INTRODUCTION
Asthma is the most common chronic disease of childhood; it is a worldwide problem
that affects approximately 100 million people worldwide. During the past several
decades, this prevalence has been increasing by 5 to 6% per year reaching rates
of 30 to 40% in many countries. Therefore, it is important to assess accurately
the impact of such a wide spread illness and its treatment regarding efficacy
and safety (National Heart, Lung and Blood Institute, 2002).
As in other chronic childhood diseases, impairment of growth may often be seen
in children with asthma. Rarely, poor asthma control is the cause. Factors that
participate in the affection of growth parameters among asthmatic cases are
variable. These include severity and duration of illness, hypoxemia, recurrent
respiratory infections, age at onset of the disease and frequency of hospitalization.
These are in addition to demographic and social factors such as age of the child,
mother's education, hormonal, nutritional and psychological factors. The most
important factors, however, may be asthma severity and treatment with exogenous
corticosteroids (Agertoft and Pedersen, 2000).
ICS are recommended as first line anti-inflammatory therapy for the treatment
of asthma. Also, they are the most effective controller therapy and are therefore
the recommended treatment for asthma in children of all ages (Global
Initiative for Asthma, 1995). However, concerns persist regarding their
potential effect on growth and, most importantly, final height. Moreover, ICS
can decrease the level of adrenal androgens, which in consequence leads to decreased
growth hormone (GH) secretion and affects the hypothalamo-pituitary-gonadal
axis. The whole process can cause growth arrest and pubertal delay (Doull,
2004). All these factors have resulted in reluctance of many physicians
and parents to use ICS (Altintas et al., 2005).
Several studies have addressed the effect of ICS on linear growth and final
height of asthmatic children (Doull, 2004). Allen
(2005, 2007) concluded that the dosage, type of
inhaler device used, patient technique and characteristics of individual drug
all influence the systemic side effects of ICS especially on height. Visitsunthorn
et al. (2002) confirmed that the average dose and duration of ICS
had no significant effects on growth in prepubertal asthmatic children. Allen
(2004) found that dose related inhibition of growth is detectable as ICS
dose increases and Allen (2006) concluded that detectable
suppression of childhood growth can occur when ICS with relatively poor first
pass activation are administered at doses greater than 400 μg/day for more
than 1 year.
With this background, we were stimulated to assess growth and pubertal status among asthmatic children and adolescents on long-term ICS therapy.
MATERIALS AND METHODS
Study population: This case-control study was carried out on 30 asthmatic children and adolescents who had bronchial asthma diagnosed according to the criteria of GINA, 2006 and who were receiving ICS therapy. Patients were recruited from the Pediatric Allergy and Immunology Clinic, Children's Hospital, Ain Shams University during the period from September 2006 until June 2008. They were 18 males (60%) and 12 females (40%). Their ages ranged from 9 to 16 years with a mean of 12.445±1.895 years.
Asthmatic patients were studied in comparison to 20 healthy age- and sex-matched control children who had no clinical findings suggestive of any endocrinal disorder or any disease that might affect growth or puberty. They were recruited from the outpatient clinic of the same hospital. They were 12 males and 8 females and their ages ranged from 10.0 to 15.9 years with a mean of 12.36±1.91 years.
An informed written consent for participation in the study was signed by the parents or legal guardians of the studied subjects.
Study measurements
Clinical evaluation of patients: This was based on clinical history
taking from caregivers, reviewing follow-up sheets and clinical examination.
Special emphasis was done on duration of illness, detailed history of ICS therapy
including dose and duration of therapy. According to the dose, patients were
classified into those who took a dose of >400 μg/day of beclomethasone
dipropionate equivalent and those who took a dose of ≤400 μg/day. In
addition, according to duration of therapy, they were classified into those
who took ICS for >1 year and those who took ICS for ≤1 year. Clinical
examination included auxological measurements (height and weight and their SDSs)
which were calculated according to the norms of Sempe et
al. (1979) and Tanner Pubertal staging which was applied to girls aged
≥11years and to boys aged ≥11.5 years; the age at which puberty is expected
to have started according to Marshall and Tanner (1969).
