative
in improving diagnostic and prognostic skills in clinical practice.

\subsection*{Methods}

{\label{methods}}

A retrospective study was conducted at Children's Hospital, Affiliate of
Vilnius University Hospital Santaros Klinikos (further - CH) during two
influenza seasons (2016/2017 and 2017/2018 year). The patients, who were
admitted to the Emergency Department of CH for suspected influenza
according clinical signs, were included in the study. Only those who had
rapid influenza antigen (nasopharyngeal swabs, rapid
immunochromatographic test, Veda Lab, France) confirmed influenza
infection were included to the further analysis.

Basic demographic, vaccination for influenza status, time from the onset
of symptoms clinical data on admission and results of laboratory tests
were collected. Type of influenza virus was verified by testing of
nasopharyngeal swabs using rapid immunochromatographic test (Veda Lab,
France) and in sub-cohort of influenza patients was confirmed by
real-time RT-PCR assay (RT-PCR Influenza CDC Protocol from WHO Influenza
Cooperation Centre CDC Atlanta, USA. The primers and probes set used was
designed for universal detection of type A/B influenza viruses H1, H3,
H1PDM09, H5, H7, Victoria, Yamagata).

Statistical analysis was performed using Microsoft Excel and SPSS
v23.00. Categorical variables were expressed as number and percentages
and continuous variables values as median and range or as average and
standart deviation. Comparison of proportions between the groups was
done by the x2 test. Statistical significance was set at a P value of
less than 0.05.

The study was approved by the Regional Biomedical Ethics Committee (No.
158200-18/4- 1025-525) and the State Data Protection Inspectorate (No.
2R- 3369). As the study was retrospective, a special permission was
given by Regional Biomedical Ethics Committee to perform the study
without informed consent from the patients or their parents.

\subsection*{Results}

{\label{results}}

In total 2066 nasopharyngeal swabs were taken from the patients with
suspected influenza during two influenza seasons. Using rapid antigen
detection test influenza infection was detected in 763 cases, of which
influenza A virus was proven in 416 (54.5\%) cases, as all the rest was
influenza B virus - 347 (45.5\%).

Influenza A virus was more prevalent during 2016/2017 influenza season
(363 (86.2\%) cases) and influenza B virus during 2017/2018 influenza
season (292 (84.8 \%)). The distribution of influenza virus types during
two influenza seasons was shown in Figure 1.

Additionally, 116 randomly selected nasopharyngeal swabs positive for
influenza B virus by rapid test were further analysed using RT-PCR.
Influenza B virus lineages were identified. Victoria lineage dominated
in 2016/2017 influenza season (14 (100\%)) and there were no cases of
Yamagata lineage. In 2017/2018 influenza season 94 (92.1\%) cases of
Yamagata and 8 (7.9\%) of Victoria lineages were identified.

There were only few cases of influenza B during 2016/2017 season and
just few cases of influenza A during 2017/2018 season, therefore data on
influenza A cases from 2016/2017 season and influenza B cases from
2017/2018 season were compared. A total of 655 influenza cases were
analysed. Among them 355 (54.2\%) were boys and 300 (45.8\%) girls.

The total average age of our influenza patients was 6.25±2.1 years of
age: in influenza A group - 5.5±4.5 years, and in influenza B - 7.2±4.3
years. For more detailed analysis, all the patients were divided into
four age groups: below 2 years -- 153 (23.4 \%), 2-5 years -- 151 (23.1
\%), 6-12 years -- 239 (36.5 \%), more than 12 years - 112 (17.1\%). In
2016/2017 influenza season influenza was detected statistically
significantly more frequent in children below 2 years of age -- in 110
(30.3 \%) of all 2016/2017 influenza season children, in 2017/2018
season -- in 6 -12 years and over 12 years of age, accordingly 128
(43.8\%), 62 (21.2\%) (p=0.001). The distribution of influenza by age
groups and sex shown in Figure 2.

