Asthma

Asthma is a chronic inflammatory disorder of the airways, in which many cells and cellular elements
play a role.
The chronic inflammation is associated with airway hyper-responsiveness that leads to :
1. Recurrent episodes of wheezing,
2. Breathlessness,
3. Chest tightness
4. Coughing, particularly at night and in the early morning.

These episodes are usually associated with widespread but variable airflow obstruction within the lung
that is often reversible, either spontaneously or with treatment.

Epidemiology
The prevalence of asthma increased steadily over the latter part of the last century, first in the
developed and then in the developing world.

Current estimates suggest that asthma affects 300 million people worldwide, with a predicted additional
100 million people affected by 2025.

The socio-economic impact is enormous, as poor control leads to:

1. Days lost from school or work,
2. Unscheduled health-care visits
3. Hospital admissions.

Although the development and course of the disease, and the response to treatment, are influenced by :
1. Genetic determinants,
2. Environmental factors that’s explains the rapid rise in prevalence
To date, studies have explored the potential role of the following ……… but no clear consensus has
emerged
 indoor and outdoor allergens,
 microbial exposure,
 diet,
 vitamins,
 breastfeeding,
 tobacco smoke,
 air pollution and
 obesity
.
Asthma commonly starts in childhood between the ages of 3 and 5 years and may either worsen or
improve during adolescence.
Pathophysiology
**
Classically asthma chronic asthma
 Airflow limitation which is usually reversible inflammation may be accompanied by
spontaneously or with treatment irreversible airflow limitation as a result of
 Airway hyperresponsiveness to a wide range airway wall remodeling that may involve large
of stimuli and small airways and mucus impaction.
 Bronchial inflammation with T lymphocytes,
mast cells,
eosinophils with associated plasma exudation,
oedema,
smooth muscle hypertrophy, matrix deposition,
mucus
plugging and epithelial damage.

**
 Airway hyper-reactivity (AHR) –
The tendency for airways to narrow excessively in response to triggers that have little or no effect in
normal individuals – is integral to the diagnosis of asthma and appears to be related, to :
1. airway inflammation : not exclusively
2. The behavior of airway smooth muscle include the degree of airway narrowing
3. Neurogenic mechanisms.
Airway hyper-reactivity in asthma.
This is demonstrated by bronchial challenge tests with
sequentially increasing concentrations of either :
 histamine,
 methacholine
 mannitol.
The reactivity of the airways is expressed as the concentration
or dose of either chemical required to produce a specific
decrease (usually 20%) in the FEV1 (PC20 or PD20 respectively).

(Bronchial Provocation Tests). **

Asking patients to inhale gradually increasing concentrations of histamine or methacholine This
induces transient airflow limitation in susceptible individuals (approximately 20% of the population);
the severity of BHR can be graded according to the provocation dose (PD) or concentration (PC) of the
agonist that produces a 20% fall in FEV1 (PD20 FEV1 or PC20 FEV1).
Patients with clinical symptoms of asthma respond to very low doses of methacholine, i.e. they have a
low PD20 FEV1.

Other methods !
BHR can also be assessed by :
 exercise testing or
 inhalation of cold dry air,
 mannitol or hypertonic saline.
These are indirect tests that release endogenous mediators such as histamine, prostaglandins and
leukotrienes which then cause bronchoconstriction.
Indirect measures of BHR correlate more closely with symptoms and diurnal peak expiratory flow
rate (PEFR) variation than PC20 histamine or methacholine: both are useful in diagnosing asthma if
there is doubt and in guiding controller treatment.

Some patients also react to methacholine but at higher doses, e.g. those with:
 attacks of asthma only on extreme exertion, e.g. winter sports enthusiasts
 wheezing or prolonged periods of coughing following a viral infection
 seasonal wheeze during the pollen season
 allergic rhinitis, but not complaining of lower respiratory symptoms until specifically questioned
 and some subjects with no respiratory symptoms.
Although the degree of BHR can be influenced by allergic mechanisms , its pathogenesis and mode of
inheritance involve a combination of airway inflammation and tissue remodelling.
**
The relationship between atopy (the propensity to produce IgE) and asthma is well established, and in
many individuals there is a clear relationship between sensitisation and allergen exposure, as
demonstrated by :
1. skin prick reactivity
2. elevated serum specific IgE.
Common examples of allergens include:
1. house dust mites,
2. pets such as cats and dogs,
3. pests such as cockroaches ,and fungi.

Inhalation of an allergen into the airway is followed by an early and late-phase bronchoconstrictor
response :
** Allergen-induced asthma
The experimental inhalation of allergen by atopic asthmatic individuals leads to the development of
different types of
reaction,.
Immediate asthma (early reaction) Dual and late-phase reactions.
Airflow limitation begins within minutes of Following an immediate reaction many asthmatics
contact with the allergen, reaches develop a more prolonged and sustained attack
its maximum in 15–20 minutes and subsides by 1 of airflow limitation that responds less well to
hour. inhalation of bronchodilator drugs such as
salbutamol.