Assessment of serum FSH and LH levels (for patients only): Both basal
and stimulated serum FSH and LH levels after LHRH stimulation test were measured
by immunochemiluminometric assay (ICMA) based on direct sandwich technique on
the Immulite 2000 apparatus using commercial kits (Diagnostic Products Corp-Med
lab, Los Angeles, CA) (Babson, 1999). Samples for measurement
of FSH and LH were withdrawn before and 4 hours after subcutaneous injection
of 0.1 mg/m2 of LHRH analogue (Styne, 1997).
Both basal and stimulated values were compared to standard reference values
in normal Egyptian children (El-Sedfy and Shahin, 2001).
Assessment of bone age (for patients and controls): This was done by
performing plain x-ray left hand and wrist with calculation of bone age SDS
using the method of Greulich and Pyle (1959).
Measurements of uterine length and right ovarian volume by using pelvic
ultrasound (for patients only): This was applied for girls aged ≥11 years
by using Acouson Computed Sonography with an SL 1 Ultrasonographer (Sono Line;
Siemens, Erlangen, Germany) with 3.5 and 5 MHz linear transducer. Ovarian volume
was calculated according to the formula for ellipsoid bodies where V = longitudinal
diameterx anteroposterior diameterxtransverse diameterx0.5233. Calculation of
SDS of uterine length and right ovarian volume was done and compared to age-matched
values (Griffin et al., 1995).
Statistical analysis: Analysis of data was done on an IBM computer system using SPSS (statistical program for social science) Version 10 as follows: quantitative variables were presented as Mean±SD, median and range while qualitative variables as frequency and percentage. Student t-test was used to compare parametric data, whereas Mann Whitney and Wilcoxon tests were used for non-parametric data. Chi-square test was used to compare qualitative variables. Risk estimation was done by using the odd’s ratio which compares the odds of 2 events, where the odds of an event equals the probability that the event occurs divided by the probability that it does not occur. A 95% confidence interval for the odds ratio was also calculated. If the value of 1 is not in the range of confidence interval, it can be concluded that there is an increased relative risk in one group compared to the other. A p-value of <0.05 was considered significant.
RESULTS
Out of our 30 studied asthmatic patients, 17 (56.67%) received ICS for ≤1 year and 13 (43.33%) for >1 year. Also, 17 patients were receiving ICS at a dose of ≤400 μg/day and the remaining 13 were receiving a dose of >400 μg/day.
Auxological parameters and bone age of asthmatics versus controls: A significant reduction was noticed in each of the height and height SDS of patients in comparison to controls (133.64±9.41 cm versus 142.97±7.05 cm, respectively and -2.09, mean rank: 16.17 versus +0.55, mean rank: 29.42, respectively, p<0.05) while there was a significant increase in the weight for height SDS of patients (+1.20, mean rank: 39.50 versus -0.42, mean rank: 19.63, p<0.05). Bone age and its SDS were significantly lower among cases when compared to controls (10.62±2.12 years versus 12.52±1.88 years and -1.470±1.25 versus +0.241±0.33, respectively, p<0.05).
Growth in relation to dose and duration of ICS therapy: The height was
significantly lower in patients who took ICS at doses of >400 μg/day
when compared to those who took ≤400 μg/day (Mean±SD: 125.44±7.70
versus 135.24±10.34 cm, p<0.05). Also, a significantly lower SDS of
height for age was noticed at doses of >400 μg/day groups in comparison
to doses of ≤400 μg/day (Table 1). The weight (Mean±SD:
32.53±10.07 kg versus 30.65±10.41, respectively), weight for height
SDS, bone age and bone age SDS did not differ between the two groups (p>0.05,
Table 1).
Regarding the duration of ICS therapy, height was significantly lower while weight was significantly higher in patients who took ICS for >1 year in comparison to those who took ICS for ≤1 year (130.37±9.19 versus 138.18±8.10 cm and 36.48±12.21 versus 28.31±6.83 kg, respectively, p<0.05). In addition, significantly lower SDS of height for age, higher SDS of weight for height and lower bone age were noticed in patients who took ICS therapy for >1 year (Table 2).
Therefore, doses of ICS of >400 μg/day affected height and its SDS only with no effect on other auxological parameters (weight and its SDS and bone age and its SDS) whereas the use of ICS for >1 year affected all auxological parameters (height and its SDS, weight and its SDS and bone age).
