What Causes Airway Inflammation in Asthma, Treatment

What Causes Airway Inflammation in Asthma








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What Causes Airway Inflammation in Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These episodes may occur a few times a day or a few times per week. Depending on the person, they may become worse at night or with exercise.

Asthma is a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation [Rx]. The interaction of these features of asthma determines the clinical manifestations and severity of asthma [Rx] and the response to treatment.

What Causes Airway Inflammation in Asthma?

Asthma triggers are different from person to person and can include:

  • Airborne substances, such as pollen, dust mites, mold spores, pet dander or particles of cockroach waste
  • Respiratory infections, such as the common cold
  • Physical activity (exercise-induced asthma)
  • Cold air
  • Air pollutants and irritants, such as smoke
  • Certain medications, including beta blockers, aspirin, ibuprofen and naproxen 
  • Strong emotions and stress
  • Sulfites and preservatives added to some types of foods and beverages, including shrimp, dried fruit, processed potatoes, beer and wine
  • Gastroesophageal reflux disease (GERD), a condition in which stomach acids back up into your throat
  • Asthma is a chronic inflammatory disorder of the airways. This feature of asthma has implications for the diagnosis, management, and potential prevention of the disease.
  • The immunohistopathologic features of asthma include inflammatory cell infiltration:

    • Neutrophils (especially in sudden-onset, fatal asthma exacerbations; occupational asthma, and patients who smoke)
    • Eosinophils
    • Lymphocytes
    • Mast cell activation
    • Epithelial cell injury
  • Airway inflammation contributes to airway hyperresponsiveness, airflow limitation, respiratory symptoms, and disease chronicity.
  • In some patients, persistent changes in airway structure occur, including sub-basement fibrosis, mucus hypersecretion, injury to epithelial cells, smooth muscle hypertrophy, and angiogenesis.
  • Gene-by-environment interactions are important to the expression of asthma.
  • Atopy, the genetic predisposition for the development of an immunoglobulin E (IgE)-mediated response to common aeroallergens, is the strongest identifiable predisposing factor for developing asthma.
  • Viral respiratory infections are one of the most important causes of asthma exacerbation and may also contribute to the development of asthma.

Sign Symptoms of Asthma

Early warning signs of asthma include. Intermittent and variable (may also be absent, e.g., during symptom-free intervals or in mild disease)

Common signs and symptoms of asthma include

  • Coughing – Coughing from asthma often is worse at night or early in the morning, making it hard to sleep.
  • Wheezing – Wheezing is a whistling or squeaky sound that occurs when you breathe.
  • Chest tightness – This may feel like something is squeezing or sitting on your chest.
  • Shortness of breath. Some people who have asthma say they can’t catch their breath or they feel out of breath. You may feel like you can’t get air out of your lungs.
  • Shortness of breath
  • Trouble sleeping caused by shortness of breath, coughing or wheezing
  • A whistling or wheezing sound when exhaling (wheezing is a common sign of asthma in children)
  • Coughing or wheezing attacks that are worsened by a respiratory virus, such as a cold or the flu
  • Increasing difficulty breathing (measurable with a peak flow meter, a device used to check how well your lungs are working)
  • Exercise-induced asthma, which may be worse when the air is cold and dry
  • Occupational asthma, triggered by workplace irritants such as chemical fumes, gases or dust
  • Allergy-induced asthma, triggered by airborne substances, such as pollen, mold spores, cockroach waste or particles of skin and dried saliva shed by pets (pet dander)

Other symptoms of an asthma attack include

  • Severe wheezing when breathing both in and out
  • Coughing that won’t stop
  • Very rapid breathing
  • Chest pain or pressure
  • Tightened neck and chest muscles, called retractions
  • Difficulty talking
  • Feelings of anxiety or panic
  • Pale, sweaty face
  • Blue lips or fingernails

