PRACE ORYGINALNE
Magdalena ZASADA1
Małgorzata KLIMEK1
Wojciech DURLAK1
Monika KOTULA2
Tomasz TOMASIK1
Przemko KWINTA1
Prevalence of respiratory tract infections,
allergies and assessment of humoral immunity
within the malopolska region’s cohort of 11year old children born with extremely low birth
weight in comparison with to their term born
peers
Oszacowanie występowania infekcji dróg oddechowych i
alergii oraz ocena odporności humoralnej w małopolskiej
kohorcie 11-latków urodzonych z ekstremalnie
małą masą urodzeniową i w grupie ich równolatków
urodzonych w fizjologicznym terminie porodu
Department of Pediatrics,
Polish-American Children’s Hospital,
Jagiellonian University Medical College
Head:
Prof. UJ dr hab. med. Przemko Kwinta
1
Department of Clinical Immunology,
University Children’s Hospital
Head:
Prof. dr hab. med. Maciej Siedlar
2
Additional key words:
ELBW (extremely low birth weight)
prematurity
follow-up
adolescents
respiratory tract infections
asthma
allergy
IgE (Immunoglobulin E)
Dodatkowe słowa kluczowe:
ELBW (ekstremalnie mała masa urodzeniowa)
wcześniactwo
badanie obserwacyjne
nastolatki
infekcje dróg oddechowych
astma
alergia
immunoglobulina E
Adres do korespondencji:
Magdalena Zasada, MD
Department of Pediatrics, Polish-American
Children’s Hospital, Jagiellonian University
Medical College, Krakow, Poland
30-663 Krakow, Ul. Wielicka 265, Poland
tel.: 48 12 658 20 11
fax.: +48 12 658 44 46
e-mail: [email protected]
Przegląd Lekarski 2016 / 73 / 4
Background: Children born with
extremely low birth weight (ELBW)
have more respiratory tract complications during childhood. Little is known
about respiratory and allergy problems
in ELBW children at the threshold of
adolescence.
Materials and Methods: A follow-up study was conducted at the age of
11 among ELBW children (n=65) and
age-matched controls (n=36). The primary outcomes in the study were the
occurrence of respiratory and allergy
problems and the rate of hospitalization due to respiratory complications
at the age of 11 years, assessed with
a questionnaire. Secondary outcome
variables were serum levels of immunoglobulin classes.
Results: ELBW children had more
respiratory tract infections (31 vs.11%,
p=0.03), but less allergies (3 vs. 22%,
p<0.01) compared with controls and
had lower level of serum tIgE (geometric mean: 46.5 vs. 89.3 kU/l, p=0.02).
The risk factors for the occurrence of
respiratory tract disorders in the ELBW
group were: low gestational age, need
for surfactant therapy and length of
ventilatory support in the neonatal
period.
Conclusions: ELBW children have
more frequent respiratory tract complications, but fewer allergies at the age
of 11 years compared with children
born at term. Lower respiratory tract
problems decrease in ELBW children
with age. Respiratory tract infections
are not connected with deficiency in
humoral immunity.
Wprowadzenie: Dzieci urodzone z
ekstremalnie małą masą urodzeniową
(ELBW) w porównaniu do dzieci urodzonych w fizjologicznym terminie porodu w okresie wczesnego dzieciństwa
częściej chorują na zakażenia dróg
oddechowych. Mało jest jednak wiarygodnych danych na temat problemów
oddechowych i alergicznych u dzieci
powyżej 10 roku życia urodzonych z
ekstremalnie małą masą urodzeniową.
Materiały i metody: Badanie obserwacyjne zostało przeprowadzone w
grupie 11-letnich dzieci urodzonych z
ekstremalnie małą masą urodzeniową
(n=65) i w grupie kontrolnej dzieci
urodzonych w fizjologicznym terminie porodu (n=36). Pierwotnymi
punktami końcowymi badania były:
występowanie problemów oddechowych i alergicznych oraz częstość
hospitalizacji z powodów pulmonologicznych w wieku 11 lat, oszacowanych
za pomocą kwestionariusza. Wtórnymi
punktami końcowymi były poziomy
poszczególnych klas immunoglobulin
we krwi.
