| Adults |
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| 1. What is the rationale
for using Pulmicort in pulmonary sarcoidosis? |
Sarcoidosis is an inflammatory
multisystem granulomatous disease of unknown aetiology mostly
affecting young adults. In principle, all organs of the body can be
affected. However, most patients have pulmonary manifestations. A
reduced vital capacity and/or diffusion capacity together with
respiratory symptoms such as breathlessness and cough are the most
common indications for starting treatment of sarcoidosis.
Traditionally systemic corticosteroids have been used, but because of
steroid-induced side effects, the value of Pulmicort has been
evaluated (1). However, pulmonary sarcoidosis is not an approved
indication for Pulmicort.
After inhalation, budesonide as a
water-soluble glucocorticoid, is rapidly absorbed through the airway
mucosa. The concentration of budesonide in the pulmonary parenchymal
tissue has been found high enough to give a good anti-inflammatory
efficacy in the lung tissue (2).
This means that systemic
corticosteroids can be replaced by inhaled, totally or to a certain
degree. Treatment with Pulmicort in patients with pulmonary
sarcoidosis (or other parenchymal diseases requiring treatment with
corticosteroids) should be looked upon as an oral steroid-sparing
regimen.
It should be emphasized that only
pulmonary sarcoidosis can be treated with inhaled budesonide as drug
concentrations in extra pulmonary tissues are too low for achievement
of clinical effects.
References:
1. Selroos O. Inhaled
corticosteroids and pulmonary sarcoidosis. Sarcoidosis 1988; 5:
104-105
2. Selroos O et al.: Inhaled
budesonide for maintenance treatment of pulmonary sarcoidosis.
Sarcoidosis 1994; 11: 126-131.
3. van den Bosch JMM et al.:
Relationship between lung tissue and blood plasma concentrations of
inhaled budesonide. Biopharm Drug Dispos 1993; 14: 455-459.
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| 2. Is there a difference
in efficacy between Pulmicort and oral corticosteroids when starting
treatment of pulmonary sarcoidosis? |
Clinical studies have shown that
when starting treatment of pulmonary sarcoidosis a more rapid
improvement (radiographic and functional) has been observed with oral
prednisolone than with Pulmicort. Therefore, the clinical routine is
to give patients a 2-3 month starting course with prednisolone and to
restrict the use of Pulmicort to long-term maintenance treatment
(1-3).
References:
1. Selroos O.: Use of budesonide
in the treatment of pulmonary sarcoidosis. In.: Ellul-Micallef R, Lam
WK, Toogood JH (eds.) Advances in the use of inhaled
corticosteroids. Exerpta Medica, Hong Kong
1987; 188-197.
2. Selroos O.: Further
experiences with inhaled budesonide in the treatment of pulmonary
sarcoidosis. In.: Grassi C, Rizzato G, Pozzi E. (eds.) Sarcoidosis
and other granulomatous disorders. Elsevier, Amsterdam 1988;
637-640.
3. Selroos O et al. Inhaled
budesonide for maintenance treatment of pulmonary sarcoidosis.
Sarcoidosis 1994; 11: 126-131.
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| 3. Is there a value of
early intervention with oral steroids followed by Pulmicort in patients with
pulmonary sarcoidosis? |
A
double-blind, placebo-controlled study has shown that treatment with
prednisolone (3 months) followed by Pulmicort for 15 months in
patients who had had a diagnosis of sarcoidosis for <3 months
resulted in better lung function values and less need for subsequent
courses of oral corticosteroids than treatment with placebo (1, 2).
References:
1. Pietinalho A et al.: Oral
prednisolone followed by inhaled budesonide in newly diagnosed
pulmonary sarcoidosis: a
double-blind, placebo-controlled multicenter study. Chest 1999; 116:
424-431.
2. Pietinalho A et al.: Early
treatment of stage II sarcoidosis improves 5-year pulmonary function.
Chest 2002; 121: 24-31.
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| 4. Is Pulmicort treatment
safer than oral steroids in patients with sarcoidosis? |
Long-term studies comparing
Pulmicort treatment with oral prednisolone have shown the risk of
side effects and adverse events to be significantly lower with
Pulmicort (1,2).
No differences in adverse events
were seen between Pulmicort Turbuhaler 800 µg
twice daily and placebo for 15 months in patients with newly
diagnosed pulmonary sarcoidosis (3).
References:
1. Selroos O.: Use of budesonide
in the treatment of pulmonary sarcoidosis. In.: Ellul-Micallef R, Lam
WK, Toogood JH (eds.) Advances in the use of inhaled
corticosteroids. Exerpta Medica, Hong Kong
1987; 188-197.