The incidence of influenza B is increasing in children under 12 years of
age and the incidence of influenza A is decreasing with increasing age
of children (p =0.00). The distribution of influenza virus types in
different age groups is shown in Figure 3. Based on binary logistic
regression analysis we can predict that children over 54 month of age
are at higher risk to get influenza B (OD =2.693)

We did not find any statistically significant relationship between
influenza B lineages, and influenza incidence by age and sex.

Three participants were vaccinated with trivalent flu vaccine (0.5\%).
One of them was in age group up to 2 years and two children were in age
group from 6 to12 years. One of them had influenza A, another two -- B.
No one of the influenza vaccinated children was hospitalized or had
complications.

Most of the youngest patients (\textless{}2 years of age) and
school--age (5 -- 12 years of age) referred to medical attention on the
first three days of the disease during both influenza seasons.
Differences between the illness day during the approach to CH and
influenza type is shown in figure 4. For 12 patients who have been
diagnosed with influenza during 2016/2017 influenza season, day of
illness during visit day to the CH is not known.

\subsubsection*{}

{\label{section-1}}

The main symptoms were fever 647 (98.8\%), cough 387 (59.1\%) and
rhinitis 302 (46.1\%). The frequency of the symptoms for the different
types of influenza is presented in Figure 5.

In total 148 (22.6 \%) children had influenza-related complications.
Non-bacterial complications (serous otitis media, acid- base imbalance,
benign acute childhood myositis) had 143 (21.8 \%) children. Secondary
bacterial infection (acute bacterial otitis media, bacterial pneumonia)
had 15 (2.3 \%) and mixed complications - 10 (1.5 \%) children.
Complications were found more common in children with influenza A -- 82
(55.4 \%) and in the age group above 12 years (28/112 (25 \%) had
complications). Complications developed more frequently for children
with chronic diseases -- 29 (39.7\%) (p=0.00). Children with chronic
diseases are more likely to develop non-bacterial complications - 28
(38.4\%) (p=0.001).

Out of 655 study participants 159 (24.3\%) children were hospitalized.
Influenza A was confirmed in 90/159 (56.6\%) and influenza B -- in
59/159 (37.1\%) of all hospitalised patients. Boys were hospitalised
more often - 87 (54.7\%): 52 (57.8\%) in 2016/2017 season and 35
(50.7\%) in 2017/2018 season. Children under 2 years of age were
hospitalized because of influenza more often (51/153 (33.3\%))
comparatively with children from other age groups (p=0.011). Children
who came to CH after the third day of disease (46/138 (33.9\%)) or had
leukocytosis (WBC \textgreater{} 15*10\textsuperscript{9}) in complete
blood count (25/60 (40.3\%)) also comparatively were hospitalized more
often (for both p= 0.007).

\subsection*{Discussion}

{\label{discussion}}

The peculiarities of children flu are described. Data was collected
during two influenza seasons: 2016/2017 and 2017/2018 years at
Children's hospital in Vilnius. Two different types of influenza virus
were circulating. Type A was dominating during the 2016/2017 influenza
season and type of influenza B - during the 2017/2018 season. Global
Influenza Surveillance and Response System (GISRS) reported domination
of influenza A during 2016/2017 years, and influenza B during 2017/2018
influenza season in Lithuania. Influenza A virus dominated during both
seasons worldwide, however in the European Union countries higher than
usual proportion of influenza B compared to influenza A has been
detected in sentinel sources in 2017/2018. The B/Yamagata lineage virus
has greatly outnumbered the B/Victoria lineage. {[}7{]} The comparable
proportions of circulating types and subtypes of influenza virus was
shown also in our study.

