3. Contents of the training materials
Aetiology and pathogenesis of the disease.
The aetiology of asthma is complex, and multiple environmental and genetic determinants are implicated. The hygiene hypothesis proposes that decreased infections in early life bias the immune system towards an allergic phenotype. T lymphocytes may differentiate into two distinct subsets: Th1 and Th2. In infancy, a shift occurs from the in utero Th2 bias towards a Th1 response necessary for fighting viral and bacterial infection. A reduction in childhood infections favours persistence of a Th2 bias (characterised by cytokines such as interleukins 4, 5 and 13), directing the immune system towards an allergic type of response. In support of this hypothesis, day care attendance (which presumably increases exposure to childhood infections) is associated with lower rates of atopy, wheeze and asthma in later childhood. Other infections, however, such as respiratory syncytial virus, appear to increase the risk of developing asthma and the validity of this hypothesis (including the ability to distinguish Th1 and Th2 cells clearly in humans) has been challenged.
Causes.
Factors that can contribute to asthma or airway hyperreactivity may include any of the following:
Environmental allergens (House dust mites, animal allergens [especially cat and dog], cockroach allergens, and fungi are most commonly reported.)
Viral respiratory infections
Exercise; hyperventilation
Gastroesophageal reflux disease (GERD)
Chronic sinusitis or rhinitis
Aspirin or nonsteroidal anti-inflammatory drug hypersensitivity, sulfite sensitivity
Use of beta-adrenergic receptor blockers (including ophthalmic preparations)
Obesity (Based on a prospective cohort study of 86,000 patients, those with an elevated body mass index are more likely to have asthma.)
Environmental pollutants, tobacco smoke
Occupational exposure
Irritants such as household sprays and paint fumes
A variety of high and low molecular weight compounds are associated with the development of occupational asthma such as insects, plants, latex, gums, diisocyanates, anhydrides, wood dust, and fluxes.
Emotional factors or stress
Perinatal factors (Prematurity and increased maternal age increase the risk for asthma; breastfeeding has not been definitely shown to be protective. Both maternal smoking and prenatal exposure to tobacco smoke also increase the risk of developing asthma.)
Pathophysiology
The inhalation of an allergen in a sensitised atopic asthmatic patient results in a two-phase bronchoconstrictor response. The inhaled allergen rapidly interacts with mucosal mast cells via an IgE-dependent mechanism, resulting in the release of mediators such as histamine and the cysteinyl leukotrienes with resulting bronchoconstriction. In persistent asthma a chronic and complex inflammatory response ensues, which is characterised by an influx of numerous inflammatory cells, the transformation and participation of airway structural cells, and the secretion of an array of cytokines, chemokines and growth factors.
Airway hyper-reactivity (AHR) is integral to the diagnosis of asthma and appears to be related, but not exclusively so, to airway inflammation. Other factors are likely to be important including the behaviour of airway smooth muscle, the degree of airway narrowing and the influence of neurogenic mechanisms.
With increasing severity and chronicity of the disease, remodelling of the airway occurs, leading to fibrosis of the airway wall, fixed narrowing of the airway and a reduced response to bronchodilator medication.
Clinical features
Asthma is not a uniform disease but a dynamic clinical syndrome with a variety of features. Typical symptoms include recurrent episodes of wheezing, chest tightness, breathlessness and cough. Common precipitants include exercise, particularly in cold weather, exposure to airborne allergens or pollutants, and viral upper respiratory tract infections (beware the cold that 'goes to the chest' or takes more than 10 days to clear). Patients with mild intermittent asthma are usually asymptomatic between exacerbations which occur during viral respiratory tract infections or after exposure to allergens. In persistent asthma the pattern is one of chronic wheeze and breathlessness.
Asthma characteristically displays a diurnal pattern, with symptoms and PEF being worse in the early morning. Particularly when asthma is poorly controlled, symptoms such as cough and wheeze disturb sleep and have led to the use of the term 'nocturnal asthma'. Cough may be the dominant symptom in some patients and the lack of wheeze or breathlessness may lead to a delay in reaching the diagnosis of so-called 'cough-variant asthma'.
In some circumstances the appearance of asthma relates to the use of medications. Beta-adrenoceptor antagonists (β-blockers-even when administered topically as eye drops) may induce bronchospasm. Aspirin and other non-steroidal anti-inflammatory drugs are associated with asthma in about 10% of patients. This is believed to reflect a shift in the metabolism of arachidonic acid from the cyclo-oxygenase pathway generating prostaglandins, towards the lipo-oxygenase pathway generating cysteinyl leukotrienes. Aspirin-sensitive asthma is often associated with rhinosinusitis and nasal polyps.
