Asthma

Syndrome characterized by airflow obstruction that varies markedly,

both spontaneously and with treatment
Excessive airway narrowing, with consequent reduced airflow and
symptomatic wheezing and dyspnea
10-12% adults, 15% of children affected by the disease
rising prevalence in developing countries, where there is increase in
urbanization
most patients in affluent countries are atopic, with allergic sensitization
to the house dust mite Dermatophagoides pteronyssinus and other
environmental allergens
can present at any age, with a peak age at 3 years
sex ratio equalizes by adulthood
the commonly held belief that children grow out of their asthma is
justified to some extent
adults with asthma, particularly those that with onset during adulthood,
rarely become permanently asymptomatic
those with mild asthma rarely progress to severe disease, whereas
those with severe asthma usually have severe disease at onset
deaths from asthma are uncommon, and have been steadily declining
in affluent countries
now compelling evidence that the more widespread use of inhaled
corticosteroids in patients with persistent asthma is responsible for the
decrease in mortality in recent years
major risk factors for asthma deaths: poorly controlled disease with
frequent use of bronchodilator inhalers, lack of corticosteroid therapy,
and previous admissions of near fatal asthma

Etiology
heterogeneous disease with interplay between genetic and
environmental factors
several risk factors have been implicated

Atopy
allergic rhinitis, may be found in 80%
eczema
atopy may be found in 40-50% of the population in affluent countries,
with only a proportion of atopic individuals becoming asthmatic
therefore suggestion that some other environmental or genetic factors
predispose to the development of asthma in atopic individuals
usually proteins with protease activity
ie house dust mites, cat and dog fur, cockroaches (in inner city), grass
and tree pollens, and rodents (in laboratory workers)
atopy is due to the genetically determined production of specific IgE
antibody, with many patients showing a family history of allergic
diseases
Intrinsic asthma
minority of asthmatic patients, ~ 10%, show nonatopic or intrinsic
asthma
negative skin tests to common inhalant allergens and normal serum
concentrations of IgE
later onset of disease, typically adulthood
nasal polyps, and may be aspirin sensitive
usually have more severe, persistent asthma
immunopathology in bronchial biopsies and sputum appears to be
identical to that found in atopic asthma
? due to increased common IgE mediated mechanisms
staphylococcal enterotoxins have been implicated

Infections
? role of RSV in pathogenesis of asthma
Mycoplasma and chlamydia

Genetic considerations
Familial association and high concordance between identical twins
Increasing evidence that the severity of asthma is also genetic
Polygenic
Chromosome 5q
T helper 2 (TH2) cells: IL-4, IL-5, IL-9, IL-13; which are associated with
atopy
Largely unknown

Environmental factors
It is likely that environmental factors in early life determine which atopic
individuals become asthmatic

Hygeine hypothesis
Proposes that lack of infections in early childhood preserves the TH2
cell bias at birth, whereas exposure to infections and endotoxins results
in a shift toward a predominant protective TH1 immune response
Intestinal parasite infections may be associated with a reduced risk of
asthma
While there is considerable epidemiologic support for the hygiene
hypothesis, it cannot account for the parallel increase in TH1 driven
diseases such as DM over the same period

Diet
Controversial
Obesity is an independent risk factor for asthma

Allergens
Exposure to house dust mites in early childhood is a risk factor for
allergic sensitization and asthma, but rigorous allergen avoidance has
not shown any evidence for a reduced risk of developing asthma
Occupational asthma
Relatively common and may affect up to 10% of young adults
May lead to sensitisation independent of atopy
Should be suspected when symptoms improve during weekends or
holidays

Risk Factors and Triggers Involved in Asthma

Endogenous Factors Environmental Factors
Genetic predisposition Indoor allergens
Atopy Outdoor allergens
Airway hyperresponsiveness Occupational sensitizers
Gender Passive smoking
Ethnicity? Respiratory infections
Obesity?
Early viral infections?
Triggers
Allergens
Upper respiratory tract viral infections
Exercise and hyperventilation
Cold air
Sulfur dioxide and irritant gases
Drugs (-blockers, aspirin)
Stress
Irritants (household sprays, paint fumes)

Pathogenesis
Specific chronic inflammation of the mucosa of the lower airways
One of the main aims of treatment is to reduce this inflammation
 Chemokines in asthma.

