Asthma

§  Some asthmatics who have severe shortness of breath and tightening of the lungs never wheeze or have stridor and their symptoms may be confused with a COPD-type disease.

o    An acute exacerbation of asthma is commonly referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and either wheezing or stridor. Although the former is "often regarded as the sine qua non of asthma", some patients present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).

o    Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest.

o    During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles.

o    During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Just before loss of consciousness, there is a chance that the patient will feel numbness in the limbs and palms may start to sweat. The person's feet may become icy cold.

o    Severe asthma attacks, which may not be responsive to standard treatments (status asthmaticus), are life-threatening and may lead to respiratory arrest and death.

o    Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few or even no signs of the disease.

§  Clinical Presentation:

o    Chronic Asthma

§  Classic asthma is characterized by episodic dyspnea associated with wheezing, but the clinical presentation of asthma is diverse. Patients may also complain of chest tightness, coughing (particularly at night), or a whistling sound when breathing. These often occur with exercise but may occur spontaneously or in association with known allergens.

§  Signs include expiratory wheezing on auscultation, dry hacking cough, or signs of atopy (e.g., allergic rhinitis, urticaria or eczema).

§  Asthma can vary from chronic daily symptoms to only intermittent symptoms. There are recurrent exacerbations and remissions, and the intervals between symptoms may be weeks, months, or years.

§  The severity is determined by lung function and symptoms prior to therapy as well as by the number of medications required to control symptoms. Patients can present with mild intermittent symptoms that require no medications or only occasional use of short-acting inhaled ß₂ agonists to severe chronic asthma symptoms despite receiving multiple medications.

o    Acute Severe Asthma

§  Uncontrolled asthma can progress to an acute state where inflammation, airway edema, excessive accumulation of mucus and severe bronchospasm result in profound airway narrowing that is poorly responsive to usual bronchodilator therapy.

§  Patients may be anxious in acute distress and complain of severe dyspnea, shortness of breath, chest tightness, or burning. They may be able to say only a few words with each breath. Symptoms are unresponsive to usual measures.

§  Signs include expiratory and inspiratory wheezing on auscultation, dry hacking cough, tachypnea, tachycardia, pallor or cyanosis, and hyperinflated chest with

§  Epidemiology:

o    More than 6% of children in the United States have been diagnosed with asthma, a 75% increase in recent decades. The rate soars to 40% among some populations of urban children.

o    Asthma is usually diagnosed in childhood. The risk factors for asthma include:

§  A personal or family history of asthma or atopy

§  Triggers

§  Premature birth or low birth weight

§  Viral respiratory infection in early childhood

§  Maternal smoking

§  Being male, for asthma in prepubertal children

§  Being female, for persistence of asthma into adulthood

o    Current research suggests that the prevalence of childhood asthma has been increasing. According to the Centers for Disease Control and Prevention's National Health Interview Surveys, some 9% of US children below 18 years of age had asthma in 2001, compared with just 3.6% in 1980. The World Health Organization (WHO) reports that some 8% of the Swiss population suffers from asthma today, compared with just 2% some 25–30 years ago. Although asthma is more common in affluent countries, it is by no means a problem restricted to the affluent; the WHO estimate that there are between 15 and 20 million asthmatics in India. In the U.S., urban residents, Hispanics, and African Americans are affected more than the population as a whole.

o    Globally, asthma is responsible for around 180,000 deaths annually.

§  Causes:

o    Asthma is caused by a complex interaction of genetic and environmental factors that researchers do not fully understand yet. These factors can also influence how severe a person’s asthma is and how well they respond to medication. As with other complex diseases, many genetic and environmental factors have been suggested as causes of asthma, but not all of them have been replicated.

o    In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may only affect asthma when combined.

o    The hygiene hypothesis is a theory about the cause of asthma and other allergic disease, and is supported by epidemiologic data for asthma. For example, asthma prevalence has been increasing in developed countries along with increased use of antibiotics, c-sections, and cleaning products. All of these things may negatively affect exposure to beneficial bacteria and other immune system modulators that are important during development, and thus may cause increased risk for asthma and allergy.

o    Environmental

§  Many environmental risk factors have been associated with asthma, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association:

·         Poor air quality, from traffic pollution or high ozone levels, has been repeatedly associated with increased asthma morbidity and has a suggested association with asthma development that needs further research.

