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By Dr Ashok Kumar
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Asthma is a syndrome characterized byairflow obstruction that varies markedly,both spontaneously and with treatment.
Asthma is a heterogeneous inflammatorydisease of the airways. that makes themmore responsive than non-asthmatics to a
wide range of triggers, leading toexcessive narrowing with reduced airflow,symptomatic wheezing and dyspnea.
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Asthma is a heterogeneous disease with
interplay between genetic and environmental
factors.
Several risk factors and triggers have beenidentified.
Upper respiratory tract virus infections such
as rhinovirus, respiratory syncytial virus, and
coronavirus are the most common triggers ofacute severe exacerbations.
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There is chronic inflammation in therespiratory mucosa from the trachea to
terminal bronchioles.
The airway mucosa is infiltrated with
activated eosinophils and T lymphocytes, and
there is activation of mucosal mast cells.
Airway Remodeling with increased airway
smooth muscle, fibrosis, angiogenesis, andmucus gland hyperplasia.
The airway inflammation in asthma is
associated with airway hyper-responsiveness.
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The diagnosis of asthma is usually apparent
from the symptoms of wheezing, dyspnea, and
coughing.
Variable and intermittent airways obstruction,and airway hyperresponsiveness are
diagnostic.
Confirmed by objective measurements of lung
function.
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Simple spirometry confirms airflow limitation
with a reduced FEV1, FEV1/FVC ratio, and
Peek Expiratory Flow.
Reversibility is demonstrated by a >12% and200-mL increase in FEV1 15 minutes after an
inhaled short-acting B2-agonist or in some
patients by a 2 to 4 week trial of oral
corticosteroids.
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The increased airway response is normally
measured by methacholine or histamine
challenge with calculation of concentration
that reduces FEV1 by 20%. This is rarely useful in clinical practice.
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Non-Pharmacological
Treatment begins with the identification and
elimination of possible environmental inhalant
allergens that can trigger symptoms. Substantially reducing exposure to these
allergens significantly reduces lung inflammation,
improves clinical symptoms, and decreases the
need for medications. Allergen Immunotherapy is another option that
has been shown to provide similar effects.
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Numerous agents are used, including
1. Inhaled corticosteroids (ICSs)2. 2 agonists (short and long acting)
3. Leukotriene antagonists,4. Cromones,5. Monoclonal antibodies.
Of these, ICSs remain the mainstay oftreatment for persistent asthma according tovarious guidelines.
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ICS decrease airway inflammation and
remodeling, hyper-responsiveness, improve
asthma symptoms and decrease morbidity.
These are now considered first-line therapy in
the management of persistent asthma. ICS
therapy has been shown to have long-term
efficacy in adults as well as children.
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There are currently 6 ICSs approved by the US FDA
1. Beclomethasone dipropionate (BDP)
2. Budesonide (BUD),
3. Triamcinolone acetonide (TA)
4. Flunisolide,
5. Fluticasone propionate (FP), and
6. Mometasone furoate (MF).
All of these ICSs are effective and safe, althoughtherapeutic profiles differ slightly among ICSs.
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Local :oral candidiasis, dysphonia, and cough.
Systemic :Skin thinning and bruising.Bone mineral density can be reduced with
long-term, high-dose therapy.
Risk of cataracts and glaucoma may beincreased. In children, growth suppression and
adrenal suppression are seen with highdoses.
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Step 2
Step 1
Step 3
Step 4
Step 5
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Class Examples Mechanism of
action
ICS Ciclesonide Local activation,
depot formation,rapid metabolism.
Dissociated steroids Transrepression
without
Transactivation.Soft steroids Drug inactivated
when not in lungs
IgE and Mast
Cell Targets
Omalizumab Anti-IgE therapy
Lumiliximab Anti-CD23 antibody
Spleen tyrosine kinase
(Syk) inhibitorsInhibits Mast cell
signaling.
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Novel
Anti-
InflammatoryAgents
Roflumilast PDE4 inhibitor
Cytokine
Inhibitors
Soluble IL-4 receptor IL-4 antagonist
Mepoluzimab IL-5 antagonist
Suplatast tosilate Suppresses IL-4 and
IL-5
Daclizumab IL-2 receptor
antagonist
Etanercept TNF- antagonist
Vaccines AIC vaccine (DNA
vaccine)
Toll-like receptor 9
agonists
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The anti-inflammatory action of Corticosteroidsare mediated by inhibition of transcription(transrepression), whereas associated sideeffects are mediated by transactivation of geneexpression.