2. Selroos O.: Further
experiences with inhaled budesonide in the treatment of pulmonary
sarcoidosis. In.: Grassi C, Rizzato G, Pozzi E. (eds.) Sarcoidosis
and other granulomatous disorders. Elsevier, Amsterdam 1988;
637-640.
3. Pietinalho A et al.: Oral
prednisolone followed by inhaled budesonide in newly diagnosed
pulmonary sarcoidosis: a
double-blind, placebo-controlled multicenter study. Chest 1999; 116:
424-431.
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| 5. Pulmicort and
interstitial lung diseases |
There are a few case reports on
the use of Pulmicort in the treatment of patients with various types
of interstitial lung diseases, e.g. allergic alveolitis, idiopathic
pulmonary fibrosis, drug-induced lung diseases, eosinophilic
pneumonitis etc. There is no data from controlled clinical studies.
The use of Pulmicort in these clinical conditions could be looked
upon as an attempt to spare oral corticosteroids.
Interstitial lung diseases are
not approved indications for Pulmicort. If Pulmicort is used it
should be looked upon as an oral steroid sparing treatment regimen.
References:
1. Mönkäre S. Clinical
aspects of farmer’s lung: airway reactivity, treatment and
prognosis. Academic Thesis, University of Helsinki 1984.
2. Carlsen KH et al.: Allergic
alveolitis in a 12-year-old boy; treatment with budesonide nebulizing
solution. Pediatr Pulmonol 1992; 12: 257-259.
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| Children |
|
| 6. Can Pulmicort be used
in children with croup? |
Croup (acute
laryngotracheobronchitis) is a frequent upper airway obstruction in
young children (1). The obstruction is caused by oedema, usually as a
consequence of a viral infection (parainfluensa type 1 is the most
commonly identified virus). It is characterized by hoarseness, cough
and inspiratory stridor.
As glucocorticosteroids are
effective in reducing oedema they are considered first line therapy
of croup (1,2). The role of corticosteroid therapy in children with
croup has been evaluated in a meta-analysis of 24 randomized
controlled clinical studies (1). Nine of the studies used a nebulized
suspension of Pulmicort (Pulmicort Respules). Oral or intramuscular
dexamethasone was used in the remaining studies. Steroid treatment
with Pulmicort or dexamethasone was associated with a significant
improvement in croup scores at 6 hours with an effect size of -1.0,
which is considered clinically important. The effect persisted at 12
hours but not at 24 hours. In patients treated with Pulmicort the
need for treatment with adrenaline was reduced by 9% compared to 12 %
in children treated with dexamethasone. Corticosteroid treatment was
also associated with a decreased duration of emergency or in-patient
hospital treatment.
A recent review concluded that
available clinical data indicate that Pulmicort Respules is an
effective and well-tolerated alternative to oral steroid therapy in
children with croup (3).
Meta-analysis of systemic steroids
and Pulmicort Respules in children with croup
Pooled
effect sizes, with 95% confidence intervals (CI), in a meta-analysis
of 24 randomised controlled trials with steroids (mainly
dexamethasone and Pulmicort Respules) in children with croup (1).
This analysis showed that treatment with Pulmicort Respules produced
clinically relevant improvements in croup.
References:
1. Ausejo M et al.: The
effectiveness of glucocorticoids in treating croup: a meta-analysis.
Br Med J 1999; 319: 595-600.
2. Ausejo M et al.
Glucocorticosteroids for croup (Cochrane Review). In: The Cochrane
Library.
Issue 2. Oxford: Update Software,
2001.
3.
Hvizdos KM, Jarvis B. Budesonide inhalation suspension. A review of
its use in infants,
children
and adults with inflammatory respiratory disorders. Drugs 2000; 60:
1141-1178.
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| 7. Pulmicort in the
treatment of patients with cystic fibrosis |
Inflammation (as a consequence of
bacterial pathogens such as Pseudomonas aeruginosa) has a central
role in the pathogenesis of cystic fibrosis. Glucocorticosteroids are
effective in reducing the inflammation and represent therefore a
rational treatment strategy (1).
Treatment with oral steroids at a
dose of 2 mg/kg on alternate days appeared to slow the progression of
lung disease but was associated with a high risk of serious side
effects such as cataract formation and growth impairment (2).