·         Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections.

o    Viral respiratory infections at an early age, along with siblings and day care exposure, may be protective against asthma, although there have been controversial results, and this protection may depend on genetic context.

o    Antibiotic use early in life has been linked to development of asthma in several examples; it is thought that antibiotics make one susceptible to development of asthma because they modify gut flora, and thus the immune system (as described by the hygiene hypothesis).

o    Caesarean sections have been associated with asthma when compared with vaginal birth; a meta-analysis found a 20% increase in asthma prevalence in children delivered by Caesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Caesarean section compared with vaginal birth, which modifies the immune system (as described by the hygiene hypothesis).

o    Psychological stress on the part of a child's caregiver has been associated with asthma, and is an area of active research. Stress can modify behaviors that affect asthma, like smoking, but research suggests that stress has other effects as well. There is growing evidence that stress may influence asthma and other diseases by influencing the immune system.

o    Genetic

§  Over 100 genes have been associated with asthma in at least one genetic association study. However, as with all association studies, replication is important before genetic variation (such as a single nucleotide polymorphism, or SNP) in a certain gene is thought to influence asthma. Through the end of 2005, 25 genes had been associated with asthma in six or more separate populations:

o GSTM1 o IL10 o CTLA4 o SPINK5 o LTC4S

o LTA o GRPA o NOD1 o CC16 o GSTP1

o STAT6 o NOS1 o CCL5 o TBXA2R o TGFB1

o IL4 o IL13 o CD14 o ADRB2 (β-2 adrenergic receptor) o HLA-DRB1

o HLA-DQB1 o TNF o FCER1B o IL4R o ADAM33

§  Many of these genes are related to the immune system or to modulating inflammation. However, even among this list of highly replicated genes associated with asthma, the results have not been consistent among all of the populations that have been tested. This indicates that these genes are not associated with asthma under every condition, and that researchers need to do further investigation to figure out the complex interactions that cause asthma.

§  Stimuli

o    Allergens

§  from nature, typically inhaled, which include waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet epithelial cells.

o    Indoor air pollution

§  From volatile organic compounds, including perfumes and perfumed products. Examples include soap, dishwashing liquid, laundry detergent, fabric softener, paper tissues, paper towels, toilet paper, shampoo, hairspray, hair gel, cosmetics, facial cream, sun cream, deodorant, cologne, shaving cream, aftershave lotion, air freshener and candles, and products such as oil-based paint.

o    Medications

§  including aspirin, β-adrenergic antagonists (beta blockers), and penicillin.

o    Food

§  allergies such as milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.

o    Use of fossil fuel related allergenic air pollution, such as ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas.

o    Various industrial compounds and other chemicals:

§  notably sulfites; chlorinated swimming pools generate chloramines—monochloramine (NH2Cl), dichloramine (NHCl2) and trichloramine (NCl3)—in the air around them, which are known to induce asthma.

o    Early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. In many cases, significant asthma may not even occur until the respiratory infection is in its waning stage, and the person is seemingly improving. Eighty percent of asthma attacks in adults and 60% in children are caused by respiratory viruses.

o    Exercise or intense use of respiratory system. The effects of which differ somewhat from those of the other triggers, since they are brief. It is known that exercising regularly actually helps to cure asthma.

o    Hormonal changes in adolescent girls and adult women associated with their menstrual cycle can lead to a worsening of asthma. Some women also experience a worsening of their asthma during pregnancy whereas others find no significant changes, and in other women their asthma improves during their pregnancy.

o    Emotional stress which is poorly understood as a trigger. Emotional stress can affect breathing temporarily, however unlike something such as heart problems, it is unclear if it has any long-term effect.

o    Cold weather can make it harder for asthmatics to breathe. Whether high altitude helps or worsens asthma is debatable and may vary from person to person.