**Isolated late-phase reactions with no preceding

immediate response can occur after the inhalation
of
some occupational sensitizers such as
isocyanates.
*BHR increases during and for several weeks
after the exposure,
which may explain persisting symptoms after
allergen
exposure

Mechanism of different types of asthma :

Type Mechanism
occupational asthma Allergic mechanisms:
Occupational asthma (OA) should be considered in any individual of
working age who develops new-onset asthma, particularly if the patient
reports an improvement
in asthma symptoms during periods away from work, e.g. at
weekends and on holiday.
Workers in certain occupations appear to be at particularly high risk and
the condition is more common in smokers and atopic individuals.
 *Depending on the intensity of exposure, asthmatic symptoms usually
develop within the first year of employment but are classically
preceded by a latent period.

Symptoms :
rhinoconjunctivitis often precede the development of asthma.

Dx :
1.skin testing or measurement of specific IgE.: When OA follows
exposure to high molecular weight proteins, sensitisation to the agent
2.Confirmation of OA should be sought from lung function tests, which
usually involves serial recording of peak flow at work, at least 4 times
per day for at least
3 weeks and, if possible, including a period away from work
In certain circumstances, specific challenge tests are required to confirm
the diagnosis.

Management :
It may be possible to remove the worker from the implicated agent but
when this is not feasible, consideration of personal protective
equipment and workplace hygiene may allow patients to retain their job
and income.
 Specialist follow-up in such situations is highly advisable.
 A favourable prognosis is indicated bya short history of symptoms and
normal lung functionat diagnosis.
 Where reduction or avoidance of exposurefails to bring about
resolution, the general management does not differ from that of other
forms of asthma.

aspirin-sensitive asthma ingestion of salicylates results in inhibition of the cyclo-oxygenase

enzymes, preferentially shunting the metabolism of arachidonic acid
through the lipoxygenase pathway with resultant production of the
asthmogenic cysteinyl leukotrienes.
exercise-induced asthma hyperventilation results in :
1. water loss from the pericellular lining fluid of
the respiratory mucosa, which, in turn, triggers mediator release.
2. Heat loss from the respiratory mucosa
**Exercise-induced wheeze is driven by release of histamine,
prostaglandins (PGs) and leukotrienes (LTs) from mast cells as well as
stimulation of neural reflexes when the epithelial lining fluid of the
bronchi becomes hyperosmolar owing to drying and cooling during
exercise.
The phenomenon can be shown by exercise, cold air and hypertonic (e.g.
saline or mannitol) provocation tests**
persistent asthma a chronic and complex inflammatory response ensues, characterised
 by:
 an influx of numerous inflammatory cells,
 the transformation and participation of airway structural
cells
 the secretion of an array of cytokines, chemokines and growth
factors.
 With increasing severity and chronicity of the disease,
remodelling of the airway may occur, leading to:
a. fibrosis of the airway wall,
b. fixed narrowing of the airway
c. reduced response to bronchodilator medication

Examination of the inflammatory cell profile in induced sputum samples

demonstrates that,
a) airway eosinophilia, most predominate
b) neutrophilic inflammation predominates in some patients,
c) scant inflammation is observed: so-called ‘pauci-granulocytic’
asthma.

**Classification
Asthma is a complex disorder of the conducting airways that was often classified into extrinsic and
intrinsic asthma but there is considerable overlap.
Extrinsic asthma Intrinsic asthma
occurs most frequently in atopic individuals: often starts in middle age. / Non-atopic
i.e. those with positive skin-prick reactions to individuals
common inhalant allergens such as dust mite, But, many patients with adult-onset asthma show:
animal  positive allergen skin tests and
danders, pollens and fungi;  on close questioning some of these will
children adults give a history of childhood respiratory
90% of with persistent 70% of with persistent symptoms suggesting they have
asthma asthma extrinsic asthma.
accompanied by Sensitization to
eczema (atopic chemicals or biological Extrinsic causes such as :
dermatitis) products in the  sensitization to occupational agents such
workplace is a as toluene diisocyanate,
frequently overlooked  intolerance to NSAID such as aspirin or
cause of late-onset  already on β-adrenoceptor-blocking
asthma agents for concurrent hypertension or
angina that block the protective effect of
endogenous adrenergic agonists. ( Past
drug history )
Extrinsic causes must be considered in all cases of asthma and, where possible, avoided.