Influenza B is responsible for about 20\% of all influenza cases, with
fluctuation of either Victoria or Yamagata lineage and it was commonly
accepted that influenza B causes milder clinical symptoms and less
complications in comparison with influenza A. Epidemiology and clinical
manifestations of influenza A virus induced diseases is widely described
in the scientific sources, whilst influenza B virus is considered to be
less important pathogen. {[}6{]} Results of the large scale clinical
studies and reviews published recently changes such an understanding of
influenza epidemiology and illustrates growing importance of influenza B
virus as aetiological factor of severe diseases. {[}8-10{]}

Recent reviews report the changing burden of influenza in different age
groups and virus type. {[}11{]} We do believe that our study will
contribute to better understanding of the importance of different
influenza virus types in epidemiological process and clinical
manifestation in children.

Differences between circulation of influenza A and B type viruses and
diseases caused by these viruses could be seen in French general
practitioners-based influenza surveillance network study from 2003-2004
to 2012-2013. Screening of 49919 patients with flu like symptoms was
positive in 32.6\%. In our study, 763 samples out of 2660 taken (28.7\%)
were influenza positive. This illustrates the necessity of the rapid
influenza tests to confirm the diagnosis and to prescribe antiviral
treatment properly. In France during both season influenza B was
responsible for 23.7 \% of all the cases, (viruses of the B-Yamagata and
B-Victoria lineage caused 62.8 \% and 37.2 \% of influenza B cases,
respectively) and no differences in the duration of influenza A and B
epidemics were observed. {[}12{]}

In France and Turkey during 2010-2011 and 2011-2012 seasons data from
774 influenza cases: 419 influenza B cases (209 in France and 210 in
Turkey) and 355 influenza A cases (205 in France and 150 in Turkey) was
reported. There were no differences between influenza A and B patients
in terms of clinical presentation and number of consultations with a
practitioner; however, the use of antivirals was higher among influenza
B patients in both countries. In conclusion, findings of this study show
that influenza B infection appears not to be milder disease than
influenza A infection. {[}13{]}

European Influenza Surveillance Network (EISN) data shows that
interpretation of syndromic surveillance data without age group-specific
virology data may be misleading. Surveillance at the European level
would benefit from the reporting of age-specific influenza data as the
review data from twenty-nine countries during 1999-2014 (N=358,796
influenza cases) highlight the importance of presenting burden of
disease estimates by age group and virus type. {[}11, 14{]} According
the results of the same study in France patients aged 5-14 years were
more likely to be infected with type B viruses than children aged 0-4
years, those (OR 2.15, 95\% CI 1.87-2.47). {[}9{]} The same results are
shown in our study -- flu B was detected more frequently in older
children in comparison with 0-2 year of age group.

No statistically significant differences between circulation of flu A
and B across seasons was shown in ``The Global Influenza B study'' in
which 935,673 influenza patients were included during 2000-2013 period.
Overall, median proportion of influenza B was 22.6\%. During seasons
where influenza B was dominant or co-circulated (more than 20\% of total
detections), Victoria and Yamagata lineages predominated during 64\% and
36\% of seasons, respectively. {[}15{]} In our study influenza season of
2017/2018 was specific because Yamagata dominated and caused 80\% of all
influenza cases.

Clinical characteristics and outcomes of influenza in children below 17
years of age admitted due to laboratory-confirmed influenza B or A at 12
paediatric hospitals, participants of active surveillance Canadian
Immunization Monitoring Program were compared. Influenza A patients
compared with influenza B patients were more likely to have a
vaccine-indicated condition. Symptoms more often associated with
influenza B were headache, abdominal pain, and myalgia. {[}16{]} Similar
differences in clinical signs we found in our study in Lithuania.

