REVIEW

Systemic effects of inhaled corticosteroids

Pierre Ernst and Samy Suissa

Purpose of review
Although inhaled corticosteroids (ICSs) are the mainstay of therapy in asthma, their use raises certain safety
concerns. We review the articles appearing in the last year which have addressed the safety of ICSs when
used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Recent findings
Recent studies suggest that patients with asthma as opposed to COPD do not experience an excess risk of
pneumonia with ICS use. Patients with respiratory diseases are at increased risk of developing active
tuberculosis and this excess risk is exacerbated by the use of high doses of ICSs. ICSs have systemic effects
and one result appears to be an increase in the risk of diabetes onset and progression, especially at high
doses of ICSs. When examining cases of glaucoma requiring therapy, there was no increase in risk with
ICSs even at high current and cumulative doses. Finally, use of even high doses of ICSs during pregnancy
does not appear to affect foetal adrenal function.
Summary
ICSs are a highly effective therapy in asthma and have an excellent safety profile at the low doses usually
required in asthma. Adverse effects appear mostly at higher doses.
Keywords
adverse effects, asthma therapy, inhaled corticosteroids

INTRODUCTION having children [4]. Ciclesonide has substantially

Inhaled corticosteroids (ICSs) are the mainstay of less systemic activity than other available ICSs, such
asthma therapy at all ages. Their broad anti-inflam- that it may be preferred in patients requiring higher
matory activity controls the airway inflammation doses or in children in whom growth retardation is
&

underlying airway hypersensitivity to viral infec-
tions, allergens and irritants. ICSs are the only
asthma medication that has been shown to reduce
mortality and the risk of hospitalization over the
long term [1]. Most of the therapeutic benefit is
obtained at low doses such as fluticasone 200 mg/
day or the equivalent [2], whereas adverse effects
increase with increasing dose in an apparently linear
fashion [3]. It is therefore important to use the
lowest effective dose possible and to attempt to
reduce the dose further in patients whose asthma
has been well controlled for several months. Such
dose lowering is made safer by providing patients
with an effective action plan to increase the dose for
a short period of time if symptoms worsen.
of significant concern [5,6 ]. Furthermore, cicleso-
nide appears to be associated with fewer upper air-
way adverse effects such as hoarseness and
pharyngeal candidiasis than other ICSs of similar
potency such as fluticasone [7].
ICSs are metabolized via the cytochrome P450
system, which is involved in biotransformation of
the vast majority of all drugs currently available
[8,9]. Therefore, patients often find themselves tak-
ing several medications competing for the same
enzymes, which are required for their biotransform-
ation into inactive compounds, which can then be
excreted. The cytochrome P450 enzyme most com-
monly involved in drug metabolism is the CYP3A4
isozyme, which is responsible for the first-pass

Centre for Clinical Epidemiology, Lady Davis Research Institute, Jewish

PHARMACOLOGIC CONSIDERATIONS
Although the various ICSs available are all thera-
peutically effective, certain products present safety
advantages worth considering. Budesonide has the
most evidence for safety during pregnancy and is
therefore the drug of choice for women considering
General Hospital, Montreal, Quebec, Canada
Correspondence to Pierre Ernst, MD, MSc, Pavillon H. Room 415,
Jewish General Hospital, 3755 Côte-Ste-Catherine, Montreal, Quebec,
Canada. E-mail: pierre.ernst@mcgill.ca
Curr Opin Pulm Med 2012, 18:85–89
DOI:10.1097/MCP.0b013e32834dc51a

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 Asthma
KEY POINTS

In contrast to patients with chronic obstructive
pulmonary disease, patients with asthma prescribed
inhaled corticosteroids (ICSs) do not appear to be at
increased risk of pneumonia.

High doses of ICSs increase the risk of reactivation of
tuberculosis, although this is not additive to the risk of
oral corticosteroids.

High doses of ICSs increase the risk of clinically overt
diabetes and the progression to insulin therapy.