Aetiology and pathogenesis

The two major factors involved in the development of asthma and many other stimuli that can precipitate
attacks
.
Atopy and allergy
The term ‘atopy’ was coined in the early 20th century to describe a group of disorders, including
asthma and hayfever,
which appeared:
 to run in families
 to have characteristic wealing skin reactions to common allergens in the environment
 to have circulating allergen-specific antibodies (later shown to be IgE).
Genetic
There is no single gene for asthma, but several
genes, in
combination with environmental factors,
appear to influence the development of asthma.
 Genes controlling the production of the
cytokines IL-3,
IL-4, IL-5, IL-9, IL-13 and GM-CSF – which in
turn affect
mast and eosinophil cell development and
longevity as
well as IgE production – are present in a cluster
on
chromosome 5q31-33 (the IL-4 gene cluster).
 Polymorphic variation in proteins along the
IL-4/-13
signalling pathway is strongly associated with
allergy
and asthma.
 Novel asthma genes identified by positional
cloning
from whole genome scans are the PHF11 locus on
chromosome 2 (that includes genes SETDB2 and
RCBTB1) and transcription factors, which are
implicated
in IgE synthesis and associated more with atopy
than
asthma.
 ADAM 33 (a disintegrin and
metalloproteinase) on
chromosome 20p13 is associated with airway
hyperresponsiveness and tissue remodelling.
 Other genes associated with asthma are those
that
encode neuropeptide S receptor (GPRA or
GPR154) on
Environmental
Environmental factors
1. Early childhood exposure to allergens and
maternal smoking has a major influence on IgE
production.
2.role of intestinal bacteria and childhood
infections in shaping the immune system in early
life. It has been suggested that growing up in a
relatively ‘clean’ environment may predispose
towards an IgE response to allergens (the
‘hygiene hypothesis’). Conversely, growing up in
a ‘dirtier’ environment may allow the immune
system to avoid developing allergic responses.
3.Immunological factors : Components of
bacteria (e.g. lipopolysaccharide endotoxin,
immunostimulatory CpG DNA sequences,
flagellin), viruses (e.g. SS- and DS-RNA) and
fungi (e.g. chiton, a cell wall component)
stimulate various toll-like receptors (TLRs)
expressed on immune and epithelial cells to direct
the immune and inflammatory response away
from the allergic (Th2) towards protective
(Th1 and Treg) pathways.
** Th1 immunity is associated with antimicrobial
protective immunity whereas regulatory T cells
are strongly implicated in tolerance to allergens.
** Thus early life exposure to inhaled and
ingested products of microorganisms, as occurs in
livestock farming communities and developing
countries, may reduce the subsequent risk of a
child becoming allergic and/or developing
asthma.
** The allergens involved in allergic asthma are
similar to
those implicated in rhinitis although pollens are
 chromosome 7p15, HLA-G on chromosome 6p21,
dipeptidyl peptidase 10 on chromosome 2q14 and
ORMDL3, a member of a gene family that
encodes
transmembrane proteins anchored in the
endoplasmic
reticulum, on chromosome 17q21.
relatively less
implicated in asthma.
** The fungal spores from Aspergillus fumigatus
cause
a range of lung disorders, including asthma
Many allergens, including those from Aspergillus,
have intrinsic
biological properties, e.g. enzymes with
proteolytic function which may increase their
sensitizing capacity

Pathogenesis
The pathogenesis of asthma is complex and not fully understood.
It involves a number of cells, mediators, nerves and vascular leakage that can be activated by several
different mechanisms, including exposure to allergens
The varying clinical severity and chronicity of asthma is dependent on an interplay between airway
inflammation and airway wall remodelling.
 The inflammatory component is driven by Th2-type T lymphocytes which facilitate IgE synthesis
through production of IL-4 and eosinophilic inflammation through IL-5 .
 However, as the disease becomes more severe and chronic and loses its sensitivity to
corticosteroids, there is greater evidence of a Th1 response with:
 release of mediators such as TNF-α
 and associated tissue damage,
 mucous metaplasia and
 aberrant epithelial and
 mesenchymal repair.

Inflammation
Several key cells are involved in the inflammatory response that characterizes all types of asthma.

Mast cells These are increased in the epithelium, smooth muscle and mucous glands in asthma and
release powerful preformed and newly generated mediators that act on:
 smooth muscle,
 small blood vessels,
 mucus secreting cells and
 sensory nerves, such as histamine, tryptase, PGD2 and cysteinyl leukotrienes,
which cause the immediate asthmatic reaction.

Mast cells are inhibited by:

 sodium cromoglycate and
 β2 agonists, which may partly explain their ability to prevent acute
bronchoconstriction triggered by indirect challenges.

Types Mediators
immediate asthmatic histamine, tryptase, PGD2 and cysteinyl leukotrienes
reaction.

late asthmatic Mast cells also release an array of cytokines, chemokines and
growth factors , that contribute to the response and more
chronic aspects of asthma
Eosinophils These are found in large numbers in the bronchial wall and secretions of asthmatics.
.
They are attracted to the airways by the:
a) eosinophilopoietic cytokines IL-3, IL-5 and GM-CSF
b) chemokines which act on type 3 C-C chemokine receptors (CCR-3) (i.e.
eotaxin, RANTES, MCP-1,
MCP-3 and MCP-4).
 These mediators also prime eosinophils for enhanced mediator secretion. When
activated, eosinophils
release :
a) LTC4, and
b) basic proteins that are toxic to epithelial cells such as :
a. major basic protein (MBP),
b. eosinophil cationic protein (ECP) and
c. eosinophils peroxidase (EPX).

Both the number and activation of eosinophils are rapidly decreased by

corticosteroids.

**Sputum eosinophilia is of diagnostic help as well as providing a biomarker of

response to therapy

Dendritic These cells are abundant in the mucous membranes of the airways and the alveoli.
cells and
lymphocyte Dendritic cells have a role in the initial uptake and presentation of allergens to
s lymphocytes.
T helper lymphocytes (CD4+) show evidence of:
a) activation and the release of their cytokines plays a key part in the migration
and activation of mast cells (IL-3, IL-4, IL-9 and IL-13) and eosinophils (IL-3,
IL-5, GM-CSF).
b) , production of IL-4 and IL-13 helps maintain the proallergic Th2 phenotype,
favouring switching of antibody production by B lymphocytes to IgE.