Diagnosis of Asthma

Basic diagnostic evaluation of bronchial asthma*1

History

  • Sudden onset of symptoms, often at night or in the early morning hours, typically shortness of breath and cough (productive or unproductive), particularly
    • after allergen exposure
    • during (or, more commonly, after) physical exertion or sports (so-called
    • exercise-induced asthma)
    • in the setting of upper respiratory infection
    • on exposure to thermal stimuli, e.g., cold air
    • on exposure to smoke or dust
  • Seasonal variation of symptoms (seasonal elevation of pollen count)
  • Positive family history (allergy, asthma)
  • Precipitants of asthmatic symptoms in the patient’s environment at home, at work, and during leisure activities

Differential diagnosis

The following entities should be considered in the differential diagnosis of bronchial asthma because of their frequency and clinical significance ():

  • Chronic obstructive pulmonary disease (COPD)
  • Hyperventilation
  • Aspiration
  • Laryngeal changes/vocal cord dysfunction
  • Pneumothorax
  • Cystic fibrosis (CF)
  • Cardiac diseases, e.g., left heart failure
  • Pulmonary embolism
  • Gastroesophageal reflux disorder.

In as many as 10% to 20% of cases, a clear-cut distinction between asthma and COPD cannot be drawn.

  • Allergy test – Reasonable because many children show relevant sensitization even under 3 years of age. For example, sensitivity to house-dust mites is associated with increased asthma risk.
  • Lung function diagnostics  Children usually have to be 5–6 years old before spirometry is possible, but it can be attempted earlier with sufficient expertise and time investment. The GINA Guidelines do not make any reference to alternative technologies (forced oscillation, impulse oscillometry, multiple-breath washout etc.). In addition, these techniques currently are only available in specialized centers.
  • Exhaled NO –  Listed as a possible examination (tidal technique) in the GINA Guidelines, but not yet established for young children (apart from scientific applications). As soon as spirometry is possible, the forced expiratory flow maneuver can usually be employed in a defined flow range (“single-breath” method).
  • Further tests – mainly to rule out differential diagnoses: In addition to the lung X‑ray specified in the GINA Guidelines, further examinations (bronchoscopy, sweat test, pH measurement etc.) may be required. However, they are not part of the primary diagnosis.

You may also be given lung (pulmonary) function tests to determine how much air moves in and out as you breathe. These tests may include:

  • Spirometry – This test estimates the narrowing of your bronchial tubes by checking how much air you can exhale after a deep breath and how fast you can breathe out.
  • Peak flow – A peak flow meter is a simple device that measures how hard you can breathe out. Lower than usual peak flow readings are a sign your lungs may not be working as well and that your asthma may be getting worse. Your doctor will give you instructions on how to track and deal with low peak flow readings.

Additional tests of Asthma

Other tests to diagnose asthma include

  • Methacholine challenge – Methacholine is a known asthma trigger that, when inhaled, will cause mild constriction of your airways. If you react to the methacholine, you likely have asthma. This test may be used even if your initial lung function test is normal.
  • Imaging tests – A chest X-ray and high-resolution computerized tomography (CT) scan of your lungs and nose cavities (sinuses) can identify any structural abnormalities or diseases (such as infection) that can cause or aggravate breathing problems.
  • Allergy testing – This can be performed by a skin test or blood test. Allergy tests can identify allergy to pets, dust, mold and pollen. If important allergy triggers are identified, this can lead to a recommendation for allergen immunotherapy.
  • Sputum eosinophils – This test looks for certain white blood cells (eosinophils) in the mixture of saliva and mucus (sputum) you discharge during coughing. Eosinophils are present when symptoms develop and become visible when stained with a rose-colored dye (eosin).
  • Provocative testing for exercise and cold-induced asthma – In these tests, your doctor measures your airway obstruction before and after you perform vigorous physical activity or take several breaths of cold air.