§  Diagnosis:

o    Asthma is defined simply as reversible airway obstruction. Reversibility occurs either spontaneously or with treatment. The basic measurement is peak flow rates and the following diagnostic criteria are used by the British Thoracic Society:

§  ≥20% difference on at least three days in a week for at least two weeks;

§  ≥20% improvement of peak flow following treatment, for example:

·         10 minutes of inhaled β-agonist (e.g., salbutamol);

·         six week of inhaled corticosteroid (e.g., beclometasone);

·         14 days of 30mg prednisolone.

§  ≥20% decrease in peak flow following exposure to a trigger (e.g., exercise).

o    In many cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution—or has a family history of asthma.

o    While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication.

o    Testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. If the diagnosis is in doubt, a more formal lung function test may be conducted. Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.

o    Monitoring asthma with a peak flow meter on an ongoing basis assists with self monitoring of asthma. Peak flow readings can be charted on graph paper charts together with a record of symptoms or use peak flow charting software. This allows patients to track their peak flow readings and pass information back to their doctor or nurse.

o    In the Emergency Department doctors may use a capnography which measures the amount of exhaled carbon dioxide, along with pulse oximetry which shows the amount of oxygen dissolved in the blood, to determine the severity of an asthma attack as well as the response to treatment.

§  Differential diagnosis

o    Before diagnosing someone as asthmatic, alternative possibilities should be considered. A clinician taking a history should check whether the patient is using any known bronchoconstrictors (substances that cause narrowing of the airways, e.g., certain anti-inflammatory agents or beta-blockers).

o    Chronic obstructive pulmonary disease, which closely resembles asthma, is correlated with more exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry), and decreased likelihood of family history of atopy.

o    Pulmonary aspiration, whether direct due to dysphagia (swallowing disorder) or indirect (due to acid reflux), can show similar symptoms to asthma. However, with aspiration, fevers might also indicate aspiration pneumonia. Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow test and treated with feeding therapy by a qualified speech therapist. If the aspiration is indirect (from acid reflux) then treatment directed at this is indicated.

o    A majority of children who are asthma sufferers have an identifiable allergy trigger. Specifically, in a 2004 study, 71% had positive test results for more than 1 allergen, and 42% had positive test results for more than 3 allergens.

o    The majority of these triggers can often be identified from the history; for instance, asthmatics with hay fever or pollen allergy will have seasonal symptoms, those with allergies to pets may experience an abatement of symptoms when away from home, and those with occupational asthma may improve during leave from work. Allergy tests can help identify avoidable symptom triggers.

o    After a pulmonary function test has been carried out, radiological tests, such as a chest X-ray or CT scan, may be required to exclude the possibility of other lung diseases. In some people, asthma may be triggered by gastroesophageal reflux disease, which can be treated with suitable antacids. Very occasionally, specialized tests after inhalation of methacholine or, even less commonly, histamine — may be performed.

o    Asthma is categorized by the United States National Heart, Lung and Blood Institute as falling into one of four categories:

§  Intermittent, mild persistent, moderate persistent and severe persistent.

§  The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent night-time symptoms, result in limited physical activity and when lung function as measured by PEV or FEV1 tests is less than 60% predicted with PEF variability greater than 30%.

§  Prevention

o    Current treatment protocols recommend prevention medications such as an inhaled corticosteroid, which helps to suppress inflammation and reduces the swelling of the lining of the airways, in anyone who has frequent (greater than twice a week) need of relievers or who has severe symptoms. If symptoms persist, additional preventive drugs are added until the asthma is controlled. With the proper use of prevention drugs, asthmatics can avoid the complications that result from overuse of relief medications.

o    Asthmatics sometimes stop taking their preventive medication when they feel fine and have no problems breathing. This often results in further attacks, and no long-term improvement.

o    Patient education and the teaching of self-management skills should be the cornerstone of the treatment program. Self-management programs improve adherence to medication regimens, self-management skills, and use of health care services.

o    Preventive agents include the following:

§  Inhaled glucocorticoids are the most widely used of the prevention medications and normally come as inhaler devices (ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone).
Long-term use of corticosteroids can have many side effects including a redistribution of fat, increased appetite, blood glucose problems and weight gabin. In particular high doses of steroids may cause osteoporosis. For this reasons inhaled steroids are generally used for prevention, as their smaller doses are targeted to the lungs unlike the higher doses of oral preparations. Nevertheless, patients on high doses of inhaled steroids may still require prophylactic treatment to prevent osteoporosis.
Deposition of steroids in the mouth may cause a hoarse voice or oral thrush (due to decreased immunity). This may be minimised by rinsing the mouth with water after inhaler use, as well as by using a spacer which increases the amount of drug that reaches the lungs.

