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Bronchial Asthma Management

Aspects Present and Future

Dr. Mohammed Shahedur Rahman Khan


MBBS, MCPS(MED), FCPS(MED), MD (Chest Diseases),
FCCP(USA)
Assistant Professor, Respiratory Medicine, NIDCH,
Mohakhali, Dhaka.

The inflammatory cascade in Asthma


Role of Th2, a new attention
IgE
FcRI
B-cell
Allergen

Mast cell
IL-4
IL-13

Th2-cell
Antigen-presenting
cell

IL-5
Eosinophil

Histamine
Leukotrienes
Prostaglandins
Cytokines

Atopic
disease

IgE-dependent release
of inflammatory mediators
Allergens

IgE

FcRI

Immediate release
Granule contents:
Histamine, TNF-,
Proteases, Heparin
Sneezing
Nasal congestion
Itchy, runny nose
Watery eyes

Over minutes
Lipid mediators:
Prostaglandins
Leukotrienes
Wheezing
Bronchoconstriction

Over hours
Cytokine production:
Specifically IL-4, IL-13

Mucus production
Eosinophil
recruitment

Basic problems lying behind proper


control of bronchial asthma
Two phases responses: Early & late phases
Multiple Mediators
Preformed granule contents: Histamine, TNF-,
Proteases, Heparin

Lipid mediators: Prostaglandins, Leukotrienes


Cytokine production: Specifically IL-4, IL-13

Numerous allergens

Bronchial Asthma treatment is


complexed by
Multiple drugs
Various devices
Poor compliance
Side effects of the drugs
Easy loss of Asthma control
High costs
Airway remodelling
Refractory Asthma

According to GINA guideline Asthma


control may be
Characteristic

Controlled (All

Partly Controlled

of the
followings)

(Any measure
present in any week)

Day time
symptoms

None (twice
or less/week)

More than
twice/week

Limitations of
activities

None

Any

Nocturnal
symptoms/awak
ening

None

Any

Need for
reliever/rescue
treatment

None (twice
or less/week)

More than
twice/week

Lung Function
(PEFR or FEV1)

Normal

<80% predicted or
personal best.( if
known)

Uncontrolled

Three or more
features of partly
controlled asthma
present

Current Asthma Drugs


Relievers
Preventers
Symptom controllers

Relievers:1. Short acting -agonists


2. Short acting Aminophyllines
3. Anticholinergics
Preventers: Have anti-inflammatory property. These include

Inhaled corticosteroid: beclometasone dipropionate,


budesonide. Fluticasone propionate and ciclesonide.

Leukotriene receptor antagonists: Montelukast,


Zafirlucast.

Cromones: Cromoglycate and Nedocromil.

Symptom controllers
They are
1) Long acting 2 agonistSalmeterol
2) Long acting Theophylline/ Aminophylline,
3) Sustained release Salbutamol
.

Step Therapy Age 12 years


+

What are the limitations of Steroid in


Asthma ?
Acts as an anti-inflammatory agent in
eosinophilic inflammation
but augments a neutrophil-mediated process
in asthmatic airway often refers to be an
esinophil-independent inflammatory
mechanism
causing difficult to control asthma/steroid
resistant asthma

Glucocorticoid
May not inhibit the release of mediators from
the mast cells
Steroid has no direct bronchodilator effect
Can't prevent remodeling of airways directly
Huge side effects on prolonged systemic
uses
Inhalation form also may have few systemic
effects

Theophylline has drown new attention in


Bronchial Asthma management
inhibits migration of T lymphocyte
towards chemotactic factors
reduces IL-2 production by T cells , IL2 dependent T cell proliferation has anti
inflammatory effect on asthmatic
airways
reduced infiltration of eosinophils and
CD4+ T and CD8+T lymphocytes into
the asthmatic airways

Antileukotriene drugs
Blocks both the early and late phases
of bronchial Asthma
Can inhibit the release of Th2
cytokines(IL-3,IL-4,GM-CSF)
Size of these effects is similar to that
seen in patients treated with 400-500g
of inhaled beclomethasone daily

NEWER DRUGS

Omalizumab
Recombinant humanized monoclonal anti IgE
Ab
It inhibits binding of IgE to mast cell thus
prevents mast cell degranulation.
It is used in the treatment of asthma and in
GINA guideline it is used as add on therapy.

