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\begin{document}
\title{Subcutaneous Allergen Immunotherapy in Children: Real Life Compliance
and Effect of COVID-19 Pandemic on Compliance}
\author[1]{Elif Soyak Aytekin}%
\author[2]{Ozge Soyer}%
\author[2]{Bulent Sekerel}%
\author[2]{Umit Sahiner}%
\affil[1]{Hacettepe University}%
\affil[2]{Hacettepe University Faculty of Medicine}%
\vspace{-1em}
\date{\today}
\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup
\selectlanguage{english}
\begin{abstract}
Background: Allergen immunotherapy(AIT) is an effective treatment for
allergic rhinitis, asthma and venom allergy. Compliance is essential for
AIT to obtain maximal benefit as it is a long term treatment. Objective:
We aimed to evaluate the real life compliance of children with
subcutaneous immunotherapy(SCIT) and tried to document the factors
associated. Additionally how COVID-19 pandemic effected the compliance
of the patients and the reasons of drop-outs were also evaluated.
Method: Patients diagnosed with allergic rhinitis, allergic asthma or
venom allergy and treated with SCIT between 2012 September, 2020 July
were analyzed. Results: The study population comprised of 201 children
(66,7\% male) with a median (interquartile range) age of 12,8(9,4-15,2)
years during the first injection of SCIT. The overall compliance rate
before COVID-19 pandemic was 86,1\%. Short AIT follow up time and venom
allergy were found to be risk factors for drop out. The leading causes
of drop outs were moving to another city/country(32,1\%), improvement of
symptoms(17,8\%), ineffectiveness(14,2\%) and adverse reactions(14,2\%).
During COVID-19 pandemic, among 108 patients receiving AIT, 31(28,7\%)
dropped out the therapy. The most frequent reasons for drop-outs were
fear of being infected with COVID-19(35,4\%) and thinking that the AIT
practise stopped due to COVID-19 pandemic(29\%). Male gender and older
age were found to be the independent risk factors for drop out.
Conclusion: The real life compliance in children was higher than in
adults. Nearly one third of children dropped out during COVID-19
pandemic. Male gender and older age are associated with AIT drop out
during COVID-19 pandemic.%
\end{abstract}%
\sloppy
\textbf{Conclusion:}
The real life compliance in children was higher than in adults. Nearly
one third of children dropped out during COVID-19 pandemic. Male gender
and older age are associated with AIT drop out during COVID-19 pandemic.
\textbf{Keywords:} Aeroallergen, Allergen immunotherapy, Children,
Compliance, COVID-19,
House dust mite, Venom
\textbf{Abbreviations}
\textbf{AIT: Allergen immunotherapy}
\textbf{AR: Allergic Rhinitis}
\textbf{COVID-19: The Coronavirus disease 2019}
\textbf{HDM: House dust mite}
\textbf{SCIT: Subcutaneous allergen immunotherapy}
\textbf{SLIT: Sublingual immunotherapy}
\textbf{SPT: Skin prick test}
\textbf{VIT: Venom immunotherapy}
\textbf{Introduction}
Allergen immunotherapy is an effective and game-changing treatment
method for allergic rhinitis, venom anaphylaxis and allergic asthma
which can provide immune tolerance for many years. Subcutaneous allergen
immunotherapy (SCIT) is the most commonly used administration route, and
requires repeated administration of allergen extracts for 3 to 5 years
depending on the type of allergen applied.
Compliance is essential for AIT to obtain maximal benefit as it is a
long term treatment. However non-compliance rates may be as high as 50\%
in both adults and children\textsuperscript{1-3}. The major factors
associated to noncompliance are long duration of treatment, frequency of
injections, high medical cost, improvement of systemic reactions over
time, poor perceived efficacy, allergic reactions during vaccinations
and travelling, and differ between centres, health system structure and
cultures\textsuperscript{4-6}. Most of the studies about compliance come
either from adult studies or from study populations involving both
adults and children; the ones involving only pediatric age group are
very limited\textsuperscript{3}.
The Coronavirus disease 2019 (COVID-19) pandemic not only affected
people with COVID-19 infection but also disrupted the treatment of
patients with chronic diseases. In this period, some changes in the
pattern of hospital admissions was recognized. A study from northern
Italy showed a significant decrease in acute coronary syndrome related
hospitalization rates across several cardiovascular centers in northern
Italy during the early days of the COVID-19 outbreak\textsuperscript{7}.