Tumor necrosis factor (TNF-) and other triggers of airway epithelial cells release
thymus and activationregulated chemokine (TARC, CCL17) and macrophage-
derived chemokine (MDC, CCL22) from epithelial cells that attract TH2 cells via
activation of their CCR4 receptors. These promote eosinophilic inflammation
directly through the release of interleukin (IL)-5 and indirectly via the release of IL-4
and IL-13, which induce eotaxin (CCL11) formation in airway epithelial cells.
Pathology

Airway mucosa is infiltrated with activated eosinophils and T

lymphocytes, and there is activation of mucosal mast cells
The degree of inflammation is poorly related to disease severity and
may be found in atopic patients without asthma symptoms
The inflammation is reduced by treatment with ICS
Characteristic findings is thickening of the basement membrane due to
subepithelial collagen deposition
This is also a feature of eosinophilic bronchitis -> likely to be due to
eosinophil inflammation as they release fibrogenic factors
Airway wall may be thickened and oedematous, particularly in fatal
asthma
Another common finding in fatal asthma is occlusion of the airway
lumen by a mucous plug, which is comprised of mucous glycoproteins
secreted from goblet cells and plasma proteins from leaky bronchial
vessels
There is also vasodilation and increased numbers of blood vessels
(angiogenesis)
Direct observation by bronchoscopy indicates that the airways may be
narrowed, erythematous and oedematous
The pathology of asthma is remarkably uniform in different types of
asthma

Inflammation
Inflammation in the respiratory mucosa from the trachea to the terminal
bronchioles, but with a predominance in the bronchi
There is good evidence that the specific pattern of airway inflammation
in asthma is associated with airway hyper-responsiveness, the
physiologic abnormality of asthma, which is correlated with variable
airflow obstruction
There is evidence of chronic inflammation persisting over many years
in most patients
Superimposed on this is active inflammatory episodes, which
correspond to exacerbations of asthma
Many inflammatory cells are known to be involved in asthma with no
key cell that is predominant

Mast cells
Important in initiating the acute bronchoconstrictor responses to
allergens and several other indirectly acting stimuli such as exercise
and hyperventilation
Found at the airway surface and airway smooth muscle (but not found
in normal patients or patients with eosinophilic bronchitis)
Activated by allergens through an IgE dependent mechanism, and
binding of specific IgE to mast cells renders them more sensitive to
activation
 Importance of IgE has been highlighted with the advent of humanized
anti-IgE antibodies; which inhibit IgE mediated effects, reduce asthma
symptoms, and reduce exacerbations
Mast cells release several bronchoconstrictor mediations histamine,
prostaglandin D2, and cysteinyl-leukotrienes

Macrophages and dendritic cells

Dendritic cells are specialized macrophage-like cells in the airway
epithelium, which are the major antigen presenting cells.
Dendritic cells take up allergens, process them to peptides, and
migrate to local LNs where they present the allergenic peptides to
uncommitted T cells to program the production of allergen-specific T
cells
Immature dendritic cells in the respiratory tract promote TH2 cell
differentiation and require cytokines such as IL-12 and TNF-alpha to
promote the normally preponderant TH1 response
The cytokine thymic stromal lymphoprotein (TSLP) released from
epithelial cells in asthmatic patients instructs dendritic cells to release
chemokines that attract TH2 cells into the airways

Eosinophils
Eosinophil infiltration is a characteristic feature of asthmatic airways
Blocking antibodies to IL-5 causes a profound and prolonged reduction
in circulating and sputum eosinophils, but is not associated with
reduced AHR or asthma symptoms, although in selected patients with
steroid-resistant airway eosinophils, there is a reduction in
exacerbations
Eosinophilic inflammation is also seen in patients with chronic cough
(eosinophilic bronchitis) who do not have AHR or clinical features of
asthma