In view of the side effects
associated with oral steroid treatment in patients with cystic
fibrosis, inhaled corticosteroid therapy has attracted increasing
attention. This approach has been widely adopted and register data
suggests that up to 50% of children with cystic fibrosis are treated
with inhaled steroids (3). However, the benefits of inhaled steroid
therapy in cystic fibrosis have been questioned (4). A recent
Cochrane Review on inhaled corticosteroids also concluded that
further larger studies are needed to establish the role of inhaled
steroids in the treatment of patients with cystic fibrosis (5).
The use of high-dose inhaled
budesonide (Pulmicort Respules) was originally recommended for cystic
fibrosis (CF) patients having infections with Pseudomonas
aeruginosa (6). The use has later been extended to include CF
patients with other infections as well.
Cystic fibrosis is not an
approved indication for Pulmicort.
Two studies with Pulmicort have
been performed. In a Danish 6-month placebo-controlled crossover
study (n=55) treatment consisted of Pulmicort Turbuhaler at a daily
dose of 1600 µg (6). After
the first 3-month treatment period FEV1 fell by a mean of
32 mL in the budesonide group (n=30) compared with 187 mL in the
placebo group (n=25). When both 3-month periods were analysed
together absolute change in FEV1 after 6 month of
treatment was +2 mL for the budesonide and -98 mL for the
placebo group. Bronchial reactivity improved significantly compared
with placebo (p<0.05). In a Dutch 6-week crossover trial (7) with
Pulmicort pMDI and spacer, 1600 µg
per day, no change in airway function was found but a significant 58%
improvement in bronchial hyperresponsiveness.
Correlation between lung function
and bronchial responsiveness in children with CF treated with
Pulmicort
Relationship
between change in FEV1 and pre-treatment bronchial
reactivity to histamine in children with cystic fibrosis treated with
Pulmicort Turbuhaler 800 µg twice daily for 6 months (Bisgaard
et al, 1997). The improvement in FEV1 was significantly
correlated with the degree of bronchial hyperresponsiveness (r =
-0.53; p = 0.01)
References:
1. Conway SP, Watson A. Nebulised
bronchodilators, corticosteroids, and rhDNAse in adult patients with
cystic fibrosis. Thorax 1997; 52, Suppl 2: S64-S68.
2. Cheng K et al.: Oral steroids
for cystic fibrosis (Cochrane Review). In: The Cochrane Library,
Issue 3, 2000.
3. Koch C et
al. International practice patterns by age and severity of
lung disease in cystic fibrosis: data from the Epidemiologic Registry
of Cystic Fibrosis (ERCF). Pediatr Pulmonol 1997; 24: 147-154.
4. Kennedy MJ. Inflammation and
cystic fibrosis pulmonary disease. Pharmacotherapy 2001; 21: 593-603.
5. Dezateux C et al.: Inhaled
corticosteroids for cystic fibrosis (Cochrane Review). In: The
Cochrane Library, Issue 4, 2000: Update Software.
6. Bisgaard H. et al.: Controlled
trial of inhaled budesonide in patients with cystic fibrosis and
chronic bronchopulmonary pseudomonas aeruginosa infection. Am J
Respir Crit Care Med 1997; 156: 1190-1196
7. van Haren EH et al.: The
effects of the inhaled corticosteroid budesonide on lung function and
bronchial hyperresponsiveness in adult patients with cystic fibrosis.
Respir Med 1995; 89: 209-214.
|
| 8. Wheezing in childhood |
Large epidemiological studies
have shown that although wheezy symptoms resolve in most children
after 2-3 years, recurrent airway obstruction can persist in some
children (1). These ‘non-atopic wheezers’ constitute a
subgroup of children with asthma (2). Symptomatic treatment
(bronchodilators and cough medicines) of these children is often
insufficient and maintenance therapy with corticosteroids has been
widely used. Several studies have reported good results with short
courses of oral steroids, but repeated courses raises concerns about
possible systemic side effects.
A recent review of five studies
(three with Pulmicort) concluded that episodic treatment with high
doses of inhaled corticosteroids was beneficial in children with mild
acute wheezing, whereas maintenance treatment with low doses provided
no benefit (3). The effect may be greater in older children, but may
be confounded by the presence of atopy. This was the case in a
Pulmicort study involving 31 children aged 3-10 years, of whom 21
were atopic (4). The children received Pulmicort Turbuhaler or
placebo for 9 days, starting at the onset of an upper respiratory
tract infection. The dose of Pulmicort was 200 µg
four times daily for 3 days, three times daily for 3 days, and twice
daily for 3 days. Pulmicort treatment resulted in better PEF values,
fewer emergency room visits, oral steroid courses and
hospitalisations compared with placebo.