§  Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton).

§  Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil).

§  Antimuscarinics/anticholinergics (ipratropium, oxitropium, and tiotropium), which have a mixed reliever and preventer effect. (These are rarely used in preventive treatment of asthma, except in patients who do not tolerate beta-2-agonists.)

§  Methylxanthines (theophylline and aminophylline), which are sometimes considered if sufficient control cannot be achieved with inhaled glucocorticoids and long-acting β-agonists alone.

§  Antihistamines, often used to treat allergic symptoms that may underlie the chronic inflammation.

§  Hyposensitization, (also known as immunodesensitisation therapy) may be recommended in some cases where allergy is the suspected cause or trigger of asthma. Depending on the allergen, it can be given orally or by injection.

§  Omalizumab, an IgE blocker; this can help patients with severe allergic asthma that does not respond to other drugs. However, it is expensive and must be injected.

§  Methotrexate is occasionally used in some difficult-to-treat patients.

§  If chronic acid indigestion (GERD) contributes to a patient's asthma, it should also be treated, because it may prolong the respiratory problem.

o    Trigger avoidance

§  As is common with respiratory disease, smoking is believed to adversely affect asthmatics in several ways:

·         including an increased severity of symptoms

·         a more rapid decline of lung function

·         And decreased response to preventive medications.

§  Automobile emissions are considered an even more significant cause and aggravating factor. Asthmatics who smoke or who live near traffic typically require additional medications to help control their disease.

§  Furthermore, exposure of both non-smokers and smokers to wood smoke, gas stove fumes and second-hand smoke is detrimental, resulting in more severe asthma, more emergency room visits, and more asthma-related hospital admissions.

§  Smoking cessation and avoidance of second-hand smoke is strongly encouraged in asthmatics.

§  For those in whom exercise can trigger an asthma attack (exercise-induced asthma), higher levels of ventilation and cold, dry air tend to exacerbate attacks. For this reason, activities in which a patient breathes large amounts of cold air, such as skiing and running, tend to be worse for asthmatics, whereas swimming in an indoor, heated pool, with warm, humid air, is less likely to provoke a response.

o    Air Filters

§  If an asthmatic lives with a smoker, use of air filter or room air cleaner is likely to be helpful. Secondhand smoke can worsen the symptoms. The same is true for those with hay fever (allergic rhino sinusitis) or COPD (emphysema or chronic bronchitis). Room air cleaners remove small particles that are in the air near the air cleaner. However, room air cleaners do not remove small allergen particles that are caused by local disturbances, such as the microscopic house dust mite feces that surround a pillow when your head hits it or you turn over in bed. There are several types of air filters available:

·         Mechanical air filters use a fan to force air through a special screen that traps particles such as smoke, pollens, and other airborne allergens. The high-efficiency particulate air (HEPA) filter is the best-known air filter. HEPA (which is a type of filter, not a brand name) was developed during World War II to prevent radioactive particles from escaping from laboratories.

·         Electronic air filters use electrical charges to attract and deposit allergens and irritants. If the device contains collecting plates, the particles are captured within the system; otherwise, they stick to room surfaces and have to be cleared away.

·         Hybrid air filters contain elements of both mechanical and electrostatic filters.

·         Gas phase air filters use activated carbon granules to remove odors (volatile organic compounds or VOCs) and non-particulate pollution such as cooking gas, gases emitted from paint or building materials (such as formaldehyde), and perfume.

·         Germicidal air cleaners use ultraviolet (UV) lights to kill bacteria, viruses, and molds that pass through the area with the UV light. Such UV lights can be included with other air cleaner devices, which use a fan.