Neutrophils

T Lymphocytes
Very important role in coordinating the inflammatory response in
asthma through the release of specific patterns of cytokines, resulting
in the recruitment and survival of eosinophils and in the maintenance of
a mast cell population in the airways
The nave immune system and the immune system of asthmatics are
skewed to express the TH2 phenotype, whereas in normal airways
TH1 cells predominate
TH2 cells, through the release of IL-5, are associated with eosinophilic
inflammation and, through the release of IL-4 and IL-13, are associated
with increased IgE formation
Recently, bronchial biopsies have demonstrated a preponderance of
natural killer CD4+ T lymphocytes that express high levels of IL-4
Regulatory T cells play an important role in determining the expression
of other T cells, and there is evidence for a reduction in a certain
 subset of regulatory T cells (CD4+, CD25+) in asthma that is
associated with increased TH2 cells

Structural cells
Epithelial cells, fibroblasts, and airway SM cells
Important sources of inflammatory mediators such as cytokines and
lipid mediators
Structural cells far outnumber inflammatory cells, they become major
sources of mediators driving chronic inflammation in asthmatic airways
May also have key roles in translating inhaled environmental signals
into an airway inflammatory response, and are probably major target
cells for ICS

Inflammatory mediators
Mediators such as histamines, prostaglandin D2, and cysteinyl-
leukotrienes contract airway SM, increase microvascular leakage,
increase airway mucus secretion, and attract other inflammatory cells
Recent clinical studies with anti-leukotrienes suggest that cysteinyl-
leukotrienes have clinically important effects

Cytokines
The TH2 cytokines IL-4, IL-5, IL-13 mediate allergic inflammation,
whereas pro-inflammatory cytokines such as TNF-alpha and IL-1beta,
amplify the inflammatory response and play a role in more severe
disease
Thymic stromal lymphopoietin is an upstream cytokine released from
epithelial cells of asthmatics that orchestrates the release of
chemokines that selectively attract TH2 cells
Some cytokines such as IL-10 and IL12 are anti-inflammatory and may
be deficient in asthma

Chemokines
Involved in attracting inflammatory cells from the bronchial circulation
into the airways
Eotaxin (CCL11) is selectively attractant to eosinophils via CCR3 and
is expressed by epithelial cells of asthmatics, whereas CCL17 (TARC)
and CCL22 (MDC) from epithelial cells attract TH2 cells via CCR4

Oxidative stress
Evidence of increased oxidative stress in asthmatics; as macrophages
and eosinophils produce reactive oxygen species
Increased oxidative stress is related to disease severity, may amplify
the inflammatory response, and may reduce responsiveness to
corticosteroids.

Nitric oxide
Higher than normal in exhaled breath in asthmatics
 Related to the eosinophilic inflammation
Increased NO may contribute to the bronchial vasodilation observed in
asthma
Exhaled NO is increasingly used in the diagnosis and monitoring of
asthmatic inflammation, although it is not yet used routinely in clinical
practice

Effects of inflammation
Asthma may be regarded as a disease with continuous inflammation
and repair proceeding simultaneously

Airway epithelium
Epithelial shedding may contribute to AHR

Fibrosis
Basement membrane is apparently thickened due to subepithelial
fibrosis, with deposition of types III and V collagen below the true
basement membrane and is associated with eosinophilic infiltration,
presumably through the release of profibrotic mediators such as
transforming growth factor-in beta
In more severe patients, there is also fibrosis within the airway wall,
which may contribute to irreversible narrowing of the airways

Airway smooth muscle

In asthmatic airways there is a characteristic hypertrophy and
hyperplasia of airway SM, which is presumably the result of stimulation
of airway SM cells by various growth factors such as platelet-derived
growth factor (PDGF) or endothelin-1 released from inflammatory or
epithelial cells

Vascular responses
Increased airway mucosal blood flow in asthma
There is an increase in the number of blood vessels in asthmatic
airways as a result of angiogenesis in response to growth factors,
particularly vascular-endothelial growth factor
Microvascular leakage from post-capillary venules in response to
inflammatory mediators is observed in asthma, resulting in airway
oedema and plasma exudation into the airway lumen

Mucus hypersecretion
Increased mucus secretion contributes to the viscid mucous plugs that
occlude asthmatic airways, particularly in fatal asthma
There is evidence for hyperplasia of submucosal glands that are
confined to large airways and of increased numbers of epithelial goblet
cells

