Week 2 Flashcards
Atopy is currently defined as?
Predisposition to produce IgE antibodies in response to the ordinary exposure to allergens in the environment
Who coined the term “allergy” to describe the phenomenon he had observed in which some patients, under certain conditions, developed an increased reactivity instead of immunity?
Austrian paediatrician, Clemens von Pirquet
Who proposed the term ‘atopy’ for the clinical manifestations of allergy such as hayfever and asthma in which ‘the individuals possess a peculiar capacity to become sensitive to certain proteins to which their environment and habits of life frequently expose them”.
In 1923, Coca and Cooke
Explain what is “reagin” when Prausnitz showed this in 1921
Prausnitz showed that atopic allergic sensitivity can be passively transferred from one individual to another by a serum factor
In 1967, what was the reagin known/named as?
Immunoglobulin E
Classically, allergic reactions are divided into four main types:
Gell and Coombs Types 1-4
Immediate or early reaction is defined when symptoms occur?
Occur within minutes of an immune reaction
Late reaction is when symptoms?
Start after hours
Delayed reaction is when symptoms are?
After days
Type 1 immediate reaction is caused by?
IgE and possibly IgG
Antigens which cause Type 1 reactions are called?
allergens
When the allergen reacts with IgE attached to the surface of the mast cell, what happens?
Mast cell degranulates and releases chemical mediators (histamine, SRS-A, ECF, PAF) responsible for the symptoms
Type 1 reactions depend on the presence of?
Specific IgE on high affinity receptors on mast cells.
There are also IgE receptors of both low and high affinity on other cell types, including?
Eosinophils and macrophages
Activated B cells (plasma cells) produce?
IgE
Activated B cells producing IgE which depends on exposure to the allergen and costimulation signalling via?
Activated T cells, which direct the B cell to the production of IgE
IgE synthesis results from?
Collaboration between a subset of T helper (Th) cells which produce IL-4, but not IFN-gamma (Th2 cells).
Th2 cells because of their ability to produce?
IL-5 and IL-4
IL-5 and IL-4 are responsible for the _____ which are often associated with?
Eosinophils; hyperproduction of IgE in allergic subjects
T-helper cells which do not produce IL-4 or which produce high concentrations of IFN-gamma do not support?
Do not support IgE synthesis
IFN-gamma can suppress?
Can suppress IL-4 dependent IgE synthesis
Regulatory T cells such as ___, ___ and ____ may also play a role in determining whether the response to ubiquitous environmental allergens is that of tolerance or of sensitisation and clinical allergy.
nTreg, Th3, and Tr1
Dysregulation of regulatory T cells (nTreg, Th3 and Tr1) is now thought to play a significant role in?
Development of the atopy
Promotion of a prevalent Th2 type response to environmental allergens (such as __, ____, ____, ____ etc) in atopic subjects almost certainly involves a genetic predisposition as well as environmental influences.
Foods, HDM, animal dander, pollen
What are wheezes?
Wheezes are continuous sounds generated from within the lungs during breathing
Wheezing sounds are superimposed on?
On normal breath sounds
Wheezes are sounds superimposed on normal breath sounds and are often referred to as?
Adventitial sounds
Wheezes may be characterised by their?
Pitch, intensity, location, duration in the respiratory cycle (short or long) and relationship to the phase of respiration in which they are heard (inspiratory or expiratory)
‘Continuous’ in the context of wheezes is in relationship to the phase of?
Breathing cycle, in which the sound occurs, i.e. the sound is continuous over 0.25 to 1.5 seconds of breathing
Crackles are?
They are a series of discontinuous ‘popping’ sounds
Analysing wheezing sounds using signal processing and analysis techniques has shown the dominant frequency of wheezing to be approximately?
400 Hz
Structure of the normal bronchial tree consists of a series of branches or generations from ?
- Trachea (generation 0)
- Through the left and right main bronchi (generation 1)
- Lobar bronchi
- Terminal bronchioles
- Respiratory bronchioles
- Alveolar ducts
- Alveolar sacs (with an average of 20 to 23 divisions or generations along the way)
While the calibre of each individual airway decreases with each division, total cross sectional area of the airways?