·         Ozone generators are devices that intentionally produce high concentrations of ozone to clean the air in a room. They are often used to decontaminate rooms after smoke exposure following a fire.

§  Prognosis

o    The prognosis for asthmatics is good; especially for children with mild disease.

o    For asthmatics diagnosed during childhood, 54% will no longer carry the diagnosis after a decade (grow out of asthma!!). The extent of permanent lung damage in asthmatics is unclear.

o    Airway remodelling is observed, but it is unknown whether these represent harmful or beneficial changes. Although conclusions from studies are mixed, most studies show that early treatment with glucocorticoids prevents or ameliorates decline in lung function as measured by several parameters. For those who continue to suffer from mild symptoms, corticosteroids can help most to live their lives with few disabilities.

o    The mortality rate for asthma is low, with around 6000 deaths per year in a population of some 10 million patients in the United States.

o    Better control of the condition may help prevent some of these deaths.

Treatment:

o    Desired Outcome

§  Chronic Asthma

·         goals for chronic asthma management:

o    maintain normal activity levels (including exercise)

o    maintain (near) normal pulmonary function

o    Prevent chronic and troublesome symptoms (e.g., coughing or breathlessness in the night, in the early morning, or after exertion)

o    Prevent recurrent exacerbations of asthma and minimize the need for emergency department visits or hospitalizations

o    provide optimal pharmacotherapy with minimal or no adverse effects

o    Meet patients' and families' expectations of care.

§  Acute Severe Asthma

·         The goals of treatment are as follows:

o    correction of significant hypoxemia

o    rapid reversal of airway obstruction (within minutes)

o    Reduction of the likelihood of recurrence of severe airflow obstruction;

o    Development of a written action plan in case of a future exacerbation.

So these are the three main treatment aims, and in order to achieve them we have to:

First: to prevent the exposure of the patient to the allergens whenever it is possible.

Secondly: (which is the first line of treatment) is to dilate the bronchi and to relieve the symptoms (cough, wheezing….)

Finally: we have to relieve the bronchial inflammation and the bronchial hypersensitivity.

 

 

Bronchodilators:

Which are actually considered as first line therapy, this group involves the following:

·         Sympathomimetic Drugs: since the β₂ receptors are present in the bronchial muscles we can use the β₂ agonists to dilate the bronchi, and here we particularly use the selective β₂ agonists rather than the nonselective β agonists.

·         Muscarinic receptor antagonists: which produce bronchodilation by their anticholinergic action.

·         Methylxanthines like Theophylline, which is one of the old drugs that was used to be used as a first line therapy for the management of the bronchial asthma, nowadays its use has been declined as the β₂ agonists are more effective and much safer.

The anti-inflammatory agents:

·         Steroids: which are very important in our treatment as well as

·         Cromolyn Sodium: which prevents the degranulation of the mast cells, and therefore blocking the release of histamine and other inflammatory mediators. (mast cells Stabilizer)

Leukotriene Antagonists:

And thirdly we have a group that is related to arachidonic acid products (Leukotrienes), which are very important mediators in the pathogenesis of the bronchial asthma, they are bronchoconstrictors particularly LTB4, LTC4, and LTD4 and therefore nowadays we have drugs which can either inhibit their synthesis or   block the receptors where they act on.

 

 

So in Details

Bronchodilators:

 

bronchial smooth muscles contain β₂ receptors and stimulation of these results in bronchodilation, so any sympathomimetic agent can be used for this purpose (bronchodilation), for e.g. adrenaline as one of these agents may be used in the management of the bronchial asthma, but since these drugs (adrenaline and other non-selective sympathomimetic agents) are non-selective they have a systemic β agonist effect, so they will affect the heart as well as the bronchial muscles, for that reason in order to avoid or to reduce the systemic adverse effects we use the selective β₂ agonists as a first line treatment for the bronchial asthma because they act specifically on the bronchial smooth muscles.

 

Selective B2 agents:

 

• Salbutamol (whose other name is Albuterol) and Terbutaline:

·         Selective β2 agonists.