Occupational asthma is now the most common form of occupational respiratory disorder and accounts for around 5% of all adult-onset asthma. This should be considered in all adult asthmatics of working age, particularly if symptoms improve during time away from work, e.g. weekends or holidays. Atopic individuals and smokers appear to be at increased risk. Early diagnosis and removal from exposure leads to a significantly improved prognosis and may result in cure. The recognition of occupational asthma has important medico-legal implications and should prompt screening of the workplace as other employees may also have developed the disease.
An important minority of patients appear to have a particularly severe form of asthma; this appears to be more common in women. Allergic triggers appear to be less important and airway neutrophilia predominates.
How Airways Narrow |
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During an asthma attack, the smooth muscle layer goes into spasm, narrowing the airway. The middle layer swells because of inflammation, and more mucus is produced. In some segments of the airway, the mucus forms clumps that nearly or completely block the airway. These clumps are called mucus plugs. |
Clinical classification
Step 1 - Intermittent
Intermittent symptoms occurring less than once a week
Brief exacerbations
Nocturnal symptoms occurring less than twice a month
Asymptomatic with normal lung function between exacerbations
No daily medication needed
FEV1 or PEF rate greater than 80%, with less than 20% variability
Step 2 - Mild persistent
Symptoms occurring more than once a week but less than once a day
Exacerbations affect activity and sleep
Nocturnal symptoms occurring more than twice a month
Inhaled steroid (low dose), cromolyn (adult: 2-4 puffs tid/qid; child: 1-2 puffs tid/qid), or nedocromil (adult: 2-4 puffs bid/qid; child: 1-2 puffs bid/qid)
FEV1 or PEF rate greater than 80% predicted, with variability of 20-30%
Step 3 - Moderate persistent
Daily symptoms
Exacerbations affect activity and sleep
Nocturnal symptoms occurring more than once a week
Anti-inflammatory, inhaled steroid (medium dose), or inhaled steroid (low-to-medium dose) and long-acting bronchodilator, especially for nighttime symptoms (either long-acting inhaled beta2-agonist [adult: 2 puffs q12h, child: 1-2 puffs q12h], sustained-release theophylline, or long-acting beta2-agonist tablets) (If needed, give inhaled steroids in a medium-to-high dose.)
FEV1 or PEF rate 60-80% of predicted, with variability greater than 30%
Step 4 - Severe persistent
Continuous symptoms
Frequent exacerbations
Frequent nocturnal asthma symptoms
Physical activities limited by asthma symptoms
Anti-inflammatory or inhaled steroid (high dose) and long-acting bronchodilator (either long-acting inhaled beta2-agonist [adult: 2 puffs q12h, child: 1-2 puffs q12h] and sustained-release theophylline or long-acting beta2-agonist tablets and steroid tablets or syrup long term) (Make repeated attempts to reduce systemic steroid and maintain control with high-dose inhaled steroid.)
FEV1 or PEF rate less than 60%, with variability greater than 30%
Physical
General
Evidence of respiratory distress manifests as increased respiratory rate, increased heart rate, diaphoresis, and use of accessory muscles of respiration.
Marked weight loss or severe wasting may indicate severe emphysema.
Pulsus paradoxus: This is an exaggerated fall in systolic blood pressure during inspiration and may occur during an acute asthma exacerbation.
Depressed sensorium: This finding suggests a more severe asthma exacerbation with impending respiratory failure.
Chest examination
End-expiratory wheezing or a prolonged expiratory phase is found most commonly, although inspiratory wheezing can be heard.
Diminished breath sounds and chest hyperinflation may be observed during acute exacerbations.
The presence of inspiratory wheezing or stridor may prompt an evaluation for an upper airway obstruction such as vocal cord dysfunction, vocal cord paralysis, thyroid enlargement, or a soft tissue mass (eg, malignant tumor).
Upper airway
Look for evidence of erythematous or boggy turbinates or the presence of polyps from sinusitis, allergic rhinitis, or upper respiratory infection.
Any type of nasal obstruction may result in worsening of asthma
Skin: Observe for the presence of atopic dermatitis, eczema, or other manifestations of allergic skin conditions.
Diagnosis
Investigations
The diagnosis of asthma is made on the basis of a compatible clinical history combined with the demonstration of variable airflow obstruction.
Pulmonary function tests
Peak flow meters are inexpensive and widely available, and provide a simple and straightforward method of confirming the diagnosis. Ideally 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 (the lowest values typically being recorded in the morning) of more than 20% 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 documenting the improvement in PEF seen in patients with asthma.