Increases with each generation
Linear velocity of airflow in very peripheral airways is?
Very low - far too low to produce an audible sound at this level, even with considerable airway narrowing.
Wheezing is produced by diseases or disease processes which?
Which directly or indirectly reduce the calibre or cross-sectional area of the trachea or major bronchi
While localised obstruction of the large airways can occur, dynamic narrowing of the trachea or major bronchi may also come about during expiration because of?
Widespread obstruction of the medium and smaller airways
The physiological explanation for narrowing of trachea/bronchi is referred to as?
Equal pressure point theory
Key elements involved in equal pressure point theory include:
Pleural pressure or pressure outside the airways (Ppl) which is usually negative during relaxed expiration, tending to keep the lungs inflated, and the elastic recoil pressure of the lung tissue (Pst[L]) which tends to empty the lungs.
Tissue forces driving relaxed expiration are the sum of?
Two values: pleural pressure (usually negative during relaxed expiration, keeps lungs inflated) & elastic recoil pressure of the lung tissue (tends to empty the lungs).
If airflow resistance increases, driving forces of relaxed expiration may be insufficient to produce airflow and must be an active process. So what happens?
Pleural pressure becomes positive during expiration and the pressure within the alveoli increases.
Pressure within the alveoli progressively falls along the airways to reach a pressure of zero at?
At the mouth, referred to as ‘downstream’ pressure
Downstream from the point where the pleural pressure exceeds the intraluminal pressure, what occurs?
Dynamic compression of the airways can occur
How is the wheeze is produced?
Because of the dynamic narrowing of these larger airways
High-pitched sounds of wheezing are produced when?
when the airway lumen is narrowed to the point where the opposite walls are almost in contact
Mechanisms underlying the production of a wheezing sound with breathing seem to involve an interaction between?
Airway wall and gas moving through the airway
Acceleration of gas flow through the narrowed airway induces?
Induces an oscillation of the airway walls.
Pitch of the wheeze depends upon?
Depends upon the mass and elasticity of the airway walls and on the flow velocity of the gas within the airway.
Pitch of the wheeze is not influenced by?
Influenced by the length or size of the airway
Inspiratory wheezes are explained by?
Actually, no theory has yet to be proposed.
During inspiration, airways are held open by?
Elastic tissues of the lung
In some circumstances, when airways are not sufficient to enlarge an airway, what happens?
Flow limitation with airway wall fluttering occurs
Inspiratory wheezes are often associated with?
With more severe airways obstruction or upper airways obstruction
Continuous musical respiratory sound heard in patients with upper airway obstruction is called?
Stridor
In contrast to intrapulmonary airways, upper airways tend to collapse during?
During inspiration (due to negative intra-airway pressure), and airway narrowing or closure at these sites is more prominent
Sound frequency of stridor is like that of?
wheezes
Stridor are heard during?
During inspiration, and being more prominent over the neck than the chest.
Commonest cause of stridor is?
Laryngeal obstruction or muscle weakness
Snoring is a sound generated mostly during?
Inspiration
Snoring is the result of?
Flow limitation, usually at the oropharynx, in which the soft palate flutters
List some pathophysiological processes that would lead to narrowing airway calibre
- Bronchospasm
- Intraluminal tumours or secretions
- Foreign bodies
- Mucosal oedema
- External compression of an airway by a tumour mass
- Dynamic airway compression
Healthy individuals can also produce wheeze during?
During a forced expiratory manoeuvre
Presence of a wheeze is a clinical sign found in patients with COPD, particularly during?
Acute episodes of asthma
Is there a relationship between the intensity or the pitch of wheezes and the pulmonary function?
None
Which respiratory organism causes acute episodes of asthma in school aged children?
Mycoplasma pneumoniae
Which respiratory organism causes acute episodes of asthma in infancy?
Chlamydia trachomatis
Which respiratory organism causes wheezing and acute episodes of asthma?
Chlamydia pneumoniae
Bacteria does not cause wheezing
True
Antibiotics should not routinely be prescribed for acute asthma.