Also, we found that each of the height and its SDS, weight and its SDS and bone age and its SDS did not significantly differ in patients receiving ICS therapy at doses ≤400 μg/day and those receiving ICS therapy for ≤1year from those of controls (p>0.05). This means that ICS at doses ≤400 μg/day and for ≤1 year are safe.
Pubertal development in relation to dose and duration of ICS therapy: Among the 30 asthmatic patients, 23 (76.66%) were expected to be pubertal (Tanner stages 2-5) based on their ages. These were girls aged ≥11.5 years and boys aged ≥11 years. However, 7/23 (30.43%) were still prepubertal (Tanner 1).
| Table 1: |
The effect of the dose of ICS on SDS of height for age, SDS
of weight for height, bone age and its SDS in patients’ group |
 |
| SDS: Standard deviation score. ICS: Inhaled corticosteroids,
*p<0.05: Significant |
| Table 2: |
Duration of ICS therapy in relation to SDS of height for
age, SDS of weight for height, bone age and its SDS among patients’
group |
 |
| SDS: Standard deviation score. ICS: Inhaled corticosteroids,
*p<0.05: Significant |
| Table 3: |
Basal and stimulated gonadotropins in relation to the dose
of ICS in patients’ group |
 |
| FSH: Follicle stimulating hormone, LH: Lutenizing hormone,
LHRH: Lutenizing hormone releasing hormone, ICS:L Inhaled corticosteroids,
*p<0.05: Significant |
| Table 4: |
Basal and stimulated gonadotropins with respect to duration
of ICS in the patients’ group |
 |
| FSH: Follicle stimulating hormone, LH: Lutenizing hormone,
LHRH: Lutenizing hormone releasing hormone, ICS: Inhaled corticosteroids,
*p<0.05: Significant |
All the 7 cases (100%) with delayed puberty were detected among those receiving ICS doses of >400 μg/day for > 1 year.
Uterine length and right ovarian volume did not differ significantly with respect to the dose of ICS (>400 μg/day versus ≤400 μg/day) (3.98±1.30 versus 5.05±1.36 cm and 1.66±0.36 versus 1.41±0.81 mL, respectively, p>0.05). Moreover, SDSs of both parameters did not differ significantly (-1.21, mean rank: 7.63, versus -0.14, mean rank: 11.00 and -1.27, mean rank: 19.71 versus +0.35, mean rank: 25.40 respectively, p>0.05). The same was seen with basal FSH and LH (p>0.05) whereas after LHRH stimulation, FSH and LH were significantly lower among those who received ICS therapy at doses of >400 μg/day (p<0.05, Table 3).
The duration of ICS therapy did not have a significant impact on uterine length and right ovarian volume (>1year versus ≤1 year duration: 4.92±1.4 versus 4.29±1.36 cm and 2.23±0.78 versus 1.96±0.72 mL, respectively, p>0.05). The SDSs of both parameters followed the same pattern (-0.38, mean rank: 10.50 versus -1.16, mean rank: 8.70 and +0.35, mean rank: 25.18 versus -1.21, mean rank: 21.40, respectively, p>0.05). Basal and stimulated FSH and LH were significantly lower among those who received ICS therapy for >1 year (p<0.05, Table 4).
Frequency of low basal and/or stimulated gonadotropins among asthmatic children expected to be pubertal: Of the 23 patients expected to be pubertal, seven (30.44%) had low FSH (basal and after LHRH stimulation). Only one case had low basal LH (4.35%) and seven cases (30.44%) had low LH after LHRH stimulation. All cases with low basal and stimulated FSH and low basal and stimulated LH were detected among asthmatics who took ICS at doses of >400 μg and for >1 year.
Risk estimation for the association of ICS doses of >400 μg/day with short stature (height SDS <-2), overweight (weight for height SDS >+2), low stimulated FSH and LH: ICS doses of >400 μg/day had a significant risk (p<0.05) for association with short stature with an estimated relative risk of 8.5 (95% CI: 2.15-33.8). On the other hand, ICS doses of >400 μg/day did not have a significant risk (p>0.05) for association with overweight (OR: 0.8, CI = 0.47-2.6), low stimulated FSH (OR: 1.13, CI = 0.85 -1.52) and low stimulated LH (OR: 0.3, CI = 0.03 -2.60).