Airway remodeling
 Irreversible narrowing of the airways
Some evidence that the early use of ICS may reduce the decline in
lung function
Characteristic structural changes are increased airway SM, fibrosis,
angiogenesis, and mucus hyperplasia

Asthma triggers

Allergens
Inhaled allergens activate mast cells with bound IgE directly leading to
the immediate release of bronchoconstrictor mediators, resulting in the
early response that is reversed by bronchodilators
Dermatophagoides species
Environmental exposure leads to low-grade chronic symptoms that are
perennial
Pollens usually cause allergic rhinitis rather than asthma, but in
thunderstorms the pollen grains are disrupted and the particles that
may be released can trigger severe asthma exacerbations
(thunderstorm asthma)

Virus infections
URTI
Increase in airway inflammation, with increased numbers of eosinophils
and neutrophils
Evidence for reduced production of type I interferons by epithelial cells
from asthmatic patients, resulting in increased susceptibility to these
viral infections and a greater inflammatory response

Pharmacological agents
Several drugs may trigger asthma
Beta blockers their use may be fatal
Likely mediated through increased cholinergic bronchoconstriction
ACEi theoretical as they inhibit breakdown of kinins, which are
bronchoconstrictors, however, they rarely worsen asthma
Aspirin may worsen asthma in some cases

Exercise
Common trigger, particularly in children
Mechanism is linked to hyperventilation, which results in increased
osmolality in airway lining fluid and triggers mast cell mediator release,
resulting in bronchoconstriction
Typically begins after exercise has ended, and recovers spontaneously
within about 30 minutes
Worse in cold, dry climates than in hot, humid conditions
More common in sports such as cross-country running in cold weather,
overland skiing, and ice hockey than in swimming
 May be prevented by prior beta agonists and antileukotrienes, but is
best prevented by regular treatment with ICS, which reduce the
population of surface mast cells required for this response

Cold air
Hyperventilation

Food
Little evidence
However certain food additives may trigger asthma

Occupational factors
Characteristically associated with symptoms at work with relief on
weekends and holidays
If removed from exposure within the first 6 months of symptoms, there
is usually complete recovery
More persistent symptoms lead to irreversible airway changes, and
thus, early detection and avoidance are important

Stress
Psychological factors induce bronchoconstriction through cholinergic
reflex pathways

Pathophysiology

Limitation of airflow is due mainly to bronchoconstriction, but airway

oedema, vascular congestion, and luminal occlusion with exudate may
also contribute
Reduced FEV1/FVC, and peak expiratory flow, as well as an increase
in airway resistance
Early closure of peripheral airway results in lung hyperinflation, air
trapping and increased residual volume, particularly during acute
exacerbations and in severe persistent asthma
In more severe asthma, reduced ventilation and increased pulmonary
blood flow result in mismatching of ventilation and perfusion and in
bronchial hyperaemia
Ventilatory failure is very uncommon, even in patients with severe
asthma, and arterial PaCO2 tends to be low due to increased
ventilation

Airway hyper-responsiveness
Characteristic physiologic abnormality of asthma and describes the
excessive bronchoconstrictor response to multiple inhaled triggers that
would have no effect on normal airways
Increase in AHR is linked to the frequency of asthma symptoms, and
thus, an important aim of therapy is to reduce AHR
Increased bronchoconstrictor responsiveness is seen with DIRECT
bronchoconstrictors such as histamine and methacholine, which
contract airway SM, but is characteristically also seen with many
 INDIRECT stimuli, which release bronchoconstrictors from mast cells
or activate sensory nerves
Most of the triggers for asthma symptoms appear to act indirectly,
including allergens, exercise, hyperventilation, fog, irritant dusts, and
sulfur dioxide (via a cholinergic reflex)

Clinical features and diagnosis

Wheezing
Dyspnea
Cough
May be worse at night and typically awake in the early morning hours
May report difficulty with filling their lungs with air
Increased mucus production, with typically tenacious mucus that is
difficult to expectorate
Increased ventilation and use of accessory muscles
Ex: inspiratory and expiratory rhonchi, hyperinflation
Dry cough