During that period, a significant increase in mortality was reported
that was not fully explained by COVID-19 cases alone, and thought to be
due to failure to access medical attention. In this period, we also
observed a reduction in pediatric outpatient admissions for AIT.
In the present study we aimed to investigate the real life compliance of
children with SCIT and tried to document the factors associated with
compliance. Additionally we evaluated how the COVID-19 pandemic effected
the compliance of our patients and the reasons that caused drop-outs.
\textbf{Methods}
\textbf{Study population}
Two hundred and one children who had allergic rhinitis, allergic asthma
or venom allergy and treated with SCIT at Hacettepe University Medical
School Hospital, Department of Pediatric Allergy between 2012 September,
2020 July were included in the study. The study protocol was reviewed
and approved by our University Institutional Review Board.
AIT was administered to patients with allergic rhinits and/or allergic
asthma who had uncontrolled AR symptoms along with medical treatments
and avoidance measures; AIT was given to patiens with asthma only if
their disease is allergic and mild to moderate in severity; and venom
immunotherapy (VIT) was administered to patients who had a history of at
least one systemic reaction after Apis mellifera and/or Vespula stings
and positive diagnostic test reactions (skin prick test(SPT) or specific
immunoglobulin E (sIgE) for culprit insect venom.
Patients' demographic data, diagnosis of allergic disease, AIT regimen,
date of initiation of AIT, compliance and drop-out were noted from their
medical records, retrospectively up to the COVID-19 pandemic period,
afterwards it was reported prospectively. The treatment adherence of
patients in COVID-19 period was defined as the time between the first
confirmed case of COVID-19 in Turkey (Mach 15, 2020) and June 15, 2020.
\textbf{Diagnosing Allergic rhinitis/allergic asthma and venom allergy}
The diagnoses and therapies of AR and asthma and venom allergy were
defined according to the allergic rhinitis and its impact on asthma
(ARIA)\textsuperscript{8} and Global Initiative for Asthma
(GINA)\textsuperscript{9} and European Academy of Allergy and Clinical
Immunology guidelines\textsuperscript{10}, respectively.
\textbf{Immunotherapy Application and Compliance Assessment}
Patients were applied one of Alutard SQ 100\% vespula or Apis mellifera
(Alutard SQ, ALK, H\selectlanguage{ngerman}ørsholm, Denmark) venom immunotherapy, Allergovit
Grass 006 (Allergopharma Joachim Ganzer KG, Hamburg, Germany) allergen
immunotherapy or NovoHelisen Depot HDM \%50 DP+\%50 DF (Allergopharma
Joachim Ganzer KG, Hamburg, Germany) allergen immunotherapies. VIT doses
were administered in 1-week intervals and were gradually increased to
the maintenance dose over 6 months\textsuperscript{11}. Then,
maintenance doses were administered every 4 to 6 weeks for up to 5
year\textsuperscript{12}. AIT doses for grass allergy and house dust
mite(HDM) allergy; were administered in 1-week intervals and were
gradually increased to the maintenance doses over 6 weeks in grass and
14 weeks in HDM\textsuperscript{13}. Then, maintenance doses were
administered every 4 to 6 weeks for up to 4 years.
Compliance was defined as receiving the allergen immunotherapy according
to the prescribed treatment course for each patient, and evaluated
during the \selectlanguage{english}first-year, second-year, third year, fourth-year, and
\selectlanguage{english}fifth-year, or treatment completion. Patients who had \selectlanguage{english}[?]2 two week breaks
from their de\selectlanguage{english}fined treatment schedule per year were accepted to be in
excellent compliance, 3 to 4 two week breaks were in good compliance, 5
to 6 two week breaks were fair compliance, and 7 or more two week breaks
were poor compliance\textsuperscript{14}. Patients who had three
consecutive months delay from their defined treatment schedule were
accepted as dropped out\textsuperscript{15}. The reasons for drop-out
was recorded.
\textbf{Statistics}
Statistical analyses were performed using SPSS version 22.0 statistical
software package (IBM SPSS Statistics, USA). First normality tests for
continuous variables were performed and as all of the continuous
variables were distributed non-normally the results were given as median
{[}inter-quartile range(IQR){]}. The chi-square and Mann-Whitney U tests
were used to compare nonparametric values. For the risk analysis of
drop-outs variables were selected if the p value was less than 0.20 in
the univariate analysis and included in multivariate analysis. Odds
ratios (ORs) with relevant 95\% confidence intervals (CIs) were
calculated to evaluate potential associations. Values of P\textless{}.05
were accepted as significant.