The measurement of FEV1 and VC by spirometry allows the demonstration of airflow obstruction, and following the administration of a bronchodilator, confirms the diagnosis when a 15% (and 200 ml) improvement in FEV1 is noted. Spirometry is also particularly helpful in monitoring the severity of airflow obstruction in patients with impaired lung function.
Enhanced bronchoconstriction (AHR) to a variety of direct and indirect stimuli including exercise, cold air, dusts, smoke and chemicals such as histamine and methacholine, is an integral part of the definition of asthma, and may be helpful in patients presenting with normal lung function. For patients whose symptoms are prominently related to exercise, an exercise test may be followed by a drop in PEF or FEV1. AHR is sensitive but non-specific: it therefore has a high negative predictive value but positive results may be seen in other conditions such as COPD, bronchiectasis and CF. Challenge tests using adenosine are being developed and may prove more specific.
Making 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 weeks on PEF diary
• FEV1 ≥ 15% decrease after 6 mins of exercise
Radiological examination
Radiological examination is generally unhelpful in establishing the diagnosis but may point to alternative diagnoses. Acute asthma is accompanied by hyperinflation, and lobar collapse may be seen if mucus has occluded a large bronchus. Flitting infiltrates, on occasion accompanied by lobar collapse, suggest asthma complicated by allergic bronchopulmonary aspergillosis (ABPA). An HRCT scan may be useful to detect bronchiectasis.
Measurement of allergic status
An elevated sputum or peripheral blood eosinophil count may be observed and the serum total IgE is typically elevated in atopic asthma. Skin prick tests are simple and provide a rapid assessment of atopy. Similar information may be provided by the measurement of allergen-specific IgE.
Assessment of airway inflammation
Induced sputum and exhaled breath allow the non-invasive assessment of airway inflammation and may prove useful in the diagnosis of asthma and assist in the monitoring of disease activity.
Status Asthmaticus
The most severe form of asthma is called status asthmaticus. In this condition, the lungs are no longer able to provide the body with adequate oxygen or adequately remove carbon dioxide. Without oxygen, many organs begin to malfunction. The buildup of carbon dioxide leads to acidosis, an acidic state of the blood that affects the function of almost every organ. Blood pressure may fall to low levels. The airways are so narrowed that it is difficult to move air in and out of the lungs.
Status asthmaticus requires intubation and ventilator support as well as maximum doses of several medications. Support is also given to correct acidosis
Complications
The most common complications of asthma include pneumonia, pneumothorax or pneumomediastinum, and respiratory failure requiring intubation in severe exacerbations.
Risk factors for death from asthma include the following:
Past history of sudden severe exacerbations, history of prior intubation, or ICU admission
Two or more hospitalizations or 3 or more emergency department visits in the past year; hospitalization or emergency department visit in the past month
Use of more than 2 short-acting beta-agonist canisters per month
Current use of systemic corticosteroids or recent taper
Comorbidity from cardiovascular disease
Psychosocial, psychiatric, or illicit drug use problems
Low socioeconomic status or urban residence
Complications associated with most medications used for asthma are relatively rare. However, in those patients requiring long-term corticosteroid use, complications may include osteoporosis, immunosuppression, cataracts, myopathy, weight gain, addisonian crisis, thinning of skin, easy bruising, avascular necrosis, diabetes, and psychiatric disorders.
Medical Care
The goals for successful management of asthma include the following:
Achieve and maintain control of symptoms.
Prevent asthma exacerbations.
Maintain pulmonary function as close to normal levels as possible.
Maintain normal activity levels, including exercise.
Avoid adverse effects from asthma medications.
Prevent the development of irreversible airflow limitation.
Prevent asthma mortality.
Principles of management
In the majority of patients with asthma, the disease can be effectively managed in primary care by partnerships between doctors, nurses and, most importantly, patients themselves. The goals of asthma therapy have been endorsed by several sets of guidelines. Management may be directed towards achieving these goals by following a stepwise approach.
Patient education
The variable nature of asthma suggests that encouraging patients to take responsibility for control of their disease should lead to improved clinical outcomes. Patient education should begin at the time of diagnosis and be revisited in subsequent consultations. Patients (or their carers) should be taught about the relationship between symptoms and inflammation, the importance of key symptoms such as nocturnal waking, the different types of medication and the use of PEF to guide management decisions. Written action plans may prove helpful in developing these skills.