·         Short acting drugs (which act within few minutes, around 15-30 minutes), for that reason they are considered to be useful for acute attacks as they act rapidly, but at the same time they don’t have a very much long duration of action, their effect may last only for 4-6 hours, but they are regarded as the first line treatment in the management of the bronchial asthma that’s why all the bronchodilators are referred to as Relievers because they relieve the attack of bronchoconstriction.

·         For prophylaxis (prevention of the attack before it occurs) they are not effective, meaning that if a patient takes a dose whose effect will last only for 4-6 hours and he is going to be exposed to allergen after 20 hours the drug will not be effective to prevent the attack at that time. Similarly they will not be effective during the night time. Asthmatic patients usually suffer from very boring and severe cough during sleeping, if they depend only on the short acting bronchodilators for their treatment , then they will be forced to take the drug two or three times during the night.

·         So they are not effective for prophylaxis or prevention of the attack during sleeping what we use for this purpose is actually the long acting β2 agonists.

 

• Salmeterol and Formoterol:

·         Long acting selective β2 agonists.

·         They have more gradual onset of action than the short acting agents, so they are more useful for prevention and prophylaxis but they are not good for acute attacks.

·         despite the similarities between Salmeterol and Formoterol, the second has a quicker onset of action than the first one, this is why Formoterol is more commonly used because of this quicker onset of action.

• Mechanism of Action of β2 Agonists:
• These drugs act by stimulating Adenylyl Cyclase enzyme, elevating the level of cAMP, and as we know cAMP is a quite potent bronchodilator.
• It has been also found that these agents inhibit the release of the bronchoconstrictor substances from the mast cells.
• (the mast cell may rupture if its placed under a challenge, releasing its granular contents, this rupture is found to be prevented by Adrenaline and Isoproterenol, which is also a sympathomimetic agent, so the β2 agonists can also produce this effect as they are also sympathomimetic agents).
• improve the mucociliary transport mechanism, which is an important function for these agents, because if we evacuate or clear the bronchi from the mucous secretion (which is increased in the bronchial asthma), we will allow the air to pass in and out much easier. 

 

• Rout of administration:
• The long acting β2 agonists (like Salmeterol & Formoterol) are usually given only by inhalation.
• Whereas the short acting ones (Salbutamol & terbutaline) can be given either by inhalation or orally and sometimes paranterally:
• By inhalation the drug is given as an aerosol, and this aerosol is given either by the Ordinary Inhaler or by the Nebulizer.
• With the Nebulizer there is a continuous inspiration of the bronchodilator, which is prepared by being mixed with a fluid and air within a container, and then the mixture is pushed by air through the mouth, so the patient will breathe in this air.
• Another point to remember is that sometimes the use of the Nebulizer in acute attacks is preferable over the ordinary inhaler this is because:
• when the patient is having an attack, it will be very difficult for him to use the ordinary inhaler, as the patient here has to take a very deep inspiration, hold breathing and next force expiration, and this will be very difficult for an asthmatic patient to do, therefore those coming to the hospital with moderate to severe asthmatic attacks, they receive the drug by the Nebulizer rather than the ordinary inhaler.
• Many people don’t know how to use the ordinary inhaler. Originally by ordinary inhaler not all the drug reach the site of action on the bronchi, so by the addition of the wrong use the patient may not get advantage from more than 5% of the drug.

So this is why the Nebulizer is preferred in such condition.

 

 

Paranterally: Salbutamol &Terbutaline can be given intravenously.

Adrenaline and again Terbutaline can be given subcutaneously Infact Terbutalines subcutaneous injection is quite useful because it’s a selective agonist, and at the same time it can be given by aerosol, it's quite useful for outpatients.

<< shows you how the inhaler looks like, (the presence of the spacer has an advantage here, which is that the large particles within the inhaled aerosol instead of going to the mouth and interfering with the small particles which have to reach the bronchial muscles, they (the large particles) will precipitate upon the spacer walls, giving a chance for the small particles to go through their way down to the bronchial tree producing their effect there. So generally speaking: inhaler with spacer is better than inhaler alone, but the Nebulizer is by fare the best one.