In US study combining data from four seasons (2004-2005 through
2007-2008), paediatric patients with influenza B were more likely to
have a high-risk medical condition relative to those with influenza A
(21\% and 13\%) and symptoms varied during different seasons. Cough and
wheezing were significantly associated with influenza A during the
2004--2005 season (predominant subtype H3N2), but not during the other
seasons. In the 2004--2005 season, 95\% of patients with influenza A and
79\% of patients with influenza B reported cough (P = 0.05, exact
Pearson chi-square); wheezing was reported by 51\% of influenza A cases
and 15\% of patients with influenza B (P = 0.02). Sore throat and
vomiting were associated with influenza A during the 2007--2008 season
only (predominant subtype H3N2). Seventy-six percent of influenza A
cases and 66\% of influenza B cases reported sore throat (P = 0.006);
vomiting was reported by 19\% of influenza A cases and 13\% of patients
with influenza B (P = 0.05). {[}17{]} In our study sore throat and
headache as gastrointestinal signs (diarrhoea and stomach ache) were
more common for influenza B.

In Canadian study among healthy children with influenza B, above 12
years of age was associated with the greatest odds of ICU admission.
{[}18{]} In our study admission rates were similar both for A and B
influenza cases.

Children with chronic diseases and influenza were treated in hospital
more often than otherwise healthy children. Study in Turkey shows the
same results as our study -- children below 3 years of age with
underlying chronic diseases are at the biggest risk to be treated in
hospital. {[}19{]}

All the children admitted to Children's Hospital were not vaccinated
except three. All of them were vaccinated with trivalent vaccine;
influenza B was diagnosed for 2 children. In studies from USA from 14 up
to 54 out of 1000 vaccinated were diagnosed with flu. Up to now most
vaccinated are not protected from influenza B, despite the fact that WHO
from 2013-2014 influenza season recommend vaccinate with four-component
vaccine. Vaccination program has caused meaningful reductions visits for
influenza, even in years when the vaccine was not well matched to the
dominant circulating influenza strain. {[}18, 20{]} None of vaccinated
in our study required hospitalisation and this illustrates the
importance of children vaccination against influenza. Even if the
disease is not prevented completely, it is less severe and do not
require the usage of the medical resources. Including Yamagata component
in most of vaccines will be important in further reducing the morbidity
and absenteeism particularly among school age children worldwide.

Limitation of our study is that it was retrospective study. Comparison
of the clinical manifestations of influenza during different seasons
might be considered as another limitation, however due to the seasonal
fluctuations of the structures of influenza virus this is difficult to
avoid.

\subsection*{Conclusion}

{\label{conclusion}}

\begin{enumerate}
\tightlist
\item
  The incidence of influenza B is increasing in children under 12 years
  of age and the incidence of influenza A is decreasing with increasing
  age of children (p =0.00).
\item
  No significant statistical difference was fond in clinical signs,
  complications and hospitalisation rate among two influenza virus
  types.
\item
  Despite of the limitations mentioned above we do believe that the
  unexpected distribution of influenza B Victoria and Yamagata lineages
  during 2017-2018 season and comparison of clinical manifestations of
  the diseases caused by different influenza viruses will be interesting
  data to share.
\end{enumerate}

\subsection*{Abbreviations}

{\label{abbreviations}}

Children's Hospital, Affiliate of Vilnius University Hospital Santaros
Klinikos - CH

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{\label{references}}

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\subsection*{Figure Legends}

{\label{figure-legends}}

Figure 1. Distribution of influenza virus types during two influenza
seasons.

Figure 2. The distribution of influenza cases in different age and sex
groups (2016/2017 and 2017/2018 influenza seasons).

Figure 3. The distribution of influenza types in different age groups
(2016/2017 and 2017/2018 influenza seasons).

Figure 4. The differences between the illness day of referral to CH and
influenza type (2016/2017 and 2017/2018 influenza seasons).

Figure 5. The distribution of the symptoms for the different types of
influenza virus (2016/2017 and 2017/2018 influenza seasons).

\textbf{Hosted file}

\verb`Figures.docx`  available at \url{https://authorea.com/users/339441/articles/465666-influenza-among-children-admitted-to-the-emergency-department-of-children-s-hospital-in-vilnius-two-seasons-two-viruses}

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