Treatment of Asthma

Non-pharmacological treament

  • Removal of allergens (especially pets with feathers or fur) (evidence level A)
  • Structured patient education: improved self-management leading to better symptomatic control, reduction of the number of asthma attacks and emergency situations, improved quality of life, and improvement in various other parameters of disease course including days taken off from school or work and days spent in hospital (evidence level A)
  • Physical training (reduction of asthma symptoms, improved exercise tolerance, improved quality of life, reduced morbidity) (evidence level C)
  • Respiratory therapy and physiotherapy (e.g., breathing techniques, pursed-lip breathing) (evidence level C)
  • Smoking cessation (with medical and non-medical aids, if necessary) (evidence level B)
  • Psychosocial treatment approaches (family therapy) (evidence level C)
  • For obese patients, weight loss (evidence level B)().

The goals of pharmacotherapy are the suppression of the inflammation of asthma and the reduction of bronchial hyperreactivity and airway obstruction. The medications used for these purposes belong to two groups:

  • Relievers (medications taken for symptomatic relief as necessary) include mainly the inhaled, rapidly-acting beta2 sympathomimetic agents, e.g., the short-acting drugs salbutamol, fenoterol, and terbutaline and the long-acting drug formoterol. Inhaled anticholinergic drugs and rapidly-acting theophylline (solution or drops) play a secondary role as relievers.
  • Controllers (medications used for preventive, maintenance therapy) include the inhaled corticosteroids (ICS), inhaled long-acting beta2 agonists (LABA) such as formoterol or salmeterol, montelukast, and delayed-release theophylline preparations.

Formoterol can be used as a reliever because of its rapid onset of action or as a controller in combination with corticosteroids.

Medications

Medications used to treat asthma are divided into two general classes: quick-relief medications used to treat acute symptoms; and long-term control medications used to prevent further exacerbation. Antibiotics are generally not needed for sudden worsening of symptoms.

Fast–acting

Salbutamol metered dose inhaler commonly used to treat asthma attacks.
  • Short-acting beta2-adrenoceptor agonists (SABA), such as salbutamol (albuterol USAN) are the first line of treatment for asthma symptoms. They are recommended before exercise in those with exercise induced symptoms.
  • Anticholinergic medications, such as ipratropium bromide, provide additional benefit when used in combination with SABA in those with moderate or severe symptoms. Anticholinergic bronchodilators can also be used if a person cannot tolerate a SABA. If a child requires admission to hospital additional ipratropium does not appear to help over a SABA.
  • Older, less selective adrenergic agonists, such as inhaled epinephrine, have similar efficacy to SABAs.They are however not recommended due to concerns regarding excessive cardiac stimulation.