ICSs, even at high doses, do not seem to increase the
risk of glaucoma requiring therapy.
metabolism by the liver of the commonly used
ICSs. Inhibition of this metabolism of ICSs can be
temporary and concentration dependent (competi-
tive inhibition) or irreversible through formation
of a stable metabolic intermediate through perma-
nent binding of the inhibiting drug with the P450
enzyme. Irreversible inhibitors are of particular
relevance because they can decrease the first-pass
clearance and functional catalytic activity of drugs
that are cleared by CYP3A4 until new enzyme can be
manufactured [10]. Examples of commonly used
irreversible inhibitors of CYP3A4 are clarithromycin,
erythromycin, isoniazid, carbamazepine, tamoxifen,
ritonavir, verapamil and fluoxetine [10]. Such inter-
actions may be of particular relevance to patients
with chronic obstructive pulmonary disease (COPD),
as systemic inflammation appears to be a common
accompaniment to COPD [11] and inflammation
and infection are associated with a further down-
regulation of cytochrome P450 enzymes [12]. Severe
adrenal insufficiency is now a well recognized
adverse outcome of concomitant use of the ICS
fluticasone and the potent cytochrome P450 inhibi-
tor ritonavir [13,14]. Macrolide antibiotics (clarithro-
mycin and erythromycin) and the quinolone
ciprofloxacin (a strong competitive inhibitor of
cytochrome P450 enzymes [15]) are commonly used
in patients with respiratory disease. Although less
potent inhibitors of cytochrome P450 than ritonavir,
the repetitive use of such medications may plausibly
be related to an increased risk of adverse effects seen
with ICSs.
INHALED CORTICOSTEROIDS AND
PNEUMONIA
The TORCH (Toward a Revolution in COPD Health)
trial, comparing the effect of fluticasone, salmeterol
or their combination versus placebo on mortality in
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COPD patients, was the first to report an excess of
pneumonia in patients receiving the ICS fluticasone
[16]. In a large observational study of over 175 000
patients identified using health administrative data-
bases from the province of Quebec, we confirmed
this excess [17]. Patients with COPD who had a
current prescription for an ICS were 70% more likely
to be hospitalized with a primary diagnosis of pneu-
monia: relative risk (RR) 1.70, 95% confidence inter-
val (CI) 1.63–1.77. The risk was greatest for those
receiving the highest doses equivalent to fluticasone
1000 mg/day, RR 2.25, 95% CI 2.07–2.44. An excess
of pneumonia was also confirmed in a meta-analysis
of clinical trials of ICSs in COPD [18]. Surprisingly, a
meta-analysis of individual patient data restricted to
clinical trials of budesonide in patients with COPD
did not find an excess of pneumonia [19]. Whether
or not there is an excess in mortality resulting from
pneumonia contracted by patients with COPD
who are prescribed ICSs appears to be controversial.
In the large observational study we carried out in
Quebec, we found that ICS was associated with a
53% (95% CI 30–80%) excess in pneumonia hospi-
talization ending in death within 30 days [17]. In-
hospital mortality was not different between those
prescribed and not prescribed ICS before the event.
No excess in total mortality was found in the meta-
analysis of clinical trials of ICSs in COPD [18]. This
may reflect the younger, healthier clinical trial
populations and the lack of information on cause-
specific mortality. In a reanalysis of the TORCH
study, a greater number of pneumonia deaths was
seen in the group assigned to fluticasone alone,
although no firm conclusion could be made because
of the small number of events [20]. A recent report
from the Veterans Administration in the USA
found that among patients with a listed diagnosis
of COPD hospitalized for pneumonia, those who
had been prescribed ICSs as outpatients actually
had a lower in-hospital mortality [21]. This is ikely
due to differences in type and severity of respiratory
disease in patients prescribed ICSs. Specifically,
such patients are more likely to have an asthmatic
component to their obstructive lung disease and
this is associated with a better prognosis. Recently,
&
Singanayagam et al. [22 ] carried out a careful study
of community-acquired pneumonia in patients
with COPD confirmed by spirometry and found
no difference in mortality after a hospitalization
in relation to prior ICS use, whether alone or com-
bined with a beta-agonist bronchodilator. Thus,
although in-hospital mortality is likely unrelated
to prior treatment with ICSs, the risk of severe
pneumonia is increased and therefore, at least in
our study, there is a clear excess of pneumonia
mortality with ICSs.
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Number 1
January 2012