MgSO4
Relaxation of bronchial smooth muscle
Modulation of calcium ion movement both within the cell and
through transmembrane calcium channels

Decreases superoxide production in neutrophils


obtained from adult asthmatics

Frusimide:
Frusemide acts as bronchodilator by inhibition of K channel in
bronchial smooth muscle.
May be of help as
bronchodilator in asthma patient with arrhyth

Diseases Modifying Agents


Methotrexate: Inhibit attraction of PN
cells by leukotrienes, Act as steroid
sparing agent.
Cyclosporine A: Inhibits transcription
factors for cytokines derived from Tlymphocytes. Act as steroid sparing agent
Gold Salt: lessens need for steriod

Others:
Troliendomycine (TAO) It is reduces the
theophylline clearance, histamine
sensitivity and increases effectiveness of
steroid.
Roflumilast It is the selective
phosphodiasterase 4 inhibitor.

Immunointerventions
Immunotherapy -Subcutaneous
Sublingual
--

Anti-IgE monoclonal antibody therapy


Other Immunomodulators: Interferon,
Allergen gene therapy,Allergen
peptide immunotherapy,cytokine
therapy,therapy with refined microbial
agents

ICU management
of Asthma

SpO2 <90% despite adequate


supplementary O2
A rising PCO2
PH <7.3
NIPPV or Mechanical ventilation

Refractory asthma
A patient getting step IV or V or VI treatment
with at least one of the following criteria
may be categorized as suffering from
refractory asthma.
Asthma symptoms requiring short acting B2
agonist use on a daily or near daily basis.
Persistent airway obstruction (FEV1 <80%
of predicted value; diurnal PEF- variability >
20%; morning PEF is < 80% of personal
best result).
One or more urgent care visits for asthma
per year.

Refractory asthma
Three or more course of oral rescue steroid
per year
Prompt deterioration with <25% reduction in
oral or inhaled corticosteroid dose.
Near fatal asthma event in the past.
Management: While continuing step IV or V or
VI treatment the following points should be
considered in managing refractory asthma:
Pitfalls in management
Intensive patient education- environmental
control, drug adherence, self management
plan.
Home nebulization- continuous nebulization
or as per need

Refractory asthma
Vaccination- influenza, measles and
pneumococcal vaccine.
Disease modifying agents may be helpful in
some patients.
Omalizumab and sublingual
immunotherapy.

Bronchial Thermoplasty and


Asthma
Bronchial thermoplasty is a potential new asthma
treatment currently undergoing clinical testing
Bronchial thermoplasty uses radio frequency energy to
relieve asthma symptoms.
A small, flexible tube called a bronchoscope is inserted
through the nose or mouth and guided into the lungs.
Once the bronchoscope is situated in the desired airway,
a catheter is inserted through the bronchoscope.

Bronchial Thermoplasty
The tip of the catheter is inflated until it touches the
sides of the airway wall.
Radio frequency energy is then sent through the
catheter, heating the smooth muscle walls of the airway
to approximately 149 F
This temperature is sufficient to thin the smooth airway
wall muscles without scarring or damaging them.
Thus causes bronchodilatation

Bronchial thermoplasty Instruments


Alair Catheter has an
expandable 4-wire array of
electrodes at the tip.
Radiofrequency
Controller supplies energy
via the catheter to heat
the airway wall.

Bronchial thermoplasty

Human Airway
Lobectomy Study

Untrea
ted

Treated

Cytokine Inhibitors
Newer drugs for asthma
Drug

Action

Outcomes

Mepolizumab anti-IL5

In severe refractory eosinophilic asthma, the


frequency of exacerbation is reduced by 90%.
The drug is well tolerated in the clinical trials.
Large studies are needed to confirm its
effectiveness.

Pitrakinra

antiIL4/IL13

Subcutaneous administration reduces asthma


related adverse effects. Also reduces the
magnitude of late asthmatic response. Can be
delivered as an inhalational agent.

AMG317

antiIL4/IL13

In a subgroup of severe asthmatics it improves


certain efficiency parameters. The drug is well
tolerated in initial studies.

Cytokine Inhibitors
Newer drugs for asthma
Drug

Action

Outcomes

Etanercept

anti-TNF
alpha

Improves the FEV1 but abandoned due to


adverse side effects including pneumonia,
TB, sepsis and lymphoma

Infliximab

anti TNF
alpha

Reduced asthma exacerbation but


abandoned due to adverse side effects
including pneumonia, TB, sepsis and
lymphoma

Golimumab

anti TNF
alpha

Still on trial but has several adverse


side effects including pneumonia, TB,
sepsis and lymphoma

Conclusion
Treatment of bronchial Asthma has
undergone revolutionary changes in the last
decade with the invent of drugs notably
inhaled steroids,antileukatrienes & 2agonist,Xanthine derivatives and
Omazulomab . Inspite of that worldwide
prevalence of Asthma, as well as its
morbidity and mortality is still rising. As yet
there is no cure for Asthma.Therapy only
ameliorates the symptoms. So we need more
and more new therapeutics options.