Wyniki: Dzieci urodzone z ELBW
miały więcej infekcji dróg oddechowych (31 vs. 11%; p=0,03), ale mniej alergii (3 vs. 22%; p<0,01) w porównaniu z
grupą kontrolną, ponadto miały niższy
poziom całkowitego IgE (tIgE) we krwi
(średnia geometryczna: 46,5 vs. 89,3
kU/l; p=0,02). Stężenia pozostałych
klas immunoglobulin były w obu grupach podobne. Czynnikami ryzyka
wystąpienia infekcji dróg oddechowych w grupie ELBW były: niższy wiek
płodowy, konieczność terapii surfaktantem oraz wsparcia oddechowego
w okresie noworodkowym.
Wnioski: Dzieci urodzone z ELBW
miały więcej infekcji dróg oddechowych ale mniej problemów alergicznych
201
w wieku 11 lat w porównaniu z dziećmi w tym samym wieku
urodzonymi o czasie. Ilość infekcji dolnych dróg oddechowych u dzieci z ELBW zmniejsza się z wiekiem. Infekcje dróg
oddechowych nie są związane z niedoborami odporności
humoralnej.
Introduction
Premature birth affects many aspects
of further life. Adverse outcomes of prematurity impact most often the survivors with
the lowest gestational age and birth weight
[1]. In addition to possible problems with vision, neurological development, ex-preterm
individuals may also have problems with
recurrent respiratory infections [2].
Most of the studies that track the fate of
extremely low birth weight children (ELBW)
focus on the early years of their life. Data
on children with ELBW over 10 years of age
consist mainly of an assessment of function
of the respiratory system. Information about
the incidence of respiratory tract infection
and hospitalization related to the respiratory
problems in children older than 10 years old
are scarce, this which exist, involve either
ex-preterm patients with higher birth weight
[3], or are out-of-date because of the fact
that the cohort consisted of children born
when neonatal treatment strategies were
different [4].
Therefore an ongoing follow-up and
analysis of the current ELBW survivors is
very important and provides an up-to-date
feedback on the current treatment strategies
for extremely immature neonates in the
postnatal period.
According to the current knowledge,
the increased rate of respiratory tract infections in ex-preterm children is in main part
associated with bronchopulmonary dysplasia (BPD) and a concomitant diminishing
amount of active lung tissue. In spite of the
possibility of using less invasive ventilation
support strategies, avoiding excessive oxygen supply, decreasing postnatal infections,
and optimizing nutrition, BPD still develops
in children born very prematurely. At the
present time, it is called “new BPD”, and it is
a developmental condition in which the lungs
are not able to reach complete structural
complexity and therefore the gas exchange
area is reduced [5].
Little is known about the immunological status of children with ELBW on the
threshold of adolescence. Without doubts
antibody deficiencies may result in recurrent
and severe sinopulmonary infections [6].
Children with antibody deficiency commonly
present with recurrent otitis media, sinusitis
and pneumonia [7], what is more, viral infections of the respiratory tract also occur
more frequently in these patients [8]. The
most common antibody deficiency in young
children is i.a. selective antibody deficiency
[9]. Moreover, measurement of the level of
Immunoglobulin E (IgE) is helpful in patients
with recurrent sinopulmonary infections,
because its elevation is consistent with
underlying allergic disease [10].
Our aim in this study was to estimate
the respiratory disorders and frequencies
of allergies and to determine the functioning
of the humoral immune system of preemies
born with gestational age <30 weeks and
birth weight <1000 grams (ELBW) in comparison with the control group born on term
at the age of 11 years. We also wanted to
compare our results with previous values
obtained from the follow-up assessment
when both groups were 6-7 years old to see
trends in the frequency of these problems.
What is more, we were also curious which
factors are responsible for the risk of persistence of the respiratory tract disorders in
the ELBW group.