Diagnosis
Symptoms of variable and intermittent airways obstruction, but is
usually confirmed by objective measurement of lung function

Lung function tests

Reduced FEV1, FEV1/FVC ratio, and PEF
Reversibility is demonstrated with a > 12% and 200mL increase in
FEV1 15 minutes after an inhaled short acting beta agonist or in some
patients by a 2 to 4 week trial of oral corticosteroids
Measurement of PEF twice daily may confirm the diurnal variations in
airflow obstruction
Flow-volume loops show reduced peak flow and reduced maximum
expiratory flow
Whole body plethysomography shows increased airway resistance and
may show increased TLC and RV
Gas transfer is usually normal, but may show a small increase in some
patients

Airway hyperresponsiveness
Histamine or methacholine challenge test
Calculation of the provocation that reduces FEV1 by 20%
Rarely useful
Can be used when the diagnosis is in doubt in the setting of normal
pulmonary function tests
Occasionally exercise testing is done to demonstrate post exercise
bronchoconstriction is there is a predominant history of EIA
Allergen challenge for specific occupational exposures
Skin tests
Positive tests may be useful in persuading patients to avoid certain
allergens!
 Eosinophilic pneumonias and systemic vasculitis, including Churg-
Strauss syndrome and polyarteritis nodosa, may be associated with
wheezing
COPD is usually easy to differentiate from asthma as symptoms show
less variability, never completely remit, and show much less (or no)
reversibility to bronchodilators
Approximately 10% of COPD patients have features of asthma, with
increased sputum eosinophils and a response to OCS, these patients
probably have both diseases concomitantly.

Treatment
preventors and relievers

Aims of asthma therapy

minimal chronic symptoms, including nocturnal
minimal exacerbations
no emergency visits
minimal use of required beta 2 agonist
no limitations on activities, including exercise
PEF < 20%
Normal PEF
Minimal or no adverse effects from medicine

Bronchodilator therapies
act on airway SM to reverse the bronchoconstriction of asthma
rapid relief of symptoms but has little or no effect on the underlying
inflammatory process
not sufficient to control asthma in patients with persistent symptoms
beta 2 agonists, anticholinergics, and theophylline

B2 agonists
by far the most effective
activate beta2 adrenergic receptors, widely expressed in the airways
b2 adrenergic receptors are coupled through a stimulatory G protein to
adenylyl cyclase, resulting in increased intracellular cyclic adenosine
monophosphate (AMP), which relaxes SM cells and inhibits certain
inflammatory cells, particularly mast cells
primary action is to relax airway SM cells of all airways
also non-bronchodilator effects: inhibition of mast cell mediator release,
reduction in plasma exudation, and inhibition of sensory nerve
activation
inflammatory cells express small numbers of B2 receptors, but these
are rapidly down-regulated with B2 agonist activation so that, in
contrast to corticosteroids, there are no effects on inflammatory cells in
the airways and there is no reduction in AHR
SABA = duration of action 3-6 hours
Used as needed for symptom relief
Increased use of SABA indicates that the asthma is not controlled
 Useful in preventing EIA if taken prior to exercise
LABA; duration of action > 12 hours
Given twice daily by inhalation
Improve asthma control and reduce exacerbations when added to ICS,
which allows asthma to be controlled at lower doses of corticosteroids

Side effects
Muscle tremor and palpitations
Small fall in plasma K because of increased uptake by skeletal muscle
cells

Increase use of rescue SABA reflects poor asthma control, which is a risk
factor for asthma death

Anticholinergics
Muscarinic receptor antagonists
Prevent cholinergic nerve induced bronchoconstriction and mucus
secretion
Much less effective than beta agonists as they limit only the cholinergic
reflex component, whereas beta agonists limit all mechanisms of
bronchoconstriction
Used as an additional bronchodilator in patients with asthma that is not
controlled by other inhaled medications
Can be used in severe acute asthma, but should be used after beta
agonists as they have a slower onset of bronchodilation
Common side effect is dry mouth, in elderly patients, urinary retention
and glaucoma may also be observed