\textbf{Results}
\selectlanguage{polish}\textbf{The Real Life Results Before COVİD-19 Pandemic (2012
September-2020 March)}\selectlanguage{english}
There were 201 children who received SCIT injections between 2012
September, 2020 March. According to the demographic data there was a
predominance of male gender (134, 66.7\%). The median AIT start age was
12.8 (9.4-15.2) years and the median treatment duration was 40.7
(20.4-49.9) months. Of the patients, 47.8\% had a family history of
atopy. The demographic characteristics of the study participants are
summarized in Table I.
The number of the patients treated with immunotherapy for allergic
rhinitis, asthma and venom allergy were 154 (76,6\%), 10 (5\%) and 37
(18,4\%), respectively. Regarding the immunotherapy composition, pollen
immunotherapy was predominant (78.1\%), followed by venom (18.4\%) and
house dust mite (3.5\%). Ninety three patients (46,2\%) completed the
treatment and 108 patients continued to receive AIT during the course of
the study. The overall compliance rate was 86.1\%. Among the compliant
groups, all patients had excellent compliance in first and second year
of therapy. After two years of therapy, 93.6\% of patients had excellent
compliance and 4,6\% and 1,5\% had good and fair compliance,
respectively. (Table III) Twenty eight patients(13.9\%) stopped AIT
before recommended time. Two patients dropped out in year 1 (0,99\%), 10
in year 2 (5,8\%), and 16 (10,8\%), after 2 years of therapy. Cumulative
proportions of patients who continue allergen immunotherapy over time
was analyzed using Kaplan-Meier curves. (Figure I)
In the drop-out group AIT follow up time was significiantly low
(p\textless{}0.001) whereas venom allergy and asthma were significiantly
higher compared to compliant group (p\textless{}0.001). (Table I) Among
the drop-out patients, moving to another city/country (32,1\%) was the
most frequent reason for drop-out. The other reasons included
improvement of symptoms(17,8\%), ineffectiveness of the therapy
(14,2\%), adverse reaction (14,2\%), long distance to hospital (6,8\%),
frequency of injections (10,7\%) and inability to access immunotherapy
agent (3,5\%). (Table II)
\textbf{COVID-19 pandemic period}
The COVID-19 pandemic started officially in mid March 2020 in our
country. One hundred and eight patients were receiving AIT, when
pandemic started. Among these, 31 patients (28,7\%) dropped out the
therapy and breaks were observed in 15 patients (13,8\%). Among the
drop-out group, the median treatment duration was 40 (29-49.8) months.
The most frequent reason for drop-out was fear of being infected with
COVID-19 (35.4\%), thinking that the AIT practise stopped due to
COVID-19 pandemic (29\%). The other reasons included transportation
problems due to intercity transportation and and curfew (22.7\%),
inability to access medication (6.5\%) having a COVID-19 infected family
number (3.2\%) and few doses left to finalize the treatment (3.2\%)
(Table II).
Drop-out rate was significiantly higher in older age(p=0.004) and male
gender(p=0.045).(Table IV) AIT duration was significiantly high in the
drop-out group according to the compliant group(p=0.018).
We further performed univariate and multivariate logistic regression
analysis for the risk factors for the development of the drop-out during
the COVID-19 pandemic. Male gender {[}OR:2.972, 95\%CI:1.132-7.804, P =
.027{]} and higher age {[}OR:1.209, 95\%CI:1.064-1.375, P = .004{]} were
found to be the independent risk factors for drop-out during COVID-19
pandemic.(Table V)
\textbf{Discussion}
Results of our study showed that the overall compliance rate among
patients receiving AIT was 86,1\% and short duration of AIT and
receiving venom or asthma immunotherapy were found to be associated with
non-compliance. In addition, the most common reasons for drop-out were
moving to another city, improvement of symptoms and ineffectiveness.
However, nearly one-third of children dropped out during the COVID-19
pandemic, and fear of being infected with COVID-19 was the most common
reason.
Compliance rates for SCIT range from 44\% to 89\%, in the present study
compliance found to be better than other studies\textsuperscript{3}.