Days with severe asthma symptoms in
children treated with Pulmicort or placebo for 7 days during URTIs
Proportion
of days with severe asthma symptoms in 55 children (1-3 years)
treated with Pulmicort or placebo for 7 days during upper respiratory
tract infections (Svedmyr et al, 1999). The reduction in severe
symptoms in children treated with Pulmicort was significant (p =
0.01) for cough and approached significance (p = 0.057) for noisy
breathing.
References:
1. Martinez FD. Inhaled
corticosteroids and the natural history of asthma. In: Schleimer RP,
O´Byrne PM, Szefler SJ, Brattsand R, Eds. Inhaled steroids in
asthma. Optimising effects in the airways. Marcel Dekker, New York
2002; 623-634.
2. Martinez FD. Natural history.
In: Barnes PJ, Drazen JM, Rennard S, Thomson NC,
Eds. Asthma and COPD. Basic
mechanisms and clinical management. Academic Press,
London 2002; 19-28.
3. McKean M, Ducharme F. Inhaled
steroids for episodic viral wheeze of childhood (Cochrane Review).
In: Cochrane Library, Issue 4, 2000. Oxford: Update Software.
4. Svedmyr J
et al. Intermittent treatment with inhaled
steroids for deterioration of asthma due
to upper respiratory tract infections. Acta Paediatr 1995; 84: 884-888.
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| 9. Pulmicort and RSV infections |
|
| Treatment of acute
bronchiolitis |
Respiratory syncytial virus (RSV)
bronchiolitis is the most common lower respiratory infection
occurring during infancy. It is
characterized by acute respiratory distress, and a concurrent history
of fever and cough in a previously healthy child. Clinical features
include hypoxemia, tachypnoe, tachycardia, chest wall retraction and
hyperinflation. It most commonly occurs before the age of 2 years and
thereafter wheeze tends to diminish in subsequent years (1).
The treatment of acute RSV
bronchiolitis is mainly symptomatic and supportive (1). Available
evidence suggests that such treatment is of limited benefit (1). An
early retrospective study suggested that Pulmicort Respules
(suspension for nebulisation) might reduce wheezing in these children
with acute disease (2). By contrast, in a placebo-controlled
double-blind trial treatment with Pulmicort 200 µg
twice daily via pMDI and spacer had no significant effect on the
clinical features of bronchiolitis (3).
References:
1.
Wennergren G, Kristjánsson S. Relationship between respiratory
syncytial virus bronchiolitis
and
future obstructive airway diseases. Eur Respir J 2001; 18: 1044-1058.
2. Goodwin
A. An uncontrolled assessment of nebulised budesonide in the
treatment of acute infantile bronchiolitis. Br J Clin Res 1995; 6:
113-116.
3. Sammartino
L et al. Budesonide in acute bronchiolitis.
J Paediatr Child Health 1995; 31: 61-62.
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| Prevention of asthma
development after acute viral bronchiolitis |
Following an early report (1) a
number of studies have investigated the use of inhaled
corticosteroids for prevention of asthma after an acute RSV episode.
A prospective study from Finland
involved 100 children with acute bronchiolitis (2). They were
randomized to treatment with Pulmicort Respules 0.5 mg twice daily
for 8 weeks followed by 0.25 mg twice daily for 8 weeks or disodium
cromoglycate 20 mg four times daily for 8 weeks followed by 20 mg
three times daily for 8 weeks, or no therapy. Treatment was started
on the second day of hospitalisation. Children receiving Pulmicort
experienced significantly fewer wheezing episodes and had fewer
hospitalisations than the control group. Children with atopy (32-38%)
had significantly more episodes of wheezing and hospitalisations than
the non-atopic group, and showed the greatest benefits from
Pulmicort. A long-term follow-up study involving 88 of these children
demonstrated that anti-inflammatory therapy had no effect on the
development of asthma (3).
In another study from Finland
Kajosaari et al (4) randomized 107 infants, aged 0-9 months, with RSV
bronchiolitis to symptomatic treatment with bronchodilators, to
treatment with Pulmicort Respules 0.5 mg three times daily for 1
week, or to 0.5 mg twice daily for 2 months. At the age of 2-3 years
the frequency of asthma was investigated in the three treatment
groups. 14/38 (37%) of the infants in the symptomatic treatment group
had developed asthma compared to 7/39 (15%) in the 1-week Pulmicort
group (p=0.06 vs. symptomatic treatment group) and 4/32 (12%) in the
2-month treatment group (p=0.01 vs. symptomatic treatment group).