Long–term control

Fluticasone propionate metered dose inhaler commonly used for long-term control.
  • Corticosteroids – are generally considered the most effective treatment available for long-term control. Inhaled forms such as beclomethasone are usually used except in the case of severe persistent disease, in which oral corticosteroids may be needed. It is usually recommended that inhaled formulations be used once or twice daily, depending on the severity of symptoms.
  • Long-acting beta-adrenoceptor agonists – (LABA) such as salmeterol and formoterol can improve asthma control, at least in adults, when given in combination with inhaled corticosteroids. In children this benefit is uncertain. When used without steroids they increase the risk of severe side-effects, and with corticosteroids, they may slightly increase the risk. Evidence suggests that for children who have persistent asthma, a treatment regime that includes LABA added to inhaled corticosteroids may improve lung function but does not reduce the amount of serious exacerbations. Children who require LABA as part of their asthma treatment may need to go to the hospital more frequently.
  • Leukotriene receptor antagonists – (anti-leukotriene agents such as montelukast and zafirlukast) may be used in addition to inhaled corticosteroids, typically also in conjunction with a LABA. Evidence is insufficient to support use in acute exacerbations. For adults or adolescents who have persistent asthma that is not controlled very well, the addition of anti-leukotriene agents along with daily inhaled corticosteriods improves lung function and reduces the risk of moderate and severe asthma exacerbations. Anti-leukotriene agents may be effective alone for adolescents and adults, however, there is no clear research suggesting which people with asthma would benefit from anti-leukotriene receptor alone. In those under five years of age, anti-leukotriene agents were the preferred add-on therapy after inhaled corticosteroids by the British Thoracic Society in 2009. A 2013 Cochrane systematic review concluded that anti-leukotriene agents appear to be of little benefit when added to inhaled steroids for treating children. A similar class of drugs, 5-LOX inhibitors, may be used as an alternative in the chronic treatment of mild to moderate asthma among older children and adults. As of 2013 there is one medication in this family known as zileuton.
  • aminophylline – Intravenous administration of the drug does not provide an improvement in bronchodilation when compared to standard inhaled beta-2 agonist treatment. Aminophylline treatment is associated with more adverse effects compared to inhaled beta-2 agonist treatment.
  • Mast cell stabilizers – (such as cromolyn sodium) are another non-preferred alternative to corticosteroids.
  • For children with asthma which is well-controlled on combination therapy of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA), the benefits and harms of stopping LABA and stepping down to ICS-only therapy are uncertain.
  • In adults who have stable asthma while they are taking a combination of LABA and inhaled corticosteroids (ICS), stopping LABA may increase the risk of asthma exacerbations that require treatment with corticosteroids by mouth.
  • Stopping LABA probably makes little or no important difference to asthma control or asthma-related quality of life. Whether or not stopping LABA increases the risk of serious adverse events or exacerbations requiring an emergency department visit or hospitalisation is uncertain.

Delivery methods

Medications are typically provided as metered-dose inhalers (MDIs) in combination with an asthma spacer or as a dry powder inhaler. The spacer is a plastic cylinder that mixes the medication with air, making it easier to receive a full dose of the drug. A nebulizer may also be used. Nebulizers and spacers are equally effective in those with mild to moderate symptoms. However, insufficient evidence is available to determine whether a difference exists in those with severe disease. There is no strong evidence for the use of intravenous LABA for adults or children who have acute asthma.

The most commonly used asthma medications include the following

  • Short-acting bronchodilators (albuterol) – provide quick relief and can be used in conjunction for exercise-induced symptoms.
  • Inhaled steroids fluticasone – mometasone ciclesonide, flunisolide are first-line anti-inflammatory therapy.
  • Long-acting bronchodilators – (salmeterol formoterol vilanterol) can be added to ICS as additive therapy. LABAs should never be used alone for the treatment of asthma.
  • Leukotriene – modifiers can also serve as anti-inflammatory agents.
  • Anticholinergic agents – (ipratropium , tiotropium [Spiriva], umeclidinium [Incruse Ellipta]) can help decrease sputum production.
  • Anti-IgE – treatment can be used in allergic asthma.
  • Anti-IL5 treatment – (mepolizumab , reslizumab ) can be used in eosinophilic asthma.
  • Chromones stabilize mast cells – (allergic cells) but are rarely used in clinical practice.
  • Theophylline – also helps with bronchodilation (opening the airways) but is rarely used in clinical practice due to an unfavorable side-effect profile.
  • Systemic steroids – (prednisone, prednisolone , methylprednisolone, dexamethasone ) are potent anti-inflammatory agents that are routinely used to treat asthma exacerbations but pose numerous unwanted side effects if used repeatedly or chronically.
  • Numerous additional monoclonal antibodies – are also currently being studied and will likely be available within the next couple of years.
  • Immunotherapy – or allergy shots have been shown to decrease medication reliance in allergic asthma.
  • There are no home remedies that have proven benefit for asthma.

Treatments whose effectiveness has been inadequately demonstrated, or not at all

  • Acupuncture
  • “Alexander technique” training of breathing
  • Air moisture control
  • Breathing exercises
  • Buteyko breathing technique
  • Chiropractic manipulation
  • Dietary measures: fish oil, fatty acids, mineral supplementation or restriction, vitamin C
  • Homeopathy
  • Hypnosis
  • Ionizers (room-air purifiers)
  • Plant extracts (phytotherapeutic agents)
  • Relaxation therapy, including progressive relaxation as described by Jacobson, hypnotherapy, autogenic training, biofeedback training, transcendental meditation
  • Speleotherapy (living in underground caves and mines)
  • Traditional Chinese medicine (), ().