True
Principal viruses responsible for precipitating exacerbations of asthma are?
rhinoviruses and respiratory syncytial virus (RSV)
Other viruses less commonly implicated in exacerbating asthma are?
- Parainfluenza viruses
- Coronaviruses
- Enteroviruses
- Adenoviruses
Inoculation of respiratory specimens from children with exacerbations of asthma into tissue culture yields a virus in around?
20-40% of cases
Polymerase chain reaction (PCR) to detect rhinovirus and coronavirus sequences improves viral yield to?
80-85% of exacerbations
In school age children, which is the commonest viral precipitant of asthma attacks?
Rhinoviruses
Acute viral infection of the airways stimulates production of?
Cytokines
In non-atopic individuals, the typical cytokine profile produced in response to viruses by helper T cells called Th1 is?
- Interferon gamma (IFNgamma)
- Interleukin-2 (IL-2)
In contrast, atopic individuals tend to mount a Th2 helper cell response with production of IL-4 and IL-5, but not?
IL-2 or IFN-gamma
Asthmatic individuals also tend to develop eosinophilic infiltration of the airways secondary to?
Granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine induced by virus infection
Rhinoviruses use ____, an intercellular adhesion molecule
ICAM-1
ICAM-1 is used by rhinoviruses for?
Cell receptor for attachment and entry epithelial cells, which may lead to the release of inflammatory cytokines.
Rhinoviruses stimulate marked production of?
IL-8, which may cause inflammatory changes that contribute to pathogenesis of wheezing
RSV is a potent precipitator of wheeze in which population?
School-aged asthamtic children
RSV is a virus is ubiquitous and infects over ____ of children by end of their second winter.
95%
About 40% of children infected by RSV develop?
Bronchiolitis, an acute lower respiratory infection characterised by tachypnoea, hyperinflation and crackles.
Babies who develop bronchiolitis severe enough to require hospitalisation have a high risk of developing?
Asthma, around 50%
Some workers detected RSV-specific IgE attached to nasopharyngeal cells in infants with RSV and wheezing which suggests?
RSV infection is more severe in babies who were already predisposed to asthma/atopy, rather than RSV inducing asthma by causing mucosal damage to airways allowing entry of sensitizing aero-allergens.
Principal respiratory manifestations of asthma are related to acute pathological events namely?
- Bronchoconstriction
- Mucosal oedema
- Mucus hypertension
Clinical features of asthma include:
- Wheeze
- Breathlessness (dyspnoea)
- Cough
- Respiratory distress
More severe obstruction of asthma will also manifest by?
- Complaints of breathlessness and ‘chest tightness’ and signs of respiratory distress (tachypnoea, tracheal tug, intercostal and subcostal recession, use of accessory muscles of respiration and pulsus paradoxus)
Cough in asthma is characteristically
‘tight’ and non-productive, but may become more productive in the recovery phase, particularly when asthma occurs in association with a respiratory tract infection
Most common trigger for episodes of wheezing, particularly in children, are?
Viral respiratory tract infections
There is increasing evidence that _____ is the most important viral trigger in both children and adults for asthma.
Rhinovirus
Allergic/atopic patients have an altered immune response to rhinovirus, leading to?
Persistence of the virus and in turn more severe acute episodes as well as enhanced ongoing airway inflammation
Gene environment interaction may be important in both ?
Development and clinical expression of asthma
In older children and adults, ____ becomes a more common trigger and _____ induced symptoms may be the only manifestation.
Exercise; exercise
Inhalant allergens may also trigger acute episodes of wheezing, but appear to have their most important effect on?
Enhanced airway inflammation and hyperresponsiveness
Dietary triggers may be important in patients with wheezing, and these tend to be related to direct chemically mediated effects (______, ___, _____) rather than IgE mediated pathways (ingested allergens)
Metabisulphite, MSG, aspirin
List other important triggers of wheezing
- Cigarette smoke (via passive or active inhalation)
- Indoor/outdoor air pollution
- Weather changes
Nocturnal exacerbation of asthmatic symptoms is most likely related to?
Diurnal variation of airway hyper-responsiveness, with symptoms characteristically occurring in the early morning hours
Wheezing is a common symptom in _____ and may not necessarily reflect underlying airway inflammation.