Similar to our results, Pajno et all found that AIT compliance of
children on SCIT was 89\%\textsuperscript{4}. In a population of 311
allergic adult and child patients receiving dust mite SCIT in China,
34,5\% of caseswere noncompliant and ineffectiveness(28\%) was the
leading reason for drop-out\textsuperscript{15}. The cost of AIT in our
country is under the umbrella of social security system. This may be a
major reason for high compliance rates we achieved. Additionally our
staff reminds the patients if a patient does not come to a regular visit
(except COVID-19 period).
We concluded that drop-out was significiantly higher in patients who
receiving immunotherapy for asthma and venom allergy. As the patients
who received VIT admitted from another city, most of them dropped out
due to the long distance or frequency of injections. However in previous
studies, the association of kind of respiratory allergic diseases and
adherence were inconsistent. In one study, allergic conjunctivitis were
found associated with non-adherence whereas in other study patients with
asthma and rhinitis were found more adherent\textsuperscript{16,17}.
More et all reported that the kind of respiratory allergic diseases was
not correlated with adherence\textsuperscript{18}.
In the current literature the data about the AIT compliance were mostly
attained from studies in adults, and there are few data related to SCIT
adherence in children. The studies comparing different age groups with
respect to the AIT compliance give us conflicting
results\textsuperscript{19,20}. Yang et all found that children had
higher adherence than adults\textsuperscript{15}. Lee et al concluded
that patients aged \textless{}20 years and 20-40 years were more likely
to be nonadherent than those aged \textgreater{}40 years. Rhodes found,
nonadherent patients were younger\textsuperscript{21}.
In the present study, gender did not influence the adherence rate before
pandemic. However during the COVID-19 pandemic period males droped out
more significantly. Musa, Rhodes and Gelincik found no correlation with
gender\textsuperscript{5,20,21}. Rhodes found, males were more
nonadherent\textsuperscript{21}. However in Yang' and Lower's study
males had higher adherence\textsuperscript{2,15}.
Our results suggested that moving to another city (32,9\%) was the main
cause of drop-outs. Due to the lack of allergologists in some cities,
treatment could not be resumed. In addition, all of the patients
receiving AIT were at school age, and increased injection frequency,
transportation to different city and long distances probably caused
school absences and AIT drop-out.
Improvement of symptoms was the second leading reason of drop out
(17,9\%). Lourenco reported that the frequency of drop-out because of
clinical improvement was 23\% and mostly during the second and third
year of SCIT\textsuperscript{19}. Yang reported it as
22\%\textsuperscript{15}.
We found treatment ineffectiveness (14,3\%) as another important reason
of AIT drop-outs. Ineffectiveness was reported in previous studies in 8
to 66\% of drop-out results\textsuperscript{1,4,15,19,20}. Adverse
reactions were also reported in several studies as a reason for
drop-outs in 3,9\% to -11\% of drop-outs\textsuperscript{19,21}.
Systemic reactions were also one of the leading reasons for drop-out
(14,3\%) in the present study although it was not reported frequently in
our center previously\textsuperscript{22,23}(24). In contrast to
literature, cost was not a reason for drop-out in the present study as
AIT treatment is covered by social security system of our country.
During the COVID-19 pandemic period, in allergy department, patient
admissions were stopped except for emergency situations and
immunotherapy vaccination. Even so, among the 108 patients receiving
AIT, 31 (28,7\%) dropped out. Fear of being infected with COVID-19 was
the most reason. Although the necessary precautions were taken, the
patients chose not to continue to AIT, as the hospital was a COVID-19
pandemic center. Twenty nine percent of patients dropped out thinking
that the AIT was cancelled because of the news on the press that the
admissions of patients stopped except for emergencies. In COVID-19
pandemic period, intercity transportation was banned and, in most of the
cities including Ankara curfews were declared. This situation resulted
in 22,7\% of patients's drop-out due to transportation problems. Six and
a half percent of patients could not get access to allergen extract. One
patient was unable to continue AIT, as his father, a health worker, was
hospitalized because of COVID-19 pneumonia. One patient's AIT was
terminated earlier, who was an out of town patient and in the final
months of AIT.
Older age and male gender were correlated with drop-out during the
COVID-19 pandemic. Closure of schools and home-quarantine during
pandemic was reported to cause anxiety in
adolescents\textsuperscript{24}. Older adolescens may have taken the
treatment responsibility themselves and tended to refuse outpatient
admission. Besides, male sex was reported as a risk factor for COVID-19
severity\textsuperscript{25}. These might be associated with reduced
outpatient admissions.