Others

When asthma is unresponsive to usual medications, other options are available for both emergency management and prevention of flareups. For emergency management other options include:

  • Oxygen to alleviate hypoxia if saturations fall below 92%.
  • Corticosteroid by mouth are recommended with five days of prednisone being the same 2 days of dexamethasone. One review recommended a seven-day course of steroids.
  • Magnesium sulfate intravenous treatment increases bronchodilation when used in addition to other treatment in moderate severe acute asthma attacks. In adults it results in a reduction of hospital admissions.
  • Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases.
  • Intravenous salbutamol is not supported by available evidence and is thus used only in extreme cases.
  • Methylxanthines (such as theophylline) were once widely used, but do not add significantly to the effects of inhaled beta-agonists. Their use in acute exacerbations is controversial.
  • The dissociative anesthetic ketamine is theoretically useful if intubation and mechanical ventilation is needed in people who are approaching respiratory arrest; however, there is no evidence from clinical trials to support this.
  • For those with severe persistent asthma not controlled by inhaled corticosteroids and LABAs, bronchial thermoplasty may be an option. It involves the delivery of controlled thermal energy to the airway wall during a series of bronchoscopies. While it may increase exacerbation frequency in the first few months it appears to decrease the subsequent rate. Effects beyond one year are unknown.
  • Evidence suggests that sublingual immunotherapy in those with both allergic rhinitis and asthma improve outcomes.
  • Omalizumab may also be useful in those with poorly controlled allergic asthma.
  • It is unclear if non-invasive positive pressure ventilation in children is of use as it has not been sufficiently studied.

Alternative medicine

Acupuncture is not recommended for the treatment as there is insufficient evidence to support its use. Air ionisers show no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.

Manual therapies, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic maneuvers, have insufficient evidence to support their use in treating asthma. The Buteyko breathing technique for controlling hyperventilation may result in a reduction in medication use; however, the technique does not have any effect on lung function. Thus an expert panel felt that evidence was insufficient to support its use.

The main adverse effects of anti-asthmatic medication

  • Inhaled short-acting beta2 sympathomimetic agents – Fine tremor of voluntary muscle; agitation; tachycardia; palpitations
  • Inhaled long-acting beta2 sympathomimetic agents (LABA) – Same adverse effects as short-acting agents; also: tolerance of bronchoprotective effect in the presence of bronchoconstricting stimuli (while the bronchodilating effect of the drug is maintained); to be used over the long term only in combination with glucocorticoids (usually ICS)
  • Inhaled corticosteroids (ICS) – oropharyngeal candidiasis (thrush); hoarsenessSystemic: depending on the dose and the duration of administration, osteoporosis; cataracts; glaucoma; delayed growth in childhood; suppression of adrenocortical function
  • Systemic corticosteroids – Cushing syndrome; osteoporosis; myopathy; glaucoma; cataracts; endocrine psychosyndrome; worsening of diabetes mellitus; sodium retention; hypertension; adrenocortical atrophy; elevated susceptibility to infection
  • Montelukast – Abdominal symptoms; a headache; unclear association with Churg-Strauss syndrome, thus the dose of simultaneously administered systemic glucocorticoids should be lowered cautiously
  • Theophyllin – Depending on the serum concentration: gastrointestinal disturbances; gastroesophageal reflux disorder; tachycardia; diuresis; agitation; insomnia When the serum concentration exceeds 25 mg/L: epileptic seizures; gastrointestinal bleeding; ventricular arrhythmia; hypotension
  • Omalizumab – Local reactions at the subcutaneous injection site; a headache

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References

What Causes Airway Inflammation in Asthma

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