Avoidance of aggravating factors
This is particularly important in the management of occupational asthma, when removal from the offending agent is one of the few instances when asthma may be cured or substantially improved. Similarly, the identification of sensitisation to a household pet suggests that asthma control may be improved by removing the animal from the home, although it may take several years before dander levels fall substantially. House dust mite exposure may be minimised by replacing carpets with floorboards and using mite-impermeable bedding. However, to date improvements in asthma control following such measures have been difficult to demonstrate. Many patients are sensitised to several antigens making avoidance strategies almost impossible. Measures to reduce fungal exposure and eliminate cockroaches may be applicable in specific circumstances and medications known to precipitate or aggravate asthma should be avoided. Patients should be advised not to smoke.
A 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/month), it is usually sufficient to prescribe an inhaled short-acting β2-agonist to be used on an as required basis. However, many patients, and their physicians, under-estimate the severity of asthma and these patients should be carefully supervised. A history of a severe exacerbation should lead to a reclassification of the patient's condition as persistent asthma.
Step 2: Introduction of regular preventer therapy
Regular anti-inflammatory therapy (preferably inhaled corticosteroids-ICS) should be started in addition to inhaled β2-agonists taken on an as required basis in 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.
A reasonable starting dose is 400 μg beclometasone dipropionate (BDP) or equivalent per day in adults. BDP and budesonide (BUD) are approximately equivalent in clinical practice, although there may be variations with different delivery devices. Fluticasone and mometasone provide equal clinical activity to BDP/BUD at half the dosage.
Step 3: Add-on therapy
If the patient remains poorly controlled despite regular use of ICS, a thorough review of the patient should be made with particular regard to adherence and inhaler technique. A further increase in the dose of ICS may benefit some patients but in general, add-on therapy should be considered beyond an ICS dose of 800 μg/day BDP (or equivalent) in adults.
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 as they have consistently been demonstrated to improve asthma control and 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 avoid concerns that patients may use LABAs as monotherapy.
Leukotriene receptor antagonists (e.g. montelukast 10 mg daily) are a relatively new class of agent that may be delivered orally and may reduce exacerbations. Theophyllines may be useful in some patients but their unpredictable metabolism, propensity for drug interactions and prominent side-effect profile have limited their use.
Step 4: Poor control on moderate dose of inhaled steroid and add-on therapy: addition of a fourth drug
In adults the dose of ICS may be increased to 2000 μg BDP/BUD daily. A nasal corticosteroid preparation should be used in patients with prominent upper airway symptoms. Oral therapy with leukotriene receptor antagonists, theophyllines or a slow-release β2-agonist may be considered. If the trial of add-on therapy is ineffective it should be discontinued. Oral itraconazole should be contemplated in patients with ABPA. New therapies such as monoclonal antibodies directed against IgE may prove helpful and further studies are awaited.
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 of patients using bisphosphonates. Steroid-sparing therapies such as methotrexate, ciclosporin or oral gold may be considered but should be overseen by a specialist and are accompanied by significant side-effects.
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.
Exacerbations of asthma
The course of asthma may be punctuated by exacerbations characterised by increased symptoms, deterioration in PEF and an increase in airway inflammation. Exacerbations may be precipitated by infections (most commonly viral), moulds (Alternaria and Cladosporium) and on occasion pollen (particularly following thunderstorms). Increases in air pollution are accompanied by increased hospital admissions. 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 of mild-moderate exacerbations
It has been widely believed that an impending exacerbation may be avoided by doubling the dose of ICS; however, recent studies have failed to confirm this. Short courses of 'rescue' oral corticosteroids (prednisolone 30-60 mg daily) are therefore often required to regain control of symptoms. 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
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 severe enough to require treatment with nebulised or injected bronchodilators.
Management of acute severe asthma
Initial assessment
The features of acute asthma are listed in Box 19.25. An immediate assessment of patients (Fig. 19.25) should include their ability to speak, pulse rate, respiratory rate, BP and SaO2. 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, a normal or elevated level being particularly dangerous. A chest X-ray is not immediately necessary unless pneumothorax is suspected.
IMMEDIATE ASSESSMENT OF ACUTE SEVERE ASTHMA |
Acute severe asthma |
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Life-threatening features |
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Near-fatal asthma |
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Oxygen
High concentrations of oxygen (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 is a warning sign of a severe or life-threatening attack. Failure to achieve appropriate oxygenation is an indication for assisted ventilation.
High doses of inhaled bronchodilators
Short-acting β2-agonists represent the agent of first choice. In hospital they are most conveniently administered via a nebuliser driven by oxygen but delivery of multiple doses of salbutamol via a metered dose inhaler through a spacer device provides equivalent bronchodilation and may be considered in primary care. Ipratropium bromide provides additional bronchodilator therapy and should be added to salbutamol in patients with acute severe or life-threatening attacks.