2002 to August 31, 2004, 169 newborns with
birth weight <1000 grams were born alive in
the south-east district of Poland (Malopolska
Region). All children were hospitalized in 3
tertiary care Neonatal Intensive Care Units
(NICU) in south-east Poland. Ninety-one
infants were discharged home from the
NICUs and followed longitudinally. All those,
who took part in the follow-up assessment at
6-7 years of age, were invited to participate
in the present follow-up study. Neonatal
data used for the study was recorded daily
during their hospitalization in the NICU
in a prospective manner and stored on
computer databases. For the purpose of
the study the following data was extracted
from the original databases: gender, birth
weight, gestational age, intrauterine growth
parameters, Apgar score, mode of ventilation support, ante- and postnatal steroid
treatment, presence of bronchopulmonary
dysplasia (BPD) at 36 weeks postmenstrual
age (PMA). The control group from one general practice office consisting of 40 children
born on time with birth weight >2500 grams
was recruited in 2009-2010 year, all of them
were invited for the re-assessment. Detailed
methodology and the results of the follow-up
performed at 6-7 years of life have already
been published [13].
The study was approved by the Ethical
Committee for Clinical Investigations of
Collegium Medicum, Jagiellonian University,
Krakow, Poland.
Materials and Methods
A cross-section observational study
was conducted in the Outpatient Pediatric
Department of the Polish-American Children’s Hospital, Krakow, Poland, between
December 30, 2013 and April 30, 2015. The
study cohort consisted of ELBW survivors
recruited at birth and born on term control
participants enrolled when both groups were
6-7 years old [11,12]. From September 1,
Follow Up at 11 years of age
During one visit to the Outpatient Paediatric Department of the Polish-American
Children’s Hospital in Krakow, all the invited
children underwent the following procedures: filling in a questionnaire by parents
about their children’s demographic data and
health status, physical examination, blood
sampling for the assessment of the level of
immunoglobulins.
Figure 1
Patients flow through the following steps of the study.
Schemat kolejnych etapów badania.
NICU – neonatal intensive care unit, ELBW – extremely low birth weight, FU –
follow-up
202
Figure 2
Comparison of the presence of respiratory and atopic problems between the
groups at 11 years of age.
Porównanie częstości występowania problemów oddechowych i alergicznych pomiędzy
obiema grupami w wieku 11 lat.
M. Zasada i wsp.
Questionnaire and physical examination
After signing an informed consent, parents were asked to complete a custom-made
questionnaire, containing i.e. questions
about: demographic variables, upper and
lower respiratory tract diseases and hospitalizations related to them over the past four
years, current diseases, presence of tonsils
hypertrophy, allergy, asthma and chronic
medical treatment. A physician verified all
questions during face to face discussion.
Afterwards, all children were examined
by the physician for the presence of acute
infection, hypertrophy of the tonsils; signs of
allergy (rhinoconjunctivitis, allergic rhinitis,
eczema), the current weight and height were
also measured.
Laboratory evaluation
After the physical examination, a venous
blood sample (5 ml) was taken for the assessment of serum total IgA, IgM, IgG, and
IgE level. Immunoglobulins IgG, IgA, IgM
were measured by an immunonephelometric method, using antisera from Siemens
Healthcare Diagnostics Products GmbH
(Marburg, Germany). Serum total IgE levels
were measured using particle-enhanced
immunonephelometry with System BN II
and BN ProSpec® (Siemens Healthcare
Diagnostics Products GmbH, Marburg,
Germany). Age-adjusted normal reference
ranges were used to assess the accurate
level of immunoglobulins. Normal values
of immunoglobulins [g/l] were as follow:
IgG 6.38-17.0 IgA 0.63-3.32, IgM 0.4-1.98.
Serum IgE levels above >200 kU/L were
recognized as a positive result [14].
Outcome variables
The primary outcomes at the age of 11
years were the presence of respiratory and
allergic problems and rate of hospitalization
due to respiratory problems at this age.
Upper respiratory infections were defined as
acute nasopharyngitis, sinusitis, pharyngitis,
tonsillitis, laryngitis, tracheitis or upper respiratory infections of multiple and unspecified
sites. Lower respiratory infections were
defined as acute bronchitis and pneumonia.
Hypertrophy of the tonsils and third tonsil
was recognized when a child attended
the otolaryngologist’s care because of this
condition. Allergy (i.e. rhinoconjunctivitis,
allergic rhinitis, eczema) was recognized
according to the positive medical records,
signs of allergy on physical examination and/
or anti-allergic treatment in the past 4 years.
Asthma was defined as positive medical
diagnosis of asthma and/or anti-asthmatic
treatment in the past 4 years.