Infancy
Most useful indicators for establishing the severity of asthma are:
- The frequency of acute episodes
- The presence of interval symptoms (nocturnal and/or exercise induced)
- Lifestyle disruption (hospitalisation, school/work absence, exercise restriction, growth in children)
- Frequency of bronchodilator use
List other atopic manifestations that may be present in the asthmatic patient
- Atopic dermatitis
- Allergic rhinitis (perennial or seasonal)
- Immediate food hypersensitivity
Which drugs are ‘cromones’ for long term treatment for asthma
Cromoglycate & nedocromil
Cromoglycate has been used for many years to treat?
Asthma
What does cromoglycate do?
Although mechanism is uncertain, it effectively blocks antigen induced bronchoconstriction and exercise induced asthma.
Nedocromil is a drug which has?
Anti-inflammatory activity in several experimental models
Nedocromil mechanism ?
It effectively blocks antigen induced bronchoconstriction and bronchoconstrictor response to neural stimulation such as inhalation of sulphur dioxide.
Also blocks exercise induced asthma and osmotic-induced bronchoconstriction.
Small effect on airway hyperresponsiveness which is of similar magnitude to effect seen with low dose beclomethasone
Side effects of cromones?
Infrequent local irritation in the upper airways.
Cromone drugs are available as?
Inhalational agents
List inhaled corticosteroids (ICS)
- Beclomethasone
- Budesonide
- Fluticasone
- Ciclesonide
Inhaled corticosteroids like beclomethasone, budesonide, fluticasone and ciclesonide have what property?
Potent topical anti-inflammatory activity, which means that when they are taken by inhalation, they will exert a local anti-inflammatory effect within the airways.
Regular treatment with inhaled corticosteroids?
Reduces airway hyperresponsiveness
Inhaled corticosteroids are the only currently available drugs which?
Have a substantial and sustained effect on AHR (airway hyper-reactivity)
Beclomethasone have similar potency to ______ with respect to efficacy in controlling asthma.
Budesonide
Fluticasone is about twice as potent as _____ with respect to efficacy in controlling asthma.
Beclomethasone
With an inhaled drug, up to _____ is deposited in the oropharynx and swallowed.
80%
Why does swallowed corticosteroid not gain access to the systemic circulation?
Extensive first pass metabolism in the liver.
When higher doses of ICS are inhaled, what happens?
There will be some absorption from the lung, creating potential for systemic side effects, such as easy bruising.
Local side effects of ICS include?
In the upper airway: sore throat, oral candidiasis, and dysphonia
What device can minimise upper airway deposition for ICS?
Large volume spacers, which can also enhance deposition within the lungs.
List anti-leukotriene drugs
- Cysteinyl LT receptor antagonists: montelukast and zafirlukast
Mechanism of cysteinyl LT receptor antagonists
Blocks actions of LTC4, LTD4, LTE4 at receptor sites, particularly on airway smooth muscle
Cysteinyl LT receptor antagonists afford a degree of protection against?
Antigen challenge and exercise-induced bronchospasm
Anti-leukotriene drugs like cysteinyl LT receptor antagonists can come in ______ if patients cannot tolerate inhaled corticosteroids because of local side effects.
Oral tablet preparations
List two drugs of long acting beta agonists (LABA)
- Salmeterol
- Eformoterol
Mechanism of LABA (long acting beta agonists)
Binds to beta receptors in same way as the short acting beta agonists (salbutamol and terbutaline)
List two short acting beta agonists
- Salbutamol
- Terbutaline
What is LABA (long acting beta agonists) used for?
Used as regular therapy in patients taking ICS for their asthma.
Addition of LABA to existing treatment with ICS patients are permitted a _____ dose of ICS to control the manifestations of asthma.
Lower
Fixed dose (LABA + ICS in a single inhaler device) are used in patients whose ?
Whose asthma are not adequately controlled with ICS alone
Atopic eczema affects around ____ of the population, and up to ____ of Australian children.
10%; 20%
Atopic eczema usually starts when and where?
First year of life, often on the face