Risk estimation for the association of ICS use for >1 year with short stature (height SDS <-2), overweight (weight for height SDS >+2), low stimulated FSH and LH: The use of ICS for >1 year had a significant risk (p<0.05) for association with short stature (OR: 9, 95% CI = 3.10-10.64), overweight (OR: 6.82, 95% CI = 1.36-34.27), low stimulated FSH (OR: 5.80, 95% CI = 1.54-33.70), low stimulated LH (OR: 8.31, 95% CI = 1.83-50.47).
DISCUSSION
In this study, height and its SDS were significantly lower and the weight for height SDS was significantly higher in asthmatic children than in controls. Therefore, both weight and height were considerably affected in asthmatic children: a negative impact on height and a positive one on weight. It is to be noted that the mean age of our study sample was insignificantly different from that of the control group. So, the differences in our results could not be attributed to differences in age.
The reduction in linear growth noticed in our study is in accordance with a
randomized double-blind study that compared inhaled beclomethasone dipropionate
with placebo in 94 asthmatic children. Those on beclomethasone dipropionate
grew significantly less than those on the placebo (2.66 versus 3.66 cm) (Doull,
2004). Again, our work is in accordance with the study of Skoner
et al. (2000) who reported the results of a multicenter, randomized,
open-label, active-controlled, parallel-group study that was designed to evaluate
the effect of ICS therapy on growth after 52 weeks of follow-up. The subjects
were 0.5 to 8 years old; all had a pre-existing diagnosis of asthma. Changes
in height SDS differed significantly between groups receiving budesonide inhalation
suspension and their counterparts who received conventional asthma therapy [excluding
glucocorticoids (GCs)]. At 52 weeks, the height SDS was significantly lower
by 0.19 SD among the ICS group and their growth velocity was reduced by 0.8
cm/year. In 2001, the Food and Drug Administration (FDA) recommended that all
ICSs should carry a warning regarding their potential effects on growth (Food
and Drug Administration, 2001).
It has been reported that children with chronic asthma start to show growth
retardation at the age of 10 years which is most marked at the age of 14 years
(Doull, 2004). Both asthma and its therapy could account
for the suppression in linear growth. A study done in Alexandria University
to assess whether long standing asthma affects growth in prepubertal Egyptian
children before initiation of long-term ICS therapy showed no significant major
effect of asthma on physical growth, apart from skeletal maturation, which was
found to be significantly retarded in asthmatics compared to normal children
(Ismail et al., 2006). Phelan
et al. (1994) found that the disease itself had no effect on growth
in children with infrequent episodic asthma, but those with frequent asthma
were found to have minor effects. Growth suppression due to poor asthma control
may depend on long-term catabolic stress and severe sleep disturbances interfering
with the diurnal secretion of anabolic hormones (Agertoft
and Pedersen, 2000).
The susceptibility to growth suppression by ICS could be explained by the interactions
of GCs with hypothalamo pituitary adrenal axis (HPA) axis, either GH or adrenal
hormones. Acute exposure to GCs can enhance GH release, but long-term exposure
impairs its release, both by direct and indirect mechanisms. GCs appear to augment
hypothalamic somatostatin secretion, which exerts an inhibitory effect on pituitary
pulsatile GH secretion. Directly, GCs regulate the expression and binding of
the GH receptor downward. Furthermore, exogenous GCs appear to interfere with
the bioactivity of insulin-like growth factor-1 (IGF-1), the primary second
messenger of GH, probably by altering protein binding of IGF-1 to limit the
circulation of free IGF-1 (Allen, 2006).
In the prepubertal child, GH secretion is generally confined to nighttime,
usually beginning after sleep onset, which coincides with the normal nadir in
blood cortisol levels. The risk for adverse effects of ICS therapy is increased
either when systemic exposure exceeds normal endogenous cortisol production
or when the pattern of cortisol effect is sufficiently abnormal to disrupt other
normal hormone secretion (Allen, 2006). In addition,
GCs have a direct inhibitory effect on the synthesis of new connective tissue
and at certain ages, diminish androgen production by the adrenal gland, normally
a critical stimulator of growth during the early phase of the pubertal growth
spurt (Todd et al., 2002).