Systemic corticosteroids
Systemic corticosteroids reduce the inflammatory response and hasten the resolution of exacerbations. They should be administered to all patients with an acute severe attack. They can usually be administered orally (prednisolone 30-60 mg), but intravenous hydrocortisone 200 mg may be used in patients who are unable to swallow or vomiting.
Intravenous fluids
There are no controlled trials to support the use of intravenous fluids but many patients are dehydrated due to high insensible water loss and will probably benefit from hydration therapy. Potassium supplements may be necessary because repeated doses of salbutamol can lower serum potassium.
Subsequent management
If patients fail to improve, a number of further options may be considered. Intravenous magnesium may provide additional bronchodilation in patients whose presenting PEF is < 30% predicted. Some patients appear to benefit from the use of intravenous aminophylline but careful monitoring is required. Intravenous leukotriene receptor antagonists may soon become available.
Monitoring of treatment
PEF should be recorded every 15-30 minutes and then every 4-6 hours. Pulse oximetry should ensure that SaO2 remains > 92% but repeat arterial blood gases are necessary if the initial PaCO2 measurements were normal or raised, the PaO2 was < 8 kPa (60 mmHg), or the patient deteriorates.
INDICATIONS FOR ASSISTED VENTILATION IN ACUTE SEVERE ASTHMA |
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The newest asthma medication is omalizumab (Xolair), a recombinant DNA-derived humanized immunoglobulin G monoclonal antibody that binds selectively to human immunoglobulin E on the surface of mast cells and basophils. The drug reduces mediator release, which promotes an allergic response. Indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens, in whom symptoms are not controlled by inhaled corticosteroids. The dose (adults and children >12 y) is 150-375 mg subcutaneously every 2-4 weeks (precise dose and frequency is established by serum immunoglobulin E levels). The estimated annual cost is $12,000-15,000.
Type |
Drug |
Some Side Effects |
Comments |
Beta-adrenergic agonists |
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Albuterol (PROVENTIL, VENTOLIN) (short-acting) Salmeterol (SEREVENT) (long-acting) |
Increased heart rate; shakiness |
Albuterol may be taken by mouth or inhaled through a metered-dose inhaler or by using a nebulizer; salmeterol is only taken by inhalation |
Methylxanthines |
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Theophylline (BRONKODYL,THEOLAIR) |
Increased heart rate; shakiness; stomach up-set. Seizures and serious heartbeat irregularities (if blood level is high) |
Can be used for prevention and treatment, taken by mouth but can be administered intravenously in a hospital |
Anticholinergic drugs |
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Ipratropium (ATROVENT) |
Dry mouth; rapid heart rate |
Used in combination with beta-adrenergic blockers mainly in the emergency department |
Mast cell stabilizers |
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Cromolyn (INTAL, Nedocromil |
Coughing or wheezing |
Useful for preventing attacks but not for treatment |
Corticosteroids (inhaled) |
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Beclomethasone (BECONASE,VANCENASE Budesonide (RHINOCORT) Flunisolide Fluticasone Triamcinolone |
Fungal infection of the mouth (thrush); a change in voice |
Inhaled use is for prevention (long-term control) of asthma |
Leukotriene modifiers |
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Montelukast (SINGULAIR) Zafirlukas Zileuton |
Churg-Strauss syndrome; zileuton causes an elevation in liver function test results |
Used more for prevention (long-term control) than for treatment |
4. Plan and organizational structure of educational sessions on discipline.
№ з/п |
Stages of class |
Time distribu-tion |
Types of control |
Equipment training
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1. |
The starting phase |
15% |
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1.1. |
Organizational matters
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20-25 min. |
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1.2. |
Formation of motivation
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1.3. |
Control of entry-level training
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─ written computer testing; ─ oral questioning by the standardized list of questions.
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─ textbooks treatment of internal diseases; ─ guidelines; ─ situational problem in therapy of internal medicine; ─ tests "Step 2";
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2. |
The main stage ─ demonstration of the patient - his clinical examination (history, physical examination, additional methods of investigation); ─ interpretation received symptoms |
65% 120-130 mn. |
─ practical skills at the bedside (collecting complaints, history of illness, physical examination, assessment of results of additional methods investigation); ─ interpretation of the results.
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─ themed patients. |
3. |
The final stage |
20% |
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3.1. |
Control of the final level of training
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25-30 min. |
─ situational tasks; ─ structured written work. |
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3.2. |
The total score of student workload
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3.3. |
Informing students about the topic the next lesson
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