Secondary outcome variables were
levels of immunoglobulins G, M, A and E.
Statistical methods
In order to draw a comparison between
the groups, the following tests were utilized
as was deemed appropriate: Mann–Whitney U test, Fisher’s exact test, Pearson’s
chi-squared test, Welch’s t test, Student’s
t-test, Wilcoxon Signed Rank Test, Paired T
Test. Statistical significance was defined for
two sided test at the p=0.05 level. Data was
analysed using JMP 9.0.0 Software (2010 by
SAS Institute Inc., Cary, NC, USA).
Przegląd Lekarski 2016 / 73 / 4
Results
Population characteristics
Sixty-five children born as ELBW infants
(81.25% of the available population) with a
mean birth weight of 843 grams (SD: 132
grams) and a mean gestational age of 27.3
weeks (SD: 2.3 weeks) were evaluated at a
mean age of 11 years (SD: 0.38 year). The
control group included 36 full term-children
(90% of the available cohort) – Figure 1.
All patients were in good health, free from
infection at the time of the observation; all
were fasting at the time of venepuncture.
The comparison of selected demographic variables between the studied groups
is shown in Table I. Female gender is
more frequent in the ELBW group. Vaginal
delivery was more frequent in the control
group. ELBW children were more frequently
small for gestational age compared with the
children from control group. According to
the current measurements, children from
the ELBW group had significantly lower
weight and height in comparison with the
control group.
Prevalence of respiratory tract disorders,
allergy and asthma at 11 years of age
The results of the questionnaire related
to respiratory and atopic problems are pre-
Table I
Comparison of selected demographic and clinical variables between ELBW patients and the control group.*
Porównanie wybranych danych demograficznych i klinicznych między grupą pacjentów urodzonych z ekstremalnie
niską masa urodzeniową i grupą kontrolną.*
ELBW group (n=65)
Control group (n=36)
P value
Birth weight [g], mean (SD)
843.3 (±132.4)
3589.4 (±538.8)
<0.0001U
Gestational age [weeks], mean (SD)
27.3 (±2.3)
39,8 (±1.3)
<0.0001U
Female
44 (67.7%)
17 (47.2%)
0.0566F
Vaginal delivery
11 (20.4%)
31 (86.1%)
<0.0001F
Small for gestational age
19 (31.1%)
2 (6.1%)
Perinatal Factors
5th min. Apgar score, Me; (IQR)
0.0046F
<0.0001U
6 (5;7)
10 (9;10)
Current age [years], mean (SD)
11.06 (±0.38)
10.62 (±0.82)
0.0044W
Current weight [kg], mean (SD)
33.52 (±8.41)
40.45 (±9.96)
0.0005U
Data on 10-11 years of age
Current weight (z-score), mean (SD)
-0.89 (±1.29)
0.2 (±1.15)
0.005U
Current height [cm], mean (SD)
141.23 (±7.91)
146.26 (±8.81)
0.0041S
Current height (z-score), mean (SD)
-0.89 (±1.18)
0.18 (±1.12)
0.001S
School attendance
63 (97%)
36 (100%)
0.5366F
Pets at home
7 (11.7%)
3 (9.7%)
0.9999F
Paternal history of atopy
12 (20.0%)
3 (9.7%)
0.2485F
*Expressed as a number (percentage) of patients unless otherwise indicated,
U
Mann–Whitney U test, F Fisher’s exact test, P Pearson’s chi-squared test, W Welch’s t test, S Student’s t-test
Table II
Laboratory test results in the studied groups.*
Wyniki badań laboratoryjnych w analizowanych grupach.*
Serum tIgA [g/l], Me (IQR)
ELBW group (n=65)
Control group (n=36)
p value
1.54 (0.28; 2.02)
1.53 (1.17; 1.99)
p=0.86U
High (>upper limit for age)
3 (4.6%)
3 (8.3%)
Normal
61 (93.8%)
33 (91.7%)
Low (<lower limit for age)
1 (1.5%)
0
Serum tIgM [g/l], Me (IQR)
1.08 (0.85; 1.35)
1.13 (0.91; 1.47)
High (>upper limit for age)
4 (6.2%)
6 (16.7%)
Normal
61 (63.8%)
30 (83.3%)