Theophylline
Bronchodilator effect due to inhibition of phosphodiesterases in airway
SM cells, which increases cAMP, but doses required for
bronchodilation commonly cause side effects that are mediated by
PDE inhibition
Increasing evidence that at lower doses it has anti-inflammatory
effects, and these are likely mediated through different molecular
mechanisms
Evidence that theophylline activates the key nuclear enzyme histone
deacetylase-2, which is a critical mechanism for switching off activated
inflammatory genes

Clinical use
Additional bronchodilator in patients with severe asthma
Lower doses have additive effects to ICS, and are particularly useful in
patients with severe asthma
Withdrawal of theophylline in these patients may result in marked
deterioration in asthma control
At low doses, the drug is well tolerated
Aminophylline is occasionally used in patients with severe
exacerbations that are refractory to SABAs
Side effects
Dose related
Nausea, vomiting, headaches due to PDEi
Diuresis and palpitations
High [ ] -> cardiac arrhythmias, epileptic seizures, and death may occur
due to adenosine A1 receptor antagonism
Rarely observed at concentrations < 10mg/L
Theophylline is metabolized by CYP450 in the lever, and thus plasma [
] may be elevated by drugs that block CYP450 such as erythromycin
and allopurinol
Other drugs may also reduce clearance by other mechanisms leading
to increased plasma concentrations

Preventors

ICS
Most effective anti-inflammatory agents used in asthma therapy,
reducing inflammatory cell numbers and their activation in the airways
ICS reduce eosinophils in the airways and the sputum, and numbers of
activated T lymphocytes and surface mast cells in the airway mucosa
Reduction in AHR that is seen with chronic ICS therapy
Major effect of corticosteroids is to switch off the transcription of
multiple activated genes that encode inflammatory proteins such as
cytokines, chemokines, adhesion molecules, and inflammatory
enzymes
Inhibition of the transcription factors NF-kappaB and activator protein 1,
recruitment of histone deacetylase-2 to the inflammatory gene
complex, which reverses the histone acetylation associated with
increased gene transcription
Also activate anti-inflammatory genes such as mitogen-activated
protein kinase phosphatase 1, and increase the expression of B2
receptors

Clinical use
Rapidly improves symptoms of asthma and lung function
Effective in preventing asthma symptoms, such as EIA or nocturnal
exacerbations, but also prevent severe exacerbations
Reduce AHR
Maximal improvement may take several months
Early treatment appears to prevent irreversible changes in airway
function that occur with chronic asthma
Withdrawal is association with slow deterioration of asthma control,
indicating it does not cure the underlying condition

Side effects
Local hoarsness, dysphonia
Minimal systemic side effects
 No convincing evidence that long-term treatment leads to impaired
growth in children or to OP in adults

Systemic corticosteroids
Can be given IV or oral in acute severe asthma attack (same efficacy)
30-45mg once daily for 5-10 days
no tapering required
1% may required maintenance therapy with OCS
lowest dose necessary
truncal obesity, bruising, OP, DM, HTN, gastric ulceration, proximal
myopathy, depression and cataracts, may be a major problem, and
steroid-sparing therapies may be considered if S/Es are a major
problem

Anti-leukotrienes

cysteinyl-leukotrienes are potent bronchoconstrictors, cause

microvascular leakage, and increase eosinophilic inflammation through
the activation of cys-LT1 receptors
these inflammatory mediators are produced predominantly by mast
cells and, to a lesser extent, eosinophils in asthma
montelukast and zafirlukast, block cysLT1 receptors and provide
modest clinical benefit in asthma
less effective than ICS in controlling asthma and have less effect on
airway inflammation, but are useful as an add-on therapy in some
patients not controlled with low doses of ICS, although they are less
effective than LABA
given orally once or twice daily and are well tolerated

Anti IgE
omalizumab is a blocking antibody that neutralizes circulating IgE
without binding to cell-bound IgE and thus, inhibits IgE mediated
reactions
shown to reduce the number of exacerbations in patients with severe
asthma and may improve asthma control
very expensive
only suitable for highly selected patients who are not controlled on
maximal disease of inhaler therapy and have circulating IgE within a
specified range
patients should be given a 3-4 month trial of therapy to show objective
benefit
usually given as a SC injection every 2-4 weeks