In mild/moderate asthma there is selective upregulation of Th2 T cells with reduced

evidence of the Th1 phenotype (TNF-α and IL-2),
Th1 cells are more prominent in more severe disease. This polarization is mediated
by dendritic cells and involves a combination of antigen presentation, co-stimulation
and exposure to polarizing cytokines.

The activity of both macrophages and lymphocytes is influenced by corticosteroids

but not β2-adrenoceptor agonist

Remodelling

A characteristic feature of chronic asthma is an alteration of structure and functions of the formed
elements of the airways.
Together, these structural changes interact with inflammatory cells and mediators to cause the
characteristic features of the disease. :
 Deposition of matrix proteins,
 swelling and cellular infiltration expand the submucosa beneath the epithelium so that for a given
degree of smooth muscle shortening there is excess airway narrowing.
 Swelling outside the smooth muscle layer spreads the retractile forces exerted by the surrounding
alveoli over a greater surface area so that the airways close more easily.

The  In asthma the epithelium of the conducting airways is stressed and damaged
epithelium with loss of ciliated
. columnar cells.
 Metaplasia occurs with a resultant increase in the number and activity of
mucus-secreting goblet cells.

The epithelium is a major source of mediators, cytokines and growth factors that
enhance inflammation and promote tissue remodelling .

**Damage and activation of the epithelium make it more vulnerable to infection by

 common respiratory viruses (e.g. rhinovirus, coronavirus) and to the effects of air
pollutants.

**Increased production of nitric oxide (NO), due to the increased expression of inducible
NO synthase, is a feature of epithelial damage and activation.

** Measurement of exhaled NO is proving useful as a non-invasive test of continuing

inflammation

Epithelial A pathognomonic feature of asthma is the deposition of :

basement a) repair collagens (types I, III and V) and
membrane b) proteoglycans in the lamina reticularis beneath the basement membrane.
c) matrix proteins such as laminin, tenascin and fibronectin,

this result in the : appearance of a thickened basement membrane observed by light

microscopy in asthma.

This collagen deposition reflects activation of an underlying sheath of fibroblasts that

transform into contractile myofibroblasts which also have an increased capacity to
secrete matrix.

Aberrant signalling between the epithelium and underlying myofibroblasts is thought

to be the principal cause of airway wall remodelling, since the cells are prolific producers
of a range of tissue growth factors such as epidermal growth factor (EGF),
transforming growth factor (TGF)-α and -β, connective tissue-derived growth factor
(CTGF), platelet-derived growth factor (PDGF), endothelin (ET), insulin-like growth
factors (IGF), nerve growth factors and vascular endothelial growth factors.

The same interaction between epithelium and mesenchymal tissues is central to

branching morphogenesis in the developing fetal lung. It has been suggested that these
mechanisms are reactivated in asthma, but instead of causing airway growth and
branching, they lead to thickening of the airway wall
Smooth 1. hyperplasia of the helical bands of airway smooth muscle.
muscle 2. the smooth muscle alters in function so it contracts more easily and stays
contracted because of a change in actin–myosin cross-link cycling.
These changes allow asthmatic airways to contract too much and too easily at the
least provocation.
3.Asthmatic smooth muscle also secretes a wide range of cytokines, chemokines and
growth factors that help sustain the chronic inflammatory response.

The asthma gene ADAM33 has been. implicated in driving increased airway smooth
muscle and other features of remodelling through increased availability of growth
factors.

Nerves. Neural reflexes, both central and peripheral, contribute to the irritability of asthmatic
airways

Central involve stimulation of nerve endings in the epithelium and submucosa with
reflexe transmission of impulses via the spinal cord and brain back down to the
s airways where release of acetylcholine from nerve endings stimulates M3
receptors on smooth muscle causing contraction
Local involve antidromic neurotransmission and the release of a variety of
neural neuropeptides
reflexe
s Some of these are:
 smooth muscle contractants (substance P, neurokinin A),
 some are vasoconstrictors (e.g. calcitonin gene-related peptide, CGRP)
 and
 some vasodilators (e.g. neuropeptide Y, vasoactive intestinal
polypeptide).

A polymorphism of the neuropeptide S receptor (GPR 154) is associated with

asthma susceptibility.

 Bradykinin generated by tissue and serum proteolytic enzymes

(including mast cell tryptase and tissue kallikrein) is also a potent
stimulus of local neural reflexes involving (nonmyelinated) nerve
fibres.