Dissociated steroids have only transrepressionactivity without transactivation
Soft steroids : These unique steroids are pharmacologically
active at the desired site, but their distributionaway from the site results in rapid metabolicdeactivation that prevents toxicity.
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Ciclesonide is a prodrug soft steroid that isactivated in the lungs to active metabolite
des-ciclesonide (des-CIC).
Des-CIC has 100 times greater affinity for theGR than CIC. Once in the circulation undergoes
extensive first-pass metabolism (>99%) by the
liver. Bioavailability of CIC is
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Omalizumab is a recombinant humanized
monoclonal anti-IgE antibody approved
for clinical use in severe asthma. It binds
circulating IgE and thereby prevents itfrom attaching to mast cells.
It does not affect IgE bound to mast cells,
it can take weeks to months for IgE bound
to mast cells to disappear.
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Lumiliximab : An anti-CD23 antibody, acts as
an immunomodulator, reduces IgEconcentrations in patients with mild asthma.
Spleen tyrosine kinase (Syk) is involved in the
activation of mast cells through IgE-
dependent pathway.R112 is inhibitor of Syk, has been shown to
decrease nasal symptoms in patients with
allergic rhinitis. More studies are needed to
test its efficacy in asthma.
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Th2 cells produce interleukins IL-4, IL-5, and IL-13, all of which are important in asthma and
other allergic diseases.
Mepolizumab is a monoclonal antibody that
targets IL-5, it effectively reduced eosinophillevels in blood and sputum.
Pitrakinra is a recombinant IL4 that acts as a
competitive antagonist at IL4 and IL13.Nebulized pitrakinra has improved FEV1 and
decreased inflamation.
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Etanercept shown a decrease in bronchial
hyperresponsiveness, improved FEV1 and
athma related quality of life.
Infliximab did not show any improvementin peak expiratory flow rates.
Long term treatment with anti-TNF
agents can cause reactivation of chronic
infections like Tuberculosis.
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Theophylline was commonly used in themanagement of asthma in the past. is anonselective phosphodiesterase (PDE)inhibitor has significant side effects.
Roflumilast is a selective PDE4 inhibitorgiven orally, inhibit both early and lateasthmatic responses, effects arecomparable to low doses of inhaledsteroids.
Cilomilast is another PDE4 inhibitor underevaluation
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Smooth muscle hypertrophy is an important
finding in severe athma. smooth muscle mass
can be reduced with controlled delivery of
thermal energy to bronchial wall during
bronchoscopy. Studies have shown that
Thermoplasty reduces severe exacerabations
and improves quality of life.
Bronchial Thermoplasty
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Allergen immunotherapy represents the only
disease-modifying treatment that can potentially
alter the natural course of asthma.
A new form of immunotherapy is using
oligodeoxynucleotides (short single-stranded
synthetic DNA molecules) as conjugates.
CpG oligonucleotides (CpG-ODN, resembling
bacterial DNA) engage Toll-Like Receptor 9 on B-
cells, dendritic cells resulting in induction ofTh1-type and T-regulatory-type immune
responses.
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There will be shift of Th2 IgE to Th1 CMIresponse for the conjugated antigen, after
repeated exposure.
CpG-Oligonucleotides are potent inhibitors ofatopic responses, suppressing Th2 cytokine
and, reducing airway eosinophilia, systemic
levels of IgE.
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Amb a1 (a ragweed-pollen antigen)Immunostimulatory oligonucleotide
Conjugated(AIC) vaccine
was shown to offer long-term clinical
efficacy in the treatment of ragweed
allergic rhinitis.
Immunotherapy found to be moreeffective for allergic rhinitis than for
asthma
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It is estimated that about 40% of cases
asthma is based on neutrophilic airway
inflammation.
Possibly triggered by environmental exposureto bacterial endotoxin, particulate air
pollution, and ozone, as well as viral
infections.
Patients with non-eosinophilic athma haveincreased neutrophils and IL8 in their
airways.
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Cartocosteroids are of limited efficacy in
non-eosinophilic athma.
Macrolides like Clarithomycin and
Telithromycin are active against Atypicalbacteria, which are known to cause acute
exacerebations.
They also have anti-inflammatory action,
have been shown to be effective in acuteexacerbations of asthma.
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Magnesium sulphate is smooth musle
relaxant.
Intravenous magnesium sulphate is a safe
treatment for acute asthma. Doses of up to40 mg/kg/day (maximum 2 g) by slow
infusion have been used.
It can also given by nebulisation.
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Theoretically furosemide can produce
bronchodilation.
Studies failed to show any significant benefitof treatment with nebulised furosemide
compared to 2 agonists.
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