Low (<lower limit for age)
0
0
Serum tIgG [g/l], Me (IQR)
12.5 (10.1; 14.0)
11.3 (10.0; 12.5)
High (>upper limit for age)
6 (9.2%)
1 (2.8%)
Normal
59 (90.8%)
35 (97.2%)
Low (<lower limit for age)
0
0
Serum tIgE [kU/l], geometric mean (SD)
46.53 (±157.24)
89.38 (±401.98)
Normal
57 (87.7%)
28 (77.8%)
High (>upper limit for age)
8 (12.3%)
8 (22.2%)
p=0.57P
p=0.85U
P=0.16F
p=0.08U
p=0.41F
p=0.02U
p=0.25F
*Expressed as a number (percentage) of patients unless otherwise indicated,
U
Mann–Whitney U test, F Fisher’s exact test, P Pearson’s chi-squared test
203
Table III
Change of the respiratory tract disorders and allergy between 6-7 and 11 years of age.*
Zmiana w częstości występowania infekcji dróg oddechowych i problemów alergicznych w wieku 6-7 vs. 11 lat.*
ELBW (n=65)
Control (n=36)
6-7 years of age
11 years of age
p
6-7 years of age
11 years of age
p
Asthma
2 (3%)
6(9%)
0.2188W
1(3%)
4(11%)
0.9999W
Allergy
13 (20%)
2 (3%)
0.0386W
11 (31%)
8 (22%)
0.5000W
Tonsils hypertrophy
17(27%)
6(9%)
0.0129W
6(17%)
4(11%)
0.999W
Lower respiratory infections
22(34%)
7(11%)
0.0118W
5(14%)
1(3%)
0.6250W
tIgE [kU/l] geometric mean, (SD)
90 (±207)
96 (±159)
0.9895T
113 (±136)
240 (±408)
0.3200T
*Expressed as a number (percentage) of patients unless otherwise indicated, W – Wilcoxon Signed Rank Test, T – Paired T Test
Table IV
Comparison of selected factors between the group of 11-year old ELBW children with and without respiratory tract problems (upper and lower respiratory tract disorders).*
Porównanie wybranych czynników w grupie 11-letnich dzieci urodzonych z ELBW z występującymi w okresie ostatnich 4 lat i bez występujących w okresie ostatnich 4 lat infekcji
dróg oddechowych.*
ELBW children without respiratory
problems in last 4 years
(n=45)
ELBW children with respiratory
problems in last 4 years
(n=20)
p
Perinatal factors
Birth weight (g), Me (IQR)
900 (762;967)
815 (675;937)
0.15U
Gestational age (weeks), mean (SD)
27.7 (±2.38)
26.5 (±2.01)
0.048S
Female
30 (66.7%)
14 (70%)
0.9999F
Small for gestational age
16 (36.4%)
3 (17.6%)
0.22F
5th min. Apgar score, Me; (IQR)
6 (5;7)
6 (4;7)
0.46U
Length of mechanical ventilation (days), Me (IQR)
18 (1;38.25)
30 (7;48)
0.09U
Length of CPAP therapy (days), Me (IQR)
4 (1;11)
11 (4;19)
0.02U
Length of oxygen therapy (days), Me (IQR)
40 (6;77)
62 (44;97)
0.053U
Surfactant administration
28 (67 %)
19 (100%)
0.0028F
Antenatal steroid therapy
18 (42 %)
13 (68%)
0.0971F
Postnatal steroids
18 (43%)
12(63%)
0.1737F
BPD at 36 PMA
34 (79 %)
17 (89%)
0.4778F
26 (59%)
14 (70%)
0.5783F
Respiratory disorders in 6-7 years of age
14 (32%)
8 (40%)
0.5772F
Tonsils hypertrophy at 6-7 years of age
12 (27%)
5 (25%)
0.9999F
Hospitalization due to respiratory problems at 6-7 years of age
25 (57%)
16 (80%)
0.0954F
Allergy
1 (2.2%)
1 (5.3%)
0.51F
Respiratory disorders in the first 2 years of age
Status at 6-7 years
Recent status
Asthma
5 (11.1%)
1 (5.3%)
0.66F
Tonsils hypertrophy
3 (6.7%)
3 (15%)
0.36F
Hospitalization in the last 4 years due to respiratory tract infection
0 (0.0%)
2 (10%)
0.0942F
Pets at home
5 (12%)
2 (11%)
0.9999F
Current laboratory test results
Serum tIgG [g/l], Me (IQR)
12.45 (10.23;13.83)
12.5 (9.32;14.3)
0.89U
Serum tIgA [g/l], Me (IQR)
1.46 (1.07;2.01)
1.63 (1.32;2.02)
0.58U
Serum tIgM [g/l], Me (IQR)
1.1 (0.86;1.33)
1.03 (0.83;1.46)
0.99U
Serum tIgE [kU/l], geometric mean (SD)
48.2 (±156.1)
43.0 (±168.5)
0.68U
* Expressed as a number (percentage) of patients unless otherwise indicated, U Mann–Whitney U test, F Fisher’s exact test, P Pearson’s chi-squared test
