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supplement to Journal of the association of physicians of india • march 2014 • VOL. 62
Steroid Resistant Asthma
SK Luhadia*
Abstract
Inspite of very safe and effective treatment, Bronchial asthmatics do not respond well in 5 – 10% of
cases which are labelled as Refractory Asthma. Besides compliance, presence of psychogenic and trigger
factors and comorbid illness, steroid insensitiveness or resistance may play a significant role in the poorly
controlled/ responding asthmatics. Type I Steroid resistance is due to lack of binding affinity of steroids
to glucocorticoid receptors and may respond to higher doses of steroids while type II steroid resistance is
because of reduced number of cells with glucocorticoid receptors, which is very rare and do not respond
to even higher doses of systemic steroids and these cases require alternative/ novel therapies. Future
treatment of steroid resistant and severe refractory asthma is likely to be targeted towards cytokines and
Bronchial Thermoplasty.
Introduction
B
ronchial asthma is the commonest chronic respiratory disorder world wide affecting
about 300 million individuals globally, with prevalence of 1 to 18%. 1 An estimated
25.7 million people including 7.1 million children have asthma in united states. 2 A
recent study has reported the overall prevalence of asthma is 8.7% among school
children aged 12-15 years in India. 3 Thus world wide the economic costs associated
with asthma are estimated to exceed those of TB and HIV /AIDS combined.
Airway inflammation and Immune activation are key factors in the aetiopathogenesis
of asthma and about 95% patients respond well to β2 agonist and corticosteroids with
or without add on therapies like montelukast and long acting theophyllines. However
5-10% of patients do not respond well to this treatment. These cases are labelled as
difficult/ therapy resistant asthma. 4
Incorrect diagnosis, non adherence with therapy and various co-morbidities
contribute a lot to the poor control of asthma. A study from the Brompton Hospital
over 100 patients with difficult asthma revealed alternative or additional diagnosis in
32%, non-adherence with therapy in 50% and Psychiatric Co-morbidity in 11% patients. 5
Although most patients with chronic asthma have significant improvement in their
airway function with corticosteroid therapy, a subset of asthmatics are insensitive to
corticosteroid. 6 Clinical studies have revealed suboptimal response to ICS in about
50% of asthmatics. 7 Failure to detect corticosteroid insensitivity early in the course of
illness may affect the treatment strategy and outcome.
It should be noted that the term steroid resistant (SR) asthma refer to a relative
insensitivity to corticosteroid (Corticosteroid dependent asthma) rather than absolute
resistance (Corticosteroid resistant asthma) which is very rare and found in less than
1:1000 asthmatics.
Definition
Corticosteroid resistant asthma is defined as less than 15% improvement in baseline
FEV1 after 14 days course of oral prednisolone (40 mg/day) in patients who demonstrate
more than 15% improvement in FEV1 following the inhaled β2 agonist, Salbutamol.
Furthermore the patients who show FEV1 improvement of 30% or more are considered
corticosteroid sensitive. 8
Professor and Head, Dept. of
Tuberculosis and Respiratory
Medicine, Geetanjali Medical
college and Hospital,
Udaipur-313 001
*
Immunopathology
The majority of SR asthma patients have cytokine induced corticosteroid resistance
that is likely to be acquired as a result of exposure to environmental factors like
allergens, infection, smoking, obesity, stress, Ethnicity, Vitamin D deficiency etc.
Laboratory studies have demonstrated that cytokines like Interleukin -2 (IL-2) and
supplement to Journal of the association of physicians of india • march 2014 • VOL. 62 Table 1 : Showing difference between type 1and type 2
steroid resistance
Basic defect
Cells affected
Type 1
Decrease GCR
binding affinity
Only T cells
Reversibility of defect Yes
Cause
Usually Acquired
Improvement with
Yes
higher dose of steroid
Cushingoid side
Yes
effects with higher
dose of steroid
Morning cortisol
Suppressed
levels
Type 2
Reduced number of
GCR
Both T and non T
mononuclear cells
No
Genetic
No
No
Normal
Interleukin- 4 (IL-4) can induce steroid resistance. 9
Recently a new cytokine IL-17 found in the sputum
and blood of asthmatic patients is responsible for
drawing neutrophils into the lung and making asthma
worse. 10
A new cell type T2 M has been found in mice which
cause asthma symptoms even in presence of steroid. 11
Neutrophilic inflammation in SR asthmatics have been
associated with the increased bacterial colonisation
of the airways particularly Chlamydia pneumoniae
and H. Influenzae. 12
Mechanism and Types of Steroid
Resistance
There are at least two mechanisms responsible for
SR. In type 1 SR asthma patients, the gluco-corticoid
receptor (GCR) binding affinity is abnormally reduced
with an increase in receptor sites per cell while in type
2 SR asthma the GCR binding capacity is normal but
there is marked reduction in the number of GCR cells.
Further the GCR defect in the TYPE 1 SR is reversible
with the deprivation of cytokine like IL-2 and IL-4
while it is irreversible in type 2 SR. Type 1 SR asthma
which accounts for the large majority of patients is
acquired and restricted to T cells where as type 2 SR
asthma is a form of primary cortisol resistance and is
not limited to T cells only and is rare 13 (Table1).