Management of chronic asthma

spirometry or PEF to establish a diagnosis
triggers that worsen asthma control should be avoided
those that result in transient symptoms indicate increase in controller
therapy
Stepwise therapy

SABA

If used > 3 times/week

ICS low dose

If not controlled
+
LABA (anti-leukotrienes or theophylline, however not as effective)

If not controlled
Upgrade to high dose ICS +LABA

If still not controlled

High dose ICS + LABA (+ theophylline, anticholinergic as add on therapy)
+
OCS (+ omalizumab)

Education
Written action plans have been shown to reduce hospital admissions and
morbidity rates in adults and children; recc for unstable disease who have
frequent exacerbations

Acute severe asthma

may be so breathless that they are unable to complete sentences or
are cyanosed
examination usually shows increased ventilation, hyperinflation, and
tachycardia
pulsus paradoxus
marked fall in PEF, spirometric values
ABG -> hypoxaemia, PaCO2 usually low
Normal or rising PaCO2 is an indication of impending respiratory failure
and requires immediate monitoring and therapy

Treatment
O2
High doses of SABAs
IV beta agonists if severely unwell
Inhaled anticholinergics
Slow infusion of aminophylline
MgSO4
May require intubation
Refractory asthma
Small proportion of asthmatics ~ 5% are difficult to control despite
maximal inhaled therapy
 Some of these patients will require maintenance OCS
Two types persistent symptoms and poor lung function, despite
appropriate Rx, whereas others may have normal or near normal lung
function but intermittent, severe (sometimes life threatening)
exacerbations

Mechanisms
Most common reason is non-compliance
Exposure to high, ambient levels or allergen or unidentified
occupational agents
Treatment of reflux does not usually improve asthma symptoms
Hyper and hypothyroidism

DDx
Vocal cord dysfunction -> attention seeking hysterical conversion
syndrome
May be identified by discrepancy in FEV1 and PEF, and relatively
normal airway resistance
Direction inspection by laryngoscopy may confirm vocal cord adduction

Corticosteroid resistant asthma

< 1/1000

Brittle asthma
type 2 -> normal or near normal lung function but precipitious,
predictable falls in lung function that may result in death
most effective therapy is SC epinephrine
? worsening is likely to be a localized airway anaphylactic reaction with
oedema
may be allergy to certain foods

Refractory asthma
check compliance and use of inhalers
low dose OCS
omalizumab
anti TNF therapy is not effective

Aspirin sensitive asthma

well defined subtype, usually preceeded by perennial rhinitis and nasal
polyps in non-atopic patients with a late onset of the disease
even in low doses, aspirin characteristically provokes rhinorrhea,
conjunctival irritation, facial flushing, and wheezing
all non selective COX inhibitors should be avoided
COX 2 inhibitors are sage to use
Responds to usual therapy with ICS
Aspirin desensitization may be effective
Asthma in the elderly
May start at any age!
COPD is more likely and may co-exist with asthma
 Trial of OCS

Pregnancy
1/3 improve, 1/3 deterioate, and 1/3 remain unchanged
bronchodilators are safe
better to use cortisone that prednisolone if OCS are required as cannot
be converted to active prednisolone in the fetal liver

Cigarette smoking
approx. 20% of asthmatics smoke
more severe disease, more frequent hospital admissions, a faster
decline in lung function, and a higher risk of death from asthma
interferes with the anti- inflammatory effects of corticosteroids,
necessitating higher doses
vigourous smoking cessation strategies should be used

Surgery
patients with FEV1 < 80% of their best should be given a boost of OCS
prior to surgery

Bronchopulmonary aspergillosis
uncommon and results from an allergic pulmonary reaction to inhaled
spores of aspergillus fumigates
skin prick test is always positive
fleeting eosinophilic infiltrates in the lungs, particularly in the upper
lobes
airways become blocked with mucoid plugs rich in eosinophils, and
patients may cough up brown plugs and have haemoptysis
may result in bronchiectasis, particularly affecting the central airways
treatment with oral antifungal itraconazole is beneficial
treat asthma the same way
OCS if any sign of worsening or pulmonary shadowing is found