**

Clinical features
C.C Typical symptoms include :
1. recurrent episodes of wheezing,
2. chest tightness,
3. breathlessness
4. cough
Onset / Classical precipitants include :
triggering  exercise, particularly in cold weather,
 exposure to airborne allergens or pollutants,
 viral upper respiratory tract infections
Cause Although the aetiology of asthma is often elusive, an attempt should be made to
identify any agents that may contribute to the appearance or aggravation of the
condition.
Particular enquiry should be made about potential allergens, such as exposure to a:
 pet cat,
 guinea pig,
 rabbit or horse,
 pest infestation,
 exposure to moulds following water damage to a home or building,
 and any potential occupational agents.
 Timing Asthma characteristically displays a diurnal pattern, with symptoms and lung
function being worse in the early morning.
Particularly when poorly controlled, symptoms such as cough and wheeze disturb
sleep and have led to the term ‘nocturnal asthma’.
Associated Cough may be the dominant symptom in some patients, and the lack of wheeze or
symptoms breathlessness may lead to a delay in reaching the diagnosis of so-called ‘cough-
variant asthma’.

BUT “CAUTION” !
 Some patients with asthma have a similar inflammatory response in the
upper airway.
 Careful enquiry should be made as to a history of sinusitis, sinus headache, a
blocked or runny nose, and loss of sense of smell.

Previous Patients with mild intermittent asthma are usually asymptomatic between
health sate exacerbations.
“previously
healthy or Individuals with persistent asthma report ongoing breathlessness and wheeze, but
not” these are variable, with symptoms fluctuating over the course of one day, or from
day to day or month to month
Drug  Beta-blockers,
 aspirin and other (NSAIDs). even when administered topically as eye drops,
may induce bronchospasm,
The classical aspirin sensitive patient is :
1. female
2. middle age
3. with asthma,
4. rhinosinusitis and
5. nasal polyps.
Aspirin sensitive patients may also report symptoms following:
1. alcohol (in particular, white wine)
2. foods containing salicylates.

 oral contraceptive pill,

 cholinergic agents and
 prostaglandin F2α.
 Betel nuts contain arecoline, which is structurally similar to methacholine
and can aggravate asthma.

An important minority of patients develop a particularly severe form of asthma,

and this appears to
be more common in women.
Allergic triggers are less important and airway neutrophilia predominates.

N.B : Asthma is commonly mistaken for a cold or chest infection which is taking time to resolve (e.g.
longer than 10 days).

Examination
1. Wheeze apart, there is often very little to find on examination.
2. An inspection for nasal polyps and eczema should be performed. Rarely, a vasculitic rash may
suggest Churg– Strauss syndrome

Diagnosis
 The diagnosis of asthma is predominantly clinical and based on a characteristic history.
  Supportive evidence is provided by the demonstration of variable airflow obstruction, preferably
by using spirometry to measure FEV1 and VC. , This :
o identifies the obstructive defect,
o defines its severity,
o provides a baseline for bronchodilator reversibility
** If spirometry is not available, a peak flow meter may be used.
** Patients should be instructed to record peak flow readings after rising in the morning and before
retiring in the evening.
A diurnal variation in PEF of more than 20% (the lowest values typically being recorded in the
morning) is considered diagnostic, and the magnitude of variability provides some indication of disease
severity

 A trial of corticosteroids (e.g. 30 mg daily for 2 weeks) may be useful in establishing the
diagnosis, by demonstrating an improvement in either FEV1 or PEF.
 It is common for patients whose symptoms are suggestive of asthma to have normal lung
function.
o In these circumstances, the demonstration of AHR by challenge tests may be useful to confirm the
diagnosis
o AHR is sensitive but non-specific: it has a high negative predictive value but positive results may be
seen in other conditions, such as COPD, bronchiectasis and cystic fibrosis.
o When symptoms are predominantly related to exercise, an exercise challenge may be followed by a
drop in lung function

How to make a diagnosis of asthma ?

Compatible clinical history plus either/or :
• FEV1 ≥ 15%* (and 200 mL) increase following administration of a bronchodilator/trial of
corticosteroids
• > 20% diurnal variation on ≥ 3 days in a week for 2 weekson PEF diary
• FEV1 ≥ 15% decrease after 6 mins of exercise

Reversibility test

Other investigations
Measurement of allergic status: the presence of atopy may be demonstrated by ;
skin prick tests

the measurement of
total and allergen-
specific IgE.

A full blood
picture may show
the peripheral
blood eosinophilia

Radiological examination:
chest X-ray
appearances are
often normal

show
hyperinflation of
lung fields

Lobar collapse may

be seen if mucus
occludes a large
bronchus

the presence of
flitting infiltrates,
may suggest that
asthma has been
complicated by
allergic
bronchopulmonar
y aspergillosis
 HRCT scan may
be useful to detect
bronchiectasis.

Assessment of eosinophilic airway inflammation:

an induced sputum
differential
eosinophil count of
greater than 2%

exhaled breath
nitric oxide
concentration
(FENO) may
support the
diagnosis but is
non-specific
Management
Setting goals
Asthma is a chronic condition but may be controlled with appropriate treatment in the majority of
patients.
The goal of treatment should be to obtain and maintain complete control, but aims may be modified
according to the circumstances and the patient.
Whenever possible, patients should be encouraged to take responsibility for managing their own
disease.
o A full explanation of the :
o nature of the condition,
o the relationship between symptoms and inflammation,
o the importance of key symptoms such as nocturnal waking,
o the different types of medication, and,
o if appropriate, the use of PEF to guide management decisions,
A variety of tools/questionnaires have been validated to assist in assessing asthma control.
Written action plans can be helpful in developing self management skills.