sented in Figure 2. Any respiratory tract infections (sum of upper and lower respiratory
tract infections) during the last 4 years were
reported more frequently in the ELBW group
(31 vs. 11%, p=0.03), although the statistical
difference between patients suffering from
upper (23 vs. 11%, p=0.19) and lower respiratory disorders (11 vs. 3%, p=0.25) was not
reached. There was no difference between
the hospitalization rate due to respiratory
204
tract problems between the ELBW and
control group during the last 4 years (3 vs. 0
pts, p=0.53). Tonsils hypertrophy was found
in equal percentage of patients (9 vs. 11%,
p=0.74). The same percentage of children
from both groups was currently being treated
for asthma (9 vs. 11%, p=0.74). Significantly
lower proportion of children from the ELBW
group suffered from the symptoms of allergy
(3 vs. 22%, p<0.01).
Immunoglobulins levels
Serum tIgA, tIgM and tIgG levels were
similar in both groups – Table II. No children
with diminished levels of serum tIgM or tIgG
were found in either group. However there
was one patient from the ELBW group with
lower than normal level of serum tIgA. Percentages of children with elevated tIgA, tIgM
and tIgG level were similar in both groups.
M. Zasada i wsp.
Serum tIgE level (geometric mean) was
higher in the control group.
Change of the respiratory tract disorders, allergy and asthma prevalence between 6-7 and 11 years of age
The frequency of asthma was higher in
older children in both groups, the level of
allergy, tonsil hypertrophy and lower respiratory infections were more frequent at the
younger age in both groups. Statistically
significant differences were confirmed for
allergy, tonsil hypertrophy and lower respiratory infections in the ELBW group (Tab.
III). The level of IgE was similar in both
analysed groups.
Risk factors of persistence of the respiratory tract disorders in the ELBW group
Comparison of selected factors in ELBW
children with or without respiratory tract
problems (upper and lower respiratory infections) in the last 4 years is presented in Table
IV. Children still having respiratory tract problems were born with lower gestational age
(26.5 vs. 27.7 weeks, p=0.048), more often
required surfactant therapy for respiratory
distress syndrome (100 vs. 67%, p=0.0028)
and required longer CPAP therapy (11 vs.
4 days, p=0.02). There were no differences
between groups according to: birth weight,
gender or Apgar score at 5th min. A similar
number of children from both groups had
respiratory disorders in the first two years
of age. Having analysed the current status
of these children, there was no observed
difference in the presence of allergy, asthma
or immunoglobulin serum levels.
Discussion
In this study we assessed respiratory
and allergic problems in the geographically
based cohort of ELBW children at the mean
age of 11 years in comparison with age-matched children born on term. Thanks to the
follow-up assessment we can conclude, that
children born as ELBW at 11 years of age
still have more respiratory tract infections
(understood as upper and lower respiratory
tract infections) compared with their born on
time peers. Contrary to this observation, the
rate of allergies is significantly lower in 11
years old ELBW children and the level of
serum tIgE is lower at 11 years of age in the
ELBW group compared with the control. We
didn’t notice any differences between serum
level of tIgA, IgG and IgM and didn’t find
any patient with significant immunoglobulin
deficiency.