In our series, the significantly increased weight for height of asthmatic patients
can be attributed to either asthma itself or ICS therapy. Obesity may develop
as a consequence of asthma if the disease leads to sedentary lifestyle (Mathew
et al., 2009). Meanwhile, interventions that reduce obesity in asthmatics
are followed by improvements in asthma control (El-Helaly
et al., 2009). ICS lead to impaired insulin tolerance, increased
glucose and hyperlipidaemia with rise in total and high density lipoprotein
cholesterol. It also leads to increased appetite, fluid retention and consequently
weight gain (Maniscalco et al., 2008). Contrary
to our findings, Todd et al. (2002) reported
that poor weight gain is seen commonly in patients with asthma. Also, British
Thoracic Society (1993) stated that children receiving step 4 treatment
in the British Thoracic Society’s guidelines who use hospital services
are shorter and lighter than expected and also have comparatively poor growth
rates. The decrease in body weight and body mass index despite the administration
of high dose of ICS in some asthmatic children may be related to the improvement
of pulmonary function that may lead to improvement in life style and decrease
in fatness.
One of the greatest concerns of corticosteroid therapy for asthma is its potential
for adverse effects on bone age. In the current study, we found a significant
lowering in patients bone age and its SDS as compared to those of controls.
Similar to our results, short-and medium-term studies of healthy volunteers
and asthmatic patients receiving ICS have been able to detect its effect causing
delayed bone age, which occurs less frequently than with oral corticosteroids
(Saravi et al., 2000). However, Agertoft
and Pedersen (2000), found no differences in bone age among asthmatic patients
and controls.
In the current study, a dose of >400 μg/day was associated with a significant
lowering in height and its SDS whereas doses of ≤400 μg/day were not.
This was confirmed by a study done by Childhood Asthma Management
Research Group (2000), who found that doses of less than 400 μg had
no effect on growth and bone age. Also, high daily doses of ICS (>400 μg/day)
had a statistically significant effect on reduction in both height and bone
age in another study (Priftis et al., 2006).
Therefore, ICS when administrated in low doses seem to be safe. In any case,
patient monitoring allows early detection of possible side effects associated
with ICS (Allen, 2006).
Allen et al. (1994) studied the growth curve
of the patients at the age of 15 years who used inhaled beclomethasone at a
dose of >400 μg daily. Their growth curve showed typical delayed pubertal
growth spurt and the reduction of growth velocity appeared to commence at the
age of 8 years, at about the time the ICS therapy was started. Over the 5 years
that followed, the patients’ height SDS went from around zero (the population
mean) to -1.45 at the age of 13 years. Also, Doull (2004)
found that those who received ICS had significantly lower final adult height
compared to their predicted adult height based on mid parental height.
On the other hand, other studies by Harmanci et al.
(2001) and Shonoey et al. (2006) reported
no effect on growth of children treated with a dose of >400 μg of ICS.
Hence, the reports on the effect of ICS dose have been very variable. Most studies,
however, are of the view that there is no significant evidence of adverse effects
on growth when conventional doses (<400 μg/day) of ICS are used. This
situation reflects also the extreme variability of individual sensitivity and
the need for careful surveillance for all asthmatic children treated with steroid
therapy, which may necessitate dose reduction or drug replacement (Doull,
2004).
The risk of growth rate suppression due to use of corticosteroids, was examined
with respect to the duration of ICS treatment. We found that the height and
bone age and their SDSs were significantly lower while weight and its SDS were
significantly higher in patients who received ICS for more than one year. ICS
for a duration of less than a year had no such impact. Similarly, studies submitted
to the FDA with several different active corticosteroid moieties demonstrated
reduced growth velocities over a 1 year time period of approximately 1 cm/year
among active treatment groups exposed to oral or inhaled or intranasal corticosteroids
as compared to control groups (placebo or non-corticosteroid asthma treatments
such as beta-agonists). Moreover, It has been reported that daily treatment
with any dose of corticosteroids (CSs) suppresses the growth rate for as long
as, the treatment is maintained. The longer the duration of treatment, the more
is the effect on growth. When treatment is withdrawn, catch-up growth may occur,
compensating for some, if not all, of the retardation (Reid
et al., 1996). Agertoft and Pedersen (2000)
reported that growth rates were significantly reduced during the first years
of budesonide treatment but were not significantly associated with adult height.