Avoidance of aggravating factors

This is particularly important in the management of :
o occupational asthma
o atopic patients, when removing or reducing exposure to relevant antigens, such as a pet, may
effect improvement.
 House dust mite exposure may be minimised by replacing carpets with floorboards and using
miteimpermeable bedding.
 Many patients are sensitised to several ubiquitous aeroallergens, making avoidance strategies
largely impractical.
 Measures to reduce fungal exposure and eliminate cockroaches may be applicable in specific
circumstances,
 medications known to precipitate or aggravate asthma should be avoided.
 Smoking cessation is particularly important, as smoking not only encourages sensitisation, but also
induces a relative corticosteroid resistance in the airway.

The stepwise approach to the management of asthma

Step 1: Occasional use of inhaled short-acting β2-adrenoreceptor agonist bronchodilators
For patients with mild intermittent asthma (symptoms less than once a week for 3 months and fewer than
two nocturnal episodes per month), it is usually sufficient to prescribe an inhaled short-acting β2-agonist,
such as salbutamol or terbutaline, to be used as required.
! HOWEVER, many patients (and their physicians) underestimate the severity of asthma.
 A history of a severe exacerbation should lead to a step-up in treatment.
 A variety of different inhaled devices are available and the choice of device should be guided by
patient preference and competence in its use.
 The metered-dose inhaler remains the most widely prescribed .

Spacers
 These are plastic cones or spheres inserted between the patient’s mouth and the inhaler. Some
inhalers have a built-in spacer extension. These are designed to reduce particle velocity so that
less drug is deposited in the mouth.
 Spacers also diminish the need for coordination between aerosol activation and inhalation.
  They are useful in children and in the elderly and reduce the risk of candidiasis

Step 2: Introduction of regular preventer therapy

Regular anti-inflammatory therapy (preferably inhaled corticosteroids (ICS), such as beclometasone,
budesonide (BUD), fluticasone or ciclesonide) should be started in addition to inhaled β2-agonists
taken on an as-required basis for any patient who:
• has experienced an exacerbation of asthma in the last 2 years
• uses inhaled β2-agonists three times a week or more
• reports symptoms three times a week or more
• is awakened by asthma one night per week.

For adults, a reasonable starting dose is 400 μg beclometasone dipropionate (BDP) or equivalent per day
in adults, although higher doses may be required in smokers. Alternative but much less effective
preventive agents include chromones, leukotriene receptor antagonists, and theophyllines.

Step 3: Add-on therapy

If a patient remains poorly controlled, despite regular use of ICS, a thorough review should be
undertaken of :
1. adherence,
2. inhaler technique and
3. ongoing exposure to modifiable aggravating factors.

 A further increase in the dose of ICS may benefit some patients but, in general, add-on therapy
should be considered in adults taking 800 μg/day BDP (or equivalent).

 Long-acting β2-agonists (LABAs), such as salmeterol and formoterol (duration of action of at

least 12 hours), represent the first choice of add-on therapy.
o They have consistently been demonstrated to improve asthma control and to reduce the
frequency and severity of exacerbations when compared to increasing the dose of ICS
alone.
 Fixed combination inhalers of ICS and LABAs have been developed; these are more
convenient, increase compliance and prevent patients using a LABA as monotherapy – the latter
may be accompanied by an increased risk of life-threatening attacks or asthma death.
o The onset of action of formoterol is similar to that of salbutamol such that, in carefully
selected patients, a fixed combination of budesonide and formoterol may be used as both
rescue and maintenance therapy.
 Oral leukotriene receptor antagonists (e.g. montelukast 10 mg daily ) are generally less
effective than LABA as add-on therapy, but may facilitate a reduction in the dose of ICS and
control exacerbations.
 Oral theophyllines may be considered in some patients but their unpredictable metabolism,
propensity for drug interactions and prominent side-effects limit their widespread use.

Step 4: Poor control on moderate dose of inhaled steroid and add-on therapy: addition of a fourth drug
1. In adults, the dose of ICS may be increased to 2000 μg BDP/BUD (or equivalent) daily.
2. A nasal corticosteroid preparation should be used in patients with prominent upper airway
symptoms.
3. Oral therapy with leukotriene receptor antagonists,
4. theophyllines or
5. a slow-release β2- agonist may be considered.
If the trial of add-on therapy is ineffective, it should be discontinued.
6. Oral itraconazole may be contemplated in patients with allergic bronchopulmonary aspergillosis

Step 5: Continuous or frequent use of oral steroids

 At this stage, prednisolone therapy (usually administered as a single daily dose in the morning)
should be prescribed in the lowest amount necessary to control symptoms.
 Patients on long-term corticosteroid tablets (> 3 months) or receiving more than three or four
courses per year will be at risk of systemic side-effects
 Osteoporosis can be prevented in this group by giving bisphosphonates.
 In atopic patients, omalizumab, a monoclonal antibody directed against IgE, may prove helpful in
reducing symptoms and allowing a reduction in the prednisolone dose.
 Steroid-sparing therapies, such as methotrexate, ciclosporin or oral gold, may be considered.