It is easy to conceive that ICSs might be associ-
ated with an excess in pneumonia, given the
chronic bacterial colonization found in many
patients with COPD. Furthermore, there is evidence
that corticosteroids reduce local defences in periph-
eral airways of patients with COPD [23]. One would
expect that patients with asthma might behave
&
differently. O’Byrne et al. [24 ] carried out a meta-
analysis of clinical trials of budesonide compared
to placebo or to fluticasone among patients with
asthma. There was no excess of pneumonia reported
as a severe adverse event with budesonide and
there was no difference in the risk of pneumonia
between budesonide and fluticasone in patients
with asthma. When including milder events, bude-
sonide was actually protective. This protective
effect is likely explained by a reduction in asthma
exacerbations associated with mucus plugging and
atelectasis that might be reported as pneumonia
radiographically.
INHALED CORTICOSTEROIDS AND
TUBERCULOSIS
Oral corticosteroids are a recognized risk factor for
the development of active tuberculosis. Our group
investigated whether the risk of tuberculosis was
also increased in users of ICSs using the Quebec
&
healthcare administrative databases [25 ]. We ident-
ified a cohort of 427 648 patients treated with respir-
atory medications who were on average 52 years of
age ( 27 years) at cohort entry. Overall, the risk
of active tuberculosis amongst this population of
patients with respiratory disease was nearly four
times that of the general population. Current users
of ICSs were slightly more likely to develop tuber-
culosis, RR 1.33, 95% CI 1.04–1.71. This risk was
confined to patients who had not received oral
corticosteroids in the prior year, such that ICSs
did not confer an additional risk to that of oral
corticosteroids. Amongst patients who had not been
dispensed oral corticosteroids in the last year, the
risk of active tuberculosis was increased almost two-
fold with higher doses of ICSs equivalent to 1000 mg
or more per day of fluticasone (RR 1.97, 95% CI
1.18–3.30).
INHALED CORTICOSTEROIDS AND
DIABETES
Studies from the 1990s did not find an association
between the use of ICSs and risk of diabetes [26].
Lower doses of ICSs were being used at that time
and these medications were used less extensively
in elderly patients with COPD who are at greater
risk of diabetes. We therefore re-examined the risk
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Systemic effects of inhaled corticosteroids Ernst and Suissa
of diabetes onset and progression in a large cohort
of patients prescribed respiratory medications
&
followed up to the end of 2007 [27 ]. Amongst
388 584 patients without prior treatment for dia-
betes, there was a 34% increase in the risk of new-
onset diabetes (RR 1.34, 95% CI 1.29–1.39). Risk
was greatest at higher doses of ICSs equivalent to
1000 mg or more per day of fluticasone (RR 1.64,
95% CI 1.52–1.76). Amongst 30 167 patients
who developed diabetes during follow-up, 2099
progressed from oral agents to insulin. The risk
of such a progression was also higher amongst
patients dispensed ICSs (RR 1.43, 95% CI 1.17–
1.53).
INHALED CORTICOSTEROIDS AND
GLAUCOMA
Glaucoma is the leading cause of blindness world-
wide. Raised intraocular pressure is a risk factor for
glaucoma and ocular and systemic corticosteroids
increase intraocular pressure. Whether or not ICSs
raise intraocular pressure is less clear. An earlier
study by Garbe et al. [28] found an increased risk
of glaucoma among users of ICSs. Nearly half of
the glaucoma cases were not associated with any
therapy, however, thus putting into question the
validity and importance of these diagnoses.
Furthermore, this earlier study was carried out
before the availability of the newer more potent
ICSs such as fluticasone. We therefore carried out
a large observation cohort study based on the
health administrative databases of the Province of
&
Quebec [29 ]. Cases were chosen from amongst
196 964 patients 66 years of age or older dispensed
respiratory medications. Cases were patients who
had visited an ophthalmologist in the prior 90 days
and who had been dispensed medication for
glaucoma or underwent surgery for this condition.
Controls were patients who had visited an ophthal-
mologist within the same time period but who did
not receive a glaucoma diagnosis or treatment for
this condition. There was no difference in the use of
ICSs between the 2991 cases and the 13 445 controls
(RR 1.05, 95% CI 0.91–1.20). No excess risk could be
demonstrated at the highest doses of ICSs equival-
ent to 1000 mg or more per day of fluticasone, nor
when limiting the analysis to patients who had or
had not been dispensed oral corticosteroids. We
also examined the effect of cumulative dose of ICSs
and found no increase in risk of glaucoma. There-
fore, ICSs may be used without incurring an
increase in risk of glaucoma requiring therapy. This
is in contrast to the increased risk of cataracts which
is seen even with low doses of ICSs in the elderly
[30,31].
www.co-pulmonarymedicine.com 87
 Asthma
INHALED CORTICOSTEROIDS AND
PREGNANCY
Poorly controlled asthma is associated with poor
pregnancy outcomes including preeclampsia,
preterm birth and low birth weight [32]. These
can be prevented with regular use of ICSs [33],
and therefore ICSs during pregnancy are recom-
mended in current guidelines. Despite this, there
is lingering concern regarding the safety of ICSs
during pregnancy. As an illustration, a recent
report linked the use of high doses of ICSs dis-
pensed in the first trimester of pregnancy to an
increase in the risk of congenital malformations
[34]. An earlier report from the same group had
not found an excess risk at lower doses of ICSs
[35]. A report published this year examined the
effect of ICSs use during pregnancy and maternal
and foetal hormone levels [36 ]. Although a dose-
&
dependent suppression of maternal hormone
levels was seen (cortisol, osteocalcin), there was
no effect on foetal adrenal function even at high
maternal doses of ICSs.
CONCLUSION
ICSs are a highly effective therapy in asthma and
have an excellent safety profile at the low doses
usually required in asthma. Adverse effects appear
mostly at higher doses which can usually be avoided
by using combinations of different therapeutic
classes and decreasing the dose of ICSs once asthma
control has been achieved. If high doses of ICSs are
required for prolonged periods, consideration
should be given to using an ICS with less systemic
activity such as ciclesonide.
Conflicts of interest
In the last three years, P.E. has received speaker fees
and/or has served on advisory boards for AstraZeneca,
Boehringer-Ingelheim, Merck, Novartis and Nycomed.
In the last three years, S.S. has received research grants
and/or speaker fees and/or has served on advisory boards
for Boehringer-Ingelheim, Merck, Genentech, Pfizer and
Nycomed.
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READING
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been highlighted as:
& of special interest
&& of outstanding interest
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Systemic effects of inhaled corticosteroids Ernst and Suissa
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www.co-pulmonarymedicine.com 89