These results suggest that early treatment with an inhaled
corticosteroid for RSV bronchiolitis may reduce the risk of later
development of asthma.
In conclusion: there is some
evidence that inhaled corticosteroids may reduce the subsequent
development of asthma in very young children hospitalised with RSV
infection. Atopic heredity does not appear to be a risk factor for
asthma in these children. In older infants with RSV bronchiolitis
(app. 1 year) there is some evidence that Pulmicort treatment may
reduce the incidence of post-bronchiolitic wheezing, particularly in
atopic children.
Development of asthma at the age of
2-3 years in infants given treatment with bronchodilators or
Pulmicort in connection with RSV infection
Proportion
of children receiving continuous medication for asthma 2 years after
RSV bronchiolitis in infancy (Kajosaari et al, 2000). Acute (7 days)
or maintenance (2 months) treatment with nebulised Pulmicort was
associated with a reduced risk of subsequent asthma
References:
1. Carlsen KH
et al. Nebulised beclomethasone
dipropionate in recurrent obstructive episodes after acute
bronchiolitis. Arch Dis Child 1988; 63: 1428-1433.
2. Reijonen TM et al.:
Anti-inflammatory therapy reduced wheezing after bronchiolitis. Arch
Pediatr Adolesc Med 1996; 150: 512-517.
3. Reijonen TM
et al. Predictors of asthma three years
after hospital admission for wheezing in infancy. Pediatrics 2000;
106: 1406-1412.
4. Kajosaari M et al.: Inhaled
corticosteroids during and after respiratory syncytial
virus-bronchiolitis may decrease subsequent asthma. Pediatr Allergy
Immunol 2000; 11: 198-202.
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| 10. The role of Pulmicort
in newborn with Chronic Lung Disease (CLD) of prematurity |
Chronic
Lung Disease of prematurity (CLD), which was previously called
bronchopulmonary dysplasia, is an increasingly common complication of
very premature birth (1). This syndrome encompasses both a
well-characterised clinical syndrome with respiratory stress and the
need for supplementary oxygen, and long-term adverse effects on the
respiratory tract that persist into infancy and later life (1).
Although the pathophysiology of CLD is not fully understood, it is
accepted that airway inflammation plays a central role, with elevated
concentrations of inflammatory mediators. This early inflammatory
reaction has long-term consequences on lung function.
The
recognition of persistent airway inflammation in CLD has led to
widespread use of systemic steroid treatment (1,2). Treatment with
dexamethasone has shown improvement in acute lung function and
facilitated weaning from mechanical ventilation (2).
Data
from several studies suggest that treatment with Pulmicort Respules
or pMDI may have a role in premature infants at risk of CLD. In a
randomized, placebo-controlled study treatment with Pulmicort
Respules from day 7 after birth was associated with a significant
reduction in the duration of intubation, and a decrease in systemic
steroid requirement, in premature infants (mean gestational age 26
weeks) (3). The largest study so far is the Open Study of Early
Corticosteroid Treatment (OSECT), which investigated the efficacy and
safety of early systemic and inhaled steroid therapy (4). In this
study, 570 preterm infants were randomised to early (within 72 hours)
or delayed (later than 15 days) treatment with either dexamethasone
or Pulmicort.
Dexamethasone was given at an initial dose of 0.5
mg/kg/day for 3 days and the dose subsequently reduced by half every
3 days for a total of 12 days. Pulmicort 400 µg
twice daily was given via pMDI with AeroChamber spacer. There were no
significant differences between the groups in the incidence of death
or oxygen dependency at 36 weeks. However, dexamethasone was
associated with a higher risk of hypertension, hyperglycaemia and
gastrointestinal adverse effects compared with Pulmicort. CLD is not
an approved indication for Pulmicort.
References:
1.
Pelkonen A. Bronchial lability in schoolchildren born very preterm.
Thesis, University of Helsinki, 2000.
2.
Cole CH. Postnatal glucocorticosteroid therapy for treatment and
prevention of neonatal chronic lung disease. Exp Opin Invest Drugs
2000; 9: 53-67.
3.
Jónsson B et al.: Budesonide delivered by dosimetric jet
nebulization to preterm very low birth weight infants at high risk
for development of chronic lung disease. Acta Paediatr 2000; 89:
1449-1455.
4.
Halliday HL et al. A multicenter randomized open study of early
corticosteroid treatment (OSECT) in preterm infants with respiratory
illness: comparison of early and late treatment and of dexamethasone
and inhaled budesonide. Pediatrics 2001; 107: 232-240.
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