Step-down therapy
 Once asthma control is established, the dose of inhaled (or oral) corticosteroid should be
titrated to the lowest dose at which effective control of asthma is maintained.
 Decreasing the dose of ICS by around 25–50% every 3 months is a reasonable strategy for most
patients.

Inhalers in colors :**

Blue : short acting beta 2 agonist( relievers )SABA Ventolin, Bricanyl ,Salamol, Salar , Respigen
Orange : steroids ( preventers ) Fluxotide, Floair, Pulmicort , Beclazone , QVAR
Green : long acting beta 2 agonist (controllers) LABA Serevent, Meterol, Foradil, Oxis,
Violate : combination ( steroids + LABA) Seritide, Rexair , Symbicort, Vannair, Breo Ellipta

Exacerbations of asthma
The course of asthma may be punctuated by exacerbations with :
 increased symptoms,
 deterioration in lung function,
 and an increase in airway inflammation.
Causes :
 Exacerbations are most commonly precipitated by viral infections,
 moulds (Alternaria and Cladosporium),
 pollens (particularly following thunderstorms) and air pollution are also implicated.

Clinical picture :
 Most attacks are characterised by a gradual deterioration over several hours to days
 but some appear to occur with little or no warning: so-called brittle asthma.
Management for brittle
 Optimization of standard therapy
 Emergency supplies of medications at home, in the car and at work
 Oxygen and resuscitation equipment at home and at work
 Nebulized β2-adrenoceptor agonists at home and at work
 Self-injectable adrenaline (epinephrine): two autoinjectors of 0.3 mg adrenaline at home, at work and
to be carried by the patient at all times
 Prednisolone tablets 60 mg
 Medic Alert bracelet.
** On developing wheeze, the patient should attend the nearest hospital immediately. Direct admission to
intensive care may be required.
An important minority of patients appear to have a blunted perception of airway narrowing and fail to
appreciate the early signs of deterioration.
Management of mild to moderate exacerbations
 Doubling the dose of ICS does not prevent an impending exacerbation.
 Short courses of ‘rescue’ oral corticosteroids (prednisolone 30–60 mg daily) therefore are
often required to regain control.
 Tapering of the dose to withdraw treatment is not necessary, unless given for more than 3
weeks.

Indications for ‘rescue’ courses include:

• symptoms and PEF progressively worsening day by day, with a fall of PEF below 60% of the
patient’s personal best recording
• onset or worsening of sleep disturbance by asthma
• persistence of morning symptoms until midday
• progressively diminishing response to an inhaled bronchodilator
• symptoms sufficiently severe to require treatment with nebulised or injected bronchodilators.

Management Of Acute Severe Asthma

 Acute severe asthma Life-threatening features Near-fatal asthma

• PEF 33–50% predicted (< 200 • PEF < 33% predicted (< 100 • Raised PaCO2 and/or
L/min) L/min) requiring mechanical ventilation
• Respiratory rate ≥ 25 • SpO2 < 92% or PaO2 < 8 kPa with
breaths/min (60 mmHg) (especially if being raised inflation pressures
• Heart rate ≥ 110 beats/min treated
• Inability to complete sentences with oxygen)
in 1 breath • Normal or raised PaCO2
• Silent chest
• Cyanosis
• Feeble respiratory effort
• Bradycardia or arrhythmias
• Hypotension
• Exhaustion
• Confusion
• Coma

Measurement of PEF is mandatory, unless the patient is too ill to cooperate, and is most easily
interpreted when expressed as a percentage of the predicted normal or of the previous best value obtained
on optimal treatment .
 Arterial blood gas analysis is essential to determine the PaCO2,
o a normal or elevated level being particularly dangerous.
 A chest X-ray is not immediately necessary, unless pneumothorax is suspected.

Treatment includes the following measures:

• Oxygen. High concentrations (humidified if possible) should be administered to maintain the oxygen
saturation above 92% in adults. The presence of a high PaCO2 should not be taken as an indication to
reduce oxygen concentration, but as a warning sign of a severe or life-threatening attack.
 Failure to achieve appropriate oxygenation is an indication for assisted ventilation.
Continuous5-10mg/H can be given
• High doses of inhaled bronchodilators.
a. Short-acting β2-agonists are the agent of choice. In hospital, they are most conveniently given
via a nebuliser driven by oxygen, but delivery of multiple doses of salbutamol via a metered-
dose inhaler through a spacer device provides equivalent bronchodilatation and can be used in
primary care. Make sure no contraindication such as tachycardia
ICU perspective
Terbutalin Salbutamol Epinephrine!!!
2.5-5 mg SC 15 mcg/kg IV bolus (0.2-0.3 mg 1/1000)
250-500 mcg IV bolus.. 1-2mcg/kg/min Infusion Although it is arrythmogenic
1.5-5 mcg/min infusion

b. Ipratropium bromide provides further bronchodilator therapy and should be added to

salbutamol in acute severe or life-threatening attacks.