Diagnosis
When an established patient of asthma is poorly
controlled in terms of chronic symptoms, frequent
nocturnal or episodic exacerbations, persistent
and variable airways obstruction and continued
requirement of short acting β2 agonist (SABA) despite
being given a total daily dosage in excess of 2000 mcg
beclomethasone (800 mcg in children) or equipotent
dosage of other ICS in adults is considered to be
therapy resistant asthma. These patients may require
oral corticosteroid regular or off and on basis to
maintain reasonable control of the disease. Rarely
such patients may not respond to even higher dose
of steroids. 14
39
Diagnosis of steroid resistant asthma in these
patients can be established by means of follow up
for a period of ≥ 6 months during which time asthma
management is carried out according to published
asthma guidelines and issues such as compliance
with treatment, identification of exacerbating factors,
exclusion of other diagnosis are dealt with.
The following steps may help in the diagnosis of
steroid resistant or insensitive asthma. 15
1. Patient should have a prebronchodilator morning
FEV1 < 70% of predicted with a 15% improvement
following a rapidly acting bronchodilator
treatment. This value of FEV1 is recorded as
baseline.
2. These patients should be given oral steroid
(prednisolone 40 mg/day) for at least two weeks.
3. T h e s e p a t i e n t s f a i l t o s h o w i n c r e a s e i n
prebronchodilator morning FEV1 by 15% over
baseline value even after 2 weeks of oral steroid.
The steroid resistant asthma should be differentiated
from “ Brittle asthma”, where patient experience
recurrent episode of severe airways narrowing that
appear rapidly over minute to hours, occurring any
time of the day with no obvious trigger.These patients
have either normal lung function between episodes
which cannot be prevented by steroid or a persistent
background of wide variability in airways obstruction.
Such episodes may respond to either subcutaneous
adrenaline or terbutaline. 16
Management
The management of autoimmune and inflammatory
pulmonary diseases associated with the steroid
resistance poses a significant challenge to the
clinician. In case of asthma clinical studies have
suggested that favourable response to inhaled
steroid is associated with high levels of exhaled nitric
oxide, high bronchodilator response and sputum
eosinophilia. 17 The patient with suspected steroid
resistance should be managed in a stepwise manner
as mentioned below: 18,19
Step 1 : Confirm diagnosis of asthma and rule out
concomitant medical disorder such as vocal cord
dysfunction, gastro-oesophageal reflux, chronic
sinusitis, tracheomalacia, allergic bronchopulmonary
aspergillosis, tropical pulmonary eosinophilia or
Churg –Strauss syndrome etc.
Step 2 : Identify and remove potential allergens at
home, in school and at work place that might trigger
the patient’s disease.
Step 3 : Review the patient’s compliance and
inhaler technique. Spacer device should be used to
optimise medication delivery and reduce adverse
effects.
Step 4 : Evaluate for psychological factors affecting
40
supplement to Journal of the association of physicians of india • march 2014 • VOL. 62
adherence and response to therapy. Develop strategies
to improve compliance by simplifying medication
regimen and implementing a written action plan.
inflammatory therapies. Probably cytokine based
approach and Bronchial Thermoplasty will be more
useful in patients with SR asthma.
Step 5 : Evaluate for the potential microbial infection
(e.g. Mycoplasma or Chlamydia) which can trigger
airway inflammation and steroid insensitiveness
in chronic asthmatics. These individuals might
respond to a prolonged course of antibiotics such as
clarithromycin.
References
Step 6 : Consider factor that affect life style and
steroid responsiveness. Maximise combination
(Long acting β2 agonist or Theophylline ) therapy,
assessment and correction of vitamin D deficiency,
control and treatment of obesity, cessation of smoking
etc may improve steroid responsiveness.
The above steps are helpful in type 1 steroid
resistant asthma. While patient with type 2 steroid
resistant asthma need further workup and alternative
approaches for treatment.
Step 7 : Evaluate systemic corticosteroid
pharmacokinetics to determine whether there is
incomplete corticosteroid absorption, failure to
convert into active form or rapid elimination. Patient
with poor absorption usually respond to oral liquid
preparations, in case of rapid elimination a split
dosing regimen is suggested with the first dose in
the morning and the second dose in the afternoon.
Step 8 : Assess evidence for persistent tissue
inflammation despite treatment with high dose
steroids such as exhaled Nitric oxide (FeNo), sputum
eosinophils, BAL or bronchial biopsy specimens,
studies on peripheral blood mononuclear cells
(PBMCs)etc.
Step 9 : The final step is to consider alternative antiinflammatory and immunomodulator approach such
as IV Immunoglobulin, Cyclosporin –A, Methotrexate,
Azathioprine, Gold, anti IgE antibodies (Omalizumab)
in allergen triggered airways disease. Particularly
in type 2 SR asthma Leukotriene modifiers like
Montelukast is also a good choice in such cases. 20
The novel therapies in SR asthma like antagonist
to pro-inflammatory cytokines like IL-2, IL-4, IL-5,
IL-13, TNF – α and anti inflammatory cytokine IL-10
may find a great role as anti-inflammatory and steroid
sparing agent. Further bronchial thermoplasty has
also shown significant improvement in asthma control
in severe asthmatics. 21 Recently IL-1 targeted therapies
in corticosteroid resistant neutrophilic asthma are
also being tried. 22
Conclusion
Thus absolute corticosteroid resistance is very rare
and therefore poorly responding asthmatic patients
should be evaluated and managed in a stepwise
manner before switching over to alternative anti-
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