When we took into consideration the
prevalence of respiratory and allergic problems at the age of 6-7 and four years later,
we could observe a trend of higher incidence
of asthma in both groups and diminishing
level of patients with lower respiratory tract
infections, tonsils hypertrophy and allergies,
although the statistical difference was reached only in the ELBW group.
Last but not least, evaluation of the
risk factors of the occurrence of respiratory
tract disorders at 11 years of age in the
ELBW group revealed that children born
with lower gestational age and with poorer
respiratory tract function at the beginning of
life have more respiratory problems – requiring surfactant more often because of the
respiratory distress syndrome and having
Przegląd Lekarski 2016 / 73 / 4
longer ventilation support (significant difference seen in the length of CPAP therapy,
but trends observed also for the mechanical
ventilation and oxygen supplementation).
Current patient status seems to have no
impact on the prevalence of respiratory
tract disorders.
Prevalence of respiratory tract infections
& hospitalization rate
Data presented in the publications
indicates an increased rate of recurrent
respiratory tract infections and hospitalizations of patients born with ELBW because of
respiratory-related illnesses in infancy and
early-childhood [15]. In infancy children born
prematurely are symptomatic with cough,
wheeze and have recurrent respiratory tract
infections [16]. Very prematurely born infants
in the first 2 years of life often have multiple
admissions to hospital [17], especially for
lower respiratory tract infections caused
by respiratory syncytial virus [18]. After 2
years of age the hospitalization rate due to
respiratory problems per year decreases
[19]. Nevertheless in the 6-7 year old ELBW
survivors it is still four times higher than in
their term-born peers [13]. The number of
prescriptions due to respiratory problems
remains relatively high till school age [19].
From Lum et al. research [20], performed on a subgroup of the 1995 EPICure
study, we know, that 78% of 11-year old children born with ELBW have noticeable lung
function abnormalities like airway obstruction, ventilation inhomogeneity, gas trapping
and airway hyper responsiveness. Choukron
et al. [21] showed in a cohort of school-aged
children born with a gestational age ≤32
weeks an increased level of obstructive and/
or restrictive lung abnormalities. Current
research about spirometry tests results
showing airway obstruction at school-age
ELBW children indicate a persistent problem
with the abnormal lung function [22]. But it is
unclear; if this altered function is connected
with increased level of infections. In our
study we showed, that young adolescents
born with ELBW had more respiratory tract
infections during past 4 years than the control group (31 vs. 11%). Our hypothesis is
that changes in respiratory tract observed
by the authors cited above cause, that these
children are still more predisposed to airway
tract infections. However, we also showed,
that having reached 11 years ELBW subjects did not require hospitalization due to
respiratory tract problems more frequently
than their born on time peers. However, our
results require further observation, because
according to the Walter et al. [3], young
adults born with a birth weight lower than
1500 grams require more often hospitalization due to respiratory problems.
Comparing our current results with the
results of the first-follow-up of these patients
at the age of 6-7 years [13], we can observe
decreasing rate of hospitalizations. According to our previous publication [13], 60%
of children from the ELBW group required
hospitalization due to respiratory tract infection by 7 years of age. During the 7th year of
age 11% of the whole cohort required hospitalization. Our current results show a 3%
rate of hospitalization during 7-11 years of
age. The diminished level of hospitalization
may be due to diminished infection rate, but
maybe the degree of severity of the infection
and the patients’ immunocompetency allow
for treatment at home.
Asthma
Existing publications about the pulmonary sequelae of school-age children born with
ELBW focus mainly on the poor spirometry
results pointing to an airway obstruction
[22]. In our study we can see a trend in the
increased level of patients with asthma, but
the results are similar in ELBW and control
group, and are comparable to other epidemiological studies of children at a similar
age in Europe [23].
Immunoglobulin IgA, IgM, IgG serum
levels
In our study we demonstrated, that the
humoral immune system in children with
ELBW works just as well as those born with
normal birth weight (NBW), and protects
them from increased level of respiratory
tract infections. ELBW infants suffer in the
first months of life due to the absence of maternal IgG. However studies on vaccinations
performed in young childhood proved that
ELBW children’s humoral response against
most microbial antigens in vaccinations is as
good as NBW children [24,25]. The observation that immune system of ELBW is normal
after several years is quite predictable,
however, we are one of the few researchers
who demonstrated it on an adolescent
ELBW group. What is more, according to our
results, we can state, that children born with
ELBW do not seem to have more frequently
any antibody class deficiency compared with
children born with NBW.