 

• Adverse Effects:

They are never 100% selective, so they do affect the heart stimulating β1 receptors, therefore

§  Tachycardia is possible

§  Tremor may also occur by stimulating the receptors in the skeletal muscles

• Even arrhythmia may develop if excessive doses are given particularly following the oral administration
• Tolerance might develop with this type of treatment, and this tolerance can be overcome by the use of corticosteroids.

Theophylline belongs to the Methylxanthines.

• Its one component of the purine derivatives, we have Caffeine (from coffee), Theobromine (from cocoa) and Theophylline (from tea).
• Theophylline is insoluble (actually I am  not sure where its insoluble, the doctor didn’t mention that but I think that because its well absorbed orally its water insoluble), so its usually prepared in a solution called aminophylline, where by the addition of Theophylline 20% of the drug will be dissolved.
• Theophylline is well absorbed from the GI tract and therefore it can be given both orally and rectally. It’s not given intramuscularly as IM injection is very painful.
• It can be given intravenously in severe cases or in severe acute attacks, but here it has to be given very very slowly, since the drug can induce or precipitate cardiac arrhythmia which may be fatal.
• Some pharmacokinetic properties of Theophylline:
• Theophylline has a very narrow therapeutic index (the difference between therapeutic and toxic doses), and this is one of the reasons why we have shifted from using Theophylline into other safer drugs, in addition to the possibility of the previously mentioned cardiac arrhythmia.
• The drug is metabolized in the liver by CYT P450 enzyme system, and is therefore greatly affected by other drugs which may affect the enzyme system, for that reason and because of  its narrow therapeutic index, any concurrent administration of other drugs which either inhibit or stimulate the enzymatic activity of the liver will affect the level of Theophylline, if they are of the stimulant type (like Rifampin and smoking), elimination of the drug will be elevated and we will get failure of the treatment, while if they are of the inhibitory type (like: Erythromycin and Ciprofloxacin) the conc. Of the drug will be elevated, increasing the toxic manifestation of Theophylline.
• Mechanism of Action (MOA):
• In fact till now we still don’t know exactly what's the mechanism of action of Theophylline. You can see four or five mechanisms, but none of them is regarded as the exact one.
• First of all, it inhibits the Phosphodiesterase enzyme, elevating the level of the cAMP, so its an alternative pathway increasing cAMP other than activation of Adenylyl Cyclase (as in the case of the β2 agonists).
• But The amount of Theophylline required to inhibit the Phosphodiesterase enzyme is much larger than the dose of the drug which produces bronchodilation; so probably the drug acts through other mechanisms, this is why the MOA of Theophylline is not fully understood.
• Secondly: the drug antagonizes adenosine receptors, and adenosine is known to produce bronchoconstriction, and release histamine.
• Thirdly: the drug also increases the contractility of the diaphragm, which may help in making the process of inspiration and expiration much easier.
• Fourthly: the drug may also have an anti-inflammatory activity against T lymphocytes, and it may also prevent the release of bronchoconstrictors agents from the mast cells.
• Finally: it may stimulate respiration centrally through its stimulant effect on the CNS and the respiratory center as well.
• So these are the possible MOAs of Theophylline, and Again I want to repeat that there is no known definite mechanism of action of Theophylline (which is the 100% exact mechanism), all of these are possible mechanisms of the drug.
• Adverse Effects:
• The adverse effects of the drug are dose related.         
• Regarding the GIT: the drug causes nausea and vomiting, this is when the drug concentration is around its therapeutic level.
• Once the concentration of the drug increases, we will get cardiovascular manifestations like tachycardia and arrhythmia and there will be an effect on the blood vessels as well, peripherally there will be dilation resulting in flushing (the patients face will appear red because of the peripheral blood vessel dilation), whereas centrally there will be vasoconstriction resulting in the reduction of oxygen supply.
• And with a very high dose CNS effect will appear like insomnia (أرق, سهر), anxiety, agitation, convulsion and hyperventilation at a very high dose.