Longer AIT duration, was found to be associated with drop-out during the
COVID-19 pandemic period. We may speculate that the effectiveness of the
AIT up to this period, might cause noncompliance.
Although our study brings some new data to the field there are some
limitation. Firstly, this is a retrospective study up to the COVID-19
pandemic period, and there are some missing data related laboratory
parameters. Secondly, in the present study, definition of compliance
differs from in many studies and may lead to difficulty in comparing
factors associated with AIT compliance. Thirdly, some of the patient's
immunotherapy is stilll ongoing. Therefore the compliance rate may be
higher than other studies for this reason. Despite this limitations, the
present study had the benefits of a large study population including
only children and analyzes the effect of COVID-19 pandemic on AIT for
the first time.
\textbf{Conclusion:}
In conclusion our study demonstrated that the SCIT compliance of
children is higher than adults. Moving to another city, improvement of
symptoms and ineffectiveness are the leading reasons for drop-out.
Besides, COVID-19 pandemic significiantly reduced the compliance of AIT,
nearly one-third of children, especially in older ages and males.
However, we conclude that the drop-outs during the COVID-19 pandemic can
be prevented by an effective physician and patient/family communication
and, by helping with problems and doubts.
CONFLICT OF INTEREST
All authors declared that there are no conflict of interest and no
funding. All authors approved the final version of the manuscript. The
study protocol has been approved by the local ethical committee, and all
parents/guardians provided written informed consent.
ACKNOWLEDGEMENTS
Special thanks to the pediatric allergy department staff who prepare,
coordinate and administer our clinic immunotherapy program and to the
medical staff in outlying offices who help administer the program.
\textbf{TABLES}
\textbf{Table I.} Demographic and clinical characteristics of study
population\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Whole group, n=201\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Compliant group n=173\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Drop-out Group n=28\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
P\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AIT start age*\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{12,8 (9,4-15,2)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{12,9 (9,9-15,3)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{11,1 (7,5-14,8)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0,081}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Current age*\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{15,9 (13,1-18,8)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{16,0 (13,2-18,8)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{15,5 (11,6-18,8)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0,250}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Gender M (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{134 (66,7\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{112 (64,7\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{22(78,6\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0,150}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AIT duration\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{40,7 (20,4-49,9)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{43,5 (24,1-50,4)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{23,6 (14,3-35,6)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Reasons for AIT\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Reasons for AIT\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-Asthma n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{10 (5,0\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{4 (2,3\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{6 (21,4\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-AR\selectlanguage{ngerman}±Asthma n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{154 (76,6\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{138 (79,8\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{16 (57,2\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-Venom, n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{37(18,4\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{31(17,9\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{6 (21,4\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Family history of atopy, n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{96 (47,8)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{84 (48,5\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{12 (42,8\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Type of AIT n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Type of AIT n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-Grass\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{157 (78,1)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{135 (78,1\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{22 (78,6\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-Venom\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{37 (18,4)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{31 (17,9\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{6 (21,4\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0,523}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-House dust mite\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{7 (3,5)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{7 (4,0\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{-}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Total IgE kU/L*\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{218,5 (110,2-467,7)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{202 (100-439)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{290 (184-814)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0,024}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Esinophil number /mm3*\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{200 (100-400)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{200 (100-300)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{300 (100-400)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0,108}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Eosinophil \%*\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{3,1 (1,9-5,4)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{3,1 (1,9-4,9)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{3.5 (2,4-5,9)}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0,217}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}
*Median (interquartile range)
\textbf{Table II.} Reasons of drop-outs before COVID-19 pandemics and