Also, reduced bone age z-scores was reported in asthmatics on long term treatment
>1 year with ICS (Altintas et al., 2005).
In adolescents with chronic asthma, as in any chronic illness, the progress
of puberty may be abnormal. The basis of abnormal physical development in adolescence
is multifactorial. Genetic factors, nutritional deficiency, hormonal abnormalities
or concomitants of treatment all may contribute to disordered growth (Rosen,
1991). In the present series examined cross sectionally, 7 out of the 23
(30.43%) patients who were expected to have had started puberty were still prepubertal.
This was evident only in patients on ICS doses of >400 μg/day. Similarly,
Doull (2004) found a significant delay in menarchal
age in asthmatic girls. They explained the delay in pubertal age associated
with asthma may be a consequence of increased weight as has been found in our
study. Moudiou et al. (2003) found that the growth
of asthmatic children before any long-term treatment with inhaled ICS is not
different from the control population, except for the asthmatic girls of pubertal
age who are shorter than control girls probably because of delay in pubertal
maturation. Untreated asthma results in a delay of puberty by approximately
1.3 years and pubertal delay is likely to explain the majority of apparent growth
failure in asthmatics, including retardation in height (Rosen,
1991).
Normally, a single dose of LHRH agonist stimulates release of LH within 4 hours
in teenage prepubertal children as well as in sexually mature group. The initial
rise in LH occurs earlier and is of greater magnitude in adults than in the
immature groups. The subsequent pattern of LH secretion differs markedly according
to stage of sexual development. FSH responses tend to parallel those of LH but
change less consistently with pubertal maturation. This is compatible with earlier
findings that FSH responsiveness to both LHRH bolus or infusion increases very
little during puberty (Styne, 1997).
The present work revealed significantly lower mean FSH and LH levels after
LHRH stimulation in patients who took a steroid dose of more than 400 μg/day
but not in the basal state. High doses of ICS decrease the production of LHRH
which decreases the production of LH, which leads to secondary hypogonadism,
decreased testosterone or estradiol production, with decreased bone formation
and increasing bone resorption (Styne, 1997). Also,
in our study, ICS therapy for a duration of more than one year had a negative
effect on FSH and LH, lowering their levels both in the basal and stimulated
state. This was previously shown by Doull (2004), who
found a delay in sexual maturation by approximately 1.3 years, at an ICS duration
of more than one year.
Comparison of each of the basal and stimulated FSH and LH of our studied children
supposed to be pubertal with standard levels in normal Egyptian children (El-Sedfy
and Shahin, 2001) showed that 7 (30.44%) had low basal FSH and low FSH after
LHRH stimulation, one case had low basal LH (4.35%) and 7 (30.44%) had low LH
after LHRH stimulation. All cases with low FSH (basal and after LHRH stimulation)
and low LH (basal and after LHRH stimulation) were detected among those who
took steroids doses of >400 μg and for >1 year. This supports earlier
findings by Rosen (1991).
Uterine length and right ovarian volume did not differ with respect to the
dose of ICS (>400 μg/day versus ≤400 μg/day) and its duration
(>1 year versus ≤1 year). To the best of our knowledge, we could not trace
data in literature regarding the latter issue to compare our results. One of
the crucial problems of ICS therapy is the suppression of hypothalamic-pituitary-adrenal
function. Morever, ICS show direct effects on the gonads and the target tissues
of gonadal steroids. ICS also reduce the action of FSH on granulosa cells and
inhibit the response of LH to LHRH (Todd et al.,
2002).
It can finally be concluded that ICS when used at higher doses of >400 μg/day have a significant risk of adverse effects on growth leading to retarded height while their use continuously for long periods, at least 1 year, has significant risk of short stature, weight gain as well as delayed puberty due to reduction of FSH and LH. This highlights the importance of using ICS at the lowest effective dose and for the shortest possible durations. Regular follow-up of growth and puberty parameters among asthmatic children on ICS therapy is mandatory especially those on doses of >400 μg/day and/or for more than 1 year. The need is growing for newer effective therapies that can provide a better chance for normal growth of asthmatic children.
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