Allergies and tIgE level
The level of reported/examined symptoms of allergy was significantly higher in
the control group compared with the ELBW
group. We documented significantly higher
serum tIgE in the control group. A similar
difference was observed in our previous
assessment of this cohort at 6-7 years [13].
Moreover the level of tIgE was more frequently above the upper limits in the control
group compared with the ELBW group,
although the difference was not statistically
significant. Siltanen et al. [26] in her group
of 166 18-27-year old adults born with
VLBW by measuring tIgE and 3 types of
allergen-specific (cat, birch, and timothy)
IgE, also came to similar results. According
to her study, in young adults born preterm
with VLBW the rate of atopy was lower
compared with the term-born controls. Taking into consideration our and her results,
we can hypothesize, that predisposition to
atopy is determined during early stages of
development and preterm birth affects the
development of tolerance rather than sensitization to antigen [27].
Mean value of tIgE was slightly elevated
during 4 years in both groups. Although this
difference did not reach the significance, it
is consistent with some longitudinal studies,
which show that levels of IgE increase with
age from birth regardless of atopic status
[28].
Risk factors of persistence of the respiratory tract disorders in the ELBW group
205
Evaluation of the risk factors of the occurrence of respiratory tract disorders at 11
years of age in the ELBW group revealed,
that children born with younger gestational
age and with poorer respiratory tract function
at the beginning of life have more problems
requiring surfactant more often because
of the respiratory distress syndrome and
having longer ventilation support. Current
patient status seems to have no impact on
the prevalence of respiratory tract disorders.
In an observational study Yu et al.[29] showed similarly that among all ELBW group,
children <800 g had more pneumonias
and otitis media episodes between 2 and
5 years of life.
Strengths and limitations
In our opinion, the study has a significant
value and provides a new insight into the
problem of respiratory tract infections in 11
year-old children born with ELBW. First of
all, the study group included the majority of
newborns from the whole of the Malopolska
region born in a period of 2 years that reached the age of 11 years. The data in our
multi-centre study comes from all the tertiary
referral centres from the Malopolska region.
It is a complete group of patients with a high
percentage of observation. Moreover the
assessment of the past and current health
status of the child was based on patient’s
physical examination and a custom-made
questionnaire, created by us specifically
for this research purpose. All children were
examined by an investigator for the presence of symptoms of respiratory tract or allergy
disorders. Humoral immunologic system status was partially evaluated by assessment
of serum level of immunoglobulins and the
results were compared to age-adjusted
normal reference ranges.
One of the main limitations of our study
is the fact that our groups, after several
refusals in further participation in the study,
are no longer gender-matched, moreover
the number of participants in both groups is
not equal. Our questionnaire did not contain
questions about the number of siblings, socioeconomic status, and smoking at home
and all these factors could possibly affect the
status of respiratory tract infections in our
patients. What is more, we didn’t perform
the functional tests of the respiratory tract
to assess the rate of asthma. We also had
imprecise definitions of the respiratory tract
problems, diagnoses were based not only
on medical documentation/examination but
also on parents answers, so may be subject
to some degree of reliability, similarly allergy
diagnosis was based on the history of the
patient, and no skin tests were done.
Conclusions
In summary we demonstrated that respiratory problems in ELBW children at the
206
age of 11 years compared with children born
at term still occur more often. Our results
have shown a decreasing tendency of lower
respiratory problems in ELBW children as
they grow up. The need for hospital admissions due to respiratory reasons dropped
drastically and was not different from the
NBW peers group. Mean serum tIgE levels
remain higher and the number of children
with positive results of tIgE levels were more
frequent in the control group.
Longitudinal follow up studies are required to determine if ex-preterm ELBW
subjects will be more susceptible to developing pulmonary disease later in life such
as chronic obstructive pulmonary disease.
Disclosure Policy
The authors declare that there is no
conflict of interest regarding the publication
of this paper.
Acknowledgements
The authors would like to thank the
families who participated in this study and K.
Starzec, MD, for her help in gathering data.
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