during COVID-19 pandemics\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Before COVID-19 pandemic n(\%) Total population:201 & Before COVID-19
pandemic n(\%) Total population:201 & During COVID-19 pandemic n(\%)
Total population:108 & During COVID-19 pandemic n(\%) Total
population:108\tabularnewline
\midrule
\endhead
Systemic reaction & \textbf{4 (14,3)} & \textbf{Fear of being infected
with COVID-19} & \textbf{11 (35,4)}\tabularnewline
Moving to another city & \textbf{9 (32,1)} & \textbf{Thinking that the
SIT practise was stopped due to COVID-19} & \textbf{9
(29)}\tabularnewline
Long distance & \textbf{2 (7,1)} & \textbf{Problems of transportation} &
\textbf{7 (22,7)}\tabularnewline
Poor efficacy of AIT & \textbf{4 (14,3)} & \textbf{Inability to access
allergen extract} & \textbf{2 (6,5)}\tabularnewline
Improvement of symptoms & \textbf{5 (17,9)} & \textbf{Having a COVID-19
infected family member} & \textbf{1 (3,2)}\tabularnewline
Frequency of injections & \textbf{3 (10,7)} & \textbf{Few doses left to
finalize the treatment} & \textbf{1 (3,2)}\tabularnewline
Inability to access medication & \textbf{1 (3,6)} & &\tabularnewline
Total drop-outs & \textbf{28 (100)} & \textbf{Total drop-outs} &
\textbf{31 (100\%)}\tabularnewline
\bottomrule
\end{longtable}
\textbf{Table III. The compliance and drop-out numbers of the whole
study population.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
Drop-out & Drop-out & Compliance & Compliance & Compliance &
Compliance\tabularnewline
\midrule
\endhead
& & Excellent & Good & Fair & Bad\tabularnewline
1st year n:201 & \textbf{2 (1\%)} & \textbf{199 (99\%)} & \textbf{0} &
\textbf{0} & \textbf{0}\tabularnewline
2nd year n:172 & \textbf{10 (5,7\%)} & \textbf{162 (94,3)} & \textbf{0}
& \textbf{0} & \textbf{0}\tabularnewline
[?]3rd year n:147 & \textbf{16 (10,8\%)} & \textbf{123 (83,8\%)} &
\textbf{6 (4\%)} & \textbf{2 (1,4\%)} & \textbf{0}\tabularnewline
\bottomrule
\end{longtable}
\textbf{Table IV.} Demographic and clinical characteristics of the
drop-out patients during COVID-19 pandemic\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
COVID-19 drop-out group n=31\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
COVID-19 compliant group n=77\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
AIT start age*\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{14.3 (11,0-16,4)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{12.9 (8,8-15,2)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0,094}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Current age*\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{17.5 (13,6-19,2)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{14.5 (10,8-17,1)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0,004}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Gender M (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{23/8 (66,7)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{41 (53,2)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0,045}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
AIT duration\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{40.0 (29,0-49,8)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{28.6 (9,8-42,2)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0,018}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Reasons for AIT\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Reasons for AIT\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-Asthma n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0 (0,0)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{3 (3,9)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0,356}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-AR\selectlanguage{ngerman}±Asthma n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{25 (80,6)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{60 (77.9)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-Venom, n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{6 (19,4)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{14 (18,2)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Family history of atopy, n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{20 (64,6)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{46 (59,7)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0,979}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Type of AIT n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Type of AIT n(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-Grass\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{22 (71\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{59 (76,6\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.689}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-Venom\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{6 (19,4\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{14 (18,2\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
-House dust mite\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{3 (9,6\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{4 (5,2)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Total IgE*,kU/L\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{197 (26-512)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{196 (70-312)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.918}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Eosinophil number /mm3*\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{200 (100-400)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{200 (100-400)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.765}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Eosinophil \%*\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{2.9 (1.3-6.0)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{3.2 (1.9-5.8)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.823}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}
\textbf{Table V.} Results of univariate and multivariate analysis of
factors associated with AIT compliance during the COVID-19 pandemic.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
& Univariate & Univariate & Univariate & Multivariate & Multivariate &
Multivariate\tabularnewline
\midrule
\endhead
& \textbf{OR} & \textbf{95\%CI} & \textbf{P} & \textbf{OR} &
\textbf{95\%CI} & \textbf{P}\tabularnewline
Current age & 1,193 & 1,051-1,354 & 0,006 & 1,209 & 1,064-1,375 &
0,004\tabularnewline
Gender (Male) & 2,524 & 1,005-6,339 & 0,049 & 2,972 & 1,132-7,804 &
0,027\tabularnewline
Duration of AIT & 1,040 & 1,011-1,070 & 0,007 & & &\tabularnewline
\bottomrule
\end{longtable}
\textbf{Figure Legends:}
\textbf{Figure I:Allergen immunotherapy compliance over time by
Kaplan-Meier analysis}
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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure--AIT/figure--AIT}
\end{center}
\end{figure}
\selectlanguage{english}
\FloatBarrier
\end{document}