• Systemic corticosteroids. These reduce the inflammatory response and hasten the resolution of an
exacerbation. They should be administered to all patients with an acute severe attack. They can
usually be administered orally as prednisolone, but intravenous hydrocortisone may be used in patients
who are vomiting or unable to swallow. inhaled steroids must not be used because dose required 400mg /D of
hydrocortisone , while the inhaler dosent contain that high dose
Other medications
a. There is no evidence base for the use of intravenous fluids but many patients are dehydrated due
to high insensible water loss and will probably benefit.
b. Potassium supplements may be necessary, as repeated doses of salbutamol can lower serum
potassium.
 c. Intravenous magnesium may provide additional bronchodilatation in patients whose presenting
PEF is below 30% predicted. Given as single dose infusion over 20 minutes , no clear mechanism of
action, given only once , no data suggest repearting the dose
d. Some patients appear to benefit from the use of intravenous aminophylline but cardiac
monitoring is recommended.but you have to keep monitoring serum level because of its S/E
Procedures
 PEF should be recorded every 15–30 minutes and then every 4–6 hours.
 Pulse oximetry should ensure that SaO2 remains above 92%,
 repeat arterial blood gases are necessary if the initial PaCO2 measurements were normal or
raised, the PaO2 was below 8 kPa (60 mmHg), or the patient deteriorates.

Lists the indications for endotracheal intubation and intermittent positive pressure ventilation.
• Coma
• Respiratory arrest
• Deterioration of arterial blood gas tensions despite optimal therapy
PaO2 < 8 kPa (60 mmHg) and falling
PaCO2 > 6 kPa (45 mmHg) and rising
pH low and falling (H+ high and rising)
• Exhaustion, confusion, drowsiness
Non Invasive Mask Ventilation
Can be tried with avoidance of intubation
But it is veryriskyin cases of exhaustion, coma, ornear respiratory arrest
Intubation &Assisted MV should be instituted without delay to avoid unnecessary fatal complications

Ketamine
Sub-dissociative dose IV Ketamine(0.1 mg/kg followed by IV infusion of .5 mg/kg/hour for 3 hours)
may be helpful to facilitate use of BiPAPin a hypoxic/combative patient
If you have gotten to this step you should start setting up for intubation at this point in case the patient
continues to deteriorate.
Assisted MV lifethreatening asthma
Traditionallyknown to be associated with high mortality ;
1) Severe non responsive to R
2) Complications ( Disease & R )
3) Difficult to ventilate…complications
Asthma mechanical ventilation setting
RR 6-8 / min
Tv 6 ml/kg
Inspiratory flow rate 100/ min
I:E >1: 4
Fio2 90%
PEEP 0-3 mmhg

Dynamic Hyper-inflation
↑ Airway resistance......Air trapping ..iPEEP……. Dynamic hyperinflation… ….Baro-trauma…

Permissive Hypercapnea
Low tidal volume 6-8 ml/kg
Low ventilator rate (8–10 breaths/min)
Long expiratory time (I:E ratio >1:2)
Set inspiratory pressure 30–35 cm H2O on pressure control ventilation or limit peak inspiratory
pressure to <40 cm H2O
↓↓ Mortality from 8%-0.4%
Hypercapneacan be tolerated even to high levels as long as pH can be maintained around 7.2even by
giving Sodium bicarbonateto correct acidosis
Any attempt to increase minute ventilation(to reduce PaCO2) by ↑the ventilator respiratory rate
invariably reducesthe expiratory timeand I:E ratio, increases air trappingand can lead to
graveconsequences

Inhalational Anesthetic Agents

Halothane, isoflurane, and sevofluraneare potent Bronchodilatorsin asthmatics receiving mechanical
ventilation who have failedto respondto conventional ß adrenergic agents
Availability…
Technical problem (ventilators, scavenging)
Side effects
Heliox
Helium/Oxygen mixture 80/20 or 70/30 there are some supporting evidence that it may reducethe
workof breathingand improvegas exchangebecause of its low density that reducesairway resistanceand
hyperinflation
ECMO

Hydration
Despitethere is notrialsconducted on fluid therapy in acute severe asthma…. Yet;
Dehydration….sticky secretion..
Rehydration& correction of electrolyte abnormalities (hypokalemia) is recommended
Radiology
Notroutinely indicated
Suspected Infection….
Suspected Pneumothorax…..
Failureto respond… & Requiring MV…..
Antibiotics
Routine prescription is NOTindicated

Prognosis
The outcome from acute severe asthma is generally good. Death is
fortunately rare but a considerable number of deaths occur in young
people and many are preventable.
 Most patients who died of asthma had chronically Severe
Asthma
 Most Deaths occurred before arrival / or hospital admission

Failure to recognise the severity of an attack, on the part of either the
assessing physician or the patient, contributes to delay in delivering
appropriate therapy and to under-treatment.

Prior to discharge, patients should be stable on discharge medication :

 (nebulised therapy should have been discontinued for at least 24 hours)
 PEF should have reached 75% of predicted or personal best.
 The acute attack should prompt a look for and avoidance of any trigger factors, the delivery of
asthma education and the provision of a written self-management plan.
 The patient should be offered an appointment with a GP or asthma nurse within 2 working days
of discharge,
 follow-up at a specialist hospital clinic within a month