 

3) Cholinergic Antagonists (or Anti Muscarinic Agents):

Cholinergic antagonists:

Since the cholinergic effect is to stimulate the smooth muscles including those of the bronchial tree (producing bronchoconstriction), therefore the anti-cholinergic agents are useful to block this effect.

We all know that Atropine is a universal cholinergic antagonist, so it can be used as one of the drugs in the management of the bronchial asthma, and long time ago we used to use Atropine for this purpose, but because of the diverse adverse reactions of the drug, since it has a generalized systemic effect; we are using nowadays instead of Atropine another anti-cholinergic preparation which is insoluble, not absorbed from the GIT and may be given by inhalation where it will affect the bronchial muscles directly and locally and this preparation is:

• Ipratropium:
• Ipratropium bromide or Ipratropium is the drug which is used as an anti-cholinergic agent for the relief of acute attacks of bronchial asthma.
• The drawbacks or disadvantages that limit the use of this drug are:
• It has a much slower onset of action in comparison to the β2 agonists.
• It has a bitter taste (طعم مر غير مقبول).
• And it's also less effective than the β2 agonists.
• So because of these the drug is not highly recommended for general asthmatic patients as β2 agonists are better to be used in this field, however apart from the previously mentioned drawbacks of the drug, Ipratropium is quite useful to be used for elderly patients particularly those suffering from simultaneous cardiac problems, because here the possibility of tachycardia and cardiac arrhythmia is much less than if we use Theophylline or even the selective β2 agonists.
• So the drug can be used for acute attacks as well as in exercise induced asthma.
• Adverse Effects (different from the above drawbacks):
• bitter taste as well as
•  The possibility of systemic anti-cholinergic effect like urinary retention in elderly patients and acute attacks of glaucoma in patients with increased intraocular pressure.

 

Anti-inflammatory agents:

Always remember that the anti-inflammatory drugs don’t dilate the bronchi, and therefore they can't be used to relieve the attack, actually we call them Controllers

Because they control the attacks and prevent the recurrence. So in order to relieve the attack we have to use the bronchodilators (the Relievers).

 

Steroids:

§ Are potent and very effective or even the most effective anti-inflammatory agents.

§ We have two types of Steroids:

·         The ordinary steroids or systemic steroids like Hydrocortisone, Brednison and Methylbrednisolone and others, which are taken orally, but for patients suffering from bronchial asthma for a very long time we don’t like to expose them to continuous systemic administration of steroids because their adverse reactions are very very many, so what we use in case of bronchial asthma in mild, moderate and severe persistence of the disease is the safer inhalational steroids.

·         Inhalational Steroids: again because by inhalation the drug acts locally without much adverse effects.

·         So we use the inhalational steroids in bronchial asthma rather than systemic ones, except in cases of severe acute asthmatic attacks where Hydrocortisone has to be given intravenously, possibly followed by oral steroid therapy, and then when the condition subsides and the pulmonary function returns back to normal we return back to the use of inhalational steroids.

 

·         Inhalational Steroids are like Beclomethasone, Bendisonide and others. And Beclomethasone is quite commonly used.

·         Inhaled steroids are usually given together with β2 agonists because if you return back to the definition of bronchial asthma we said that it’s a bronchoconstriction along with bronchial inflammation, so always they have to be given side by side, not only that, but there are more functions of steroids when given by this way:

o    First of all: prolonged use of steroids reduces the hypersensitivity or hyperactivity of the airways, and this hypersensitivity can't be managed by the bronchodilators.

o    Secondly: The steroids can restore the effectiveness of the β2 receptors; you remember that when we talked about β2 agonists we said that prolonged use may result in tolerance, meaning reduction in the response, now by the use of steroids β2 receptor activity will be restored, in another word, the patient will respond better to the β2 agonists.

·         Mechanism of Action:

o    we also have multiple mechanisms:

o    Induction of lipocortin which results in the inhibition of Phospholipase A2 enzyme, and you all know the role of this enzyme in arachidonic acid production, and this last is normally directed through Lipoxygenase and Cyclooxygenase pathways for the production of Leukotrienes and Prostaglandins respectively, and these are components of the inflammatory process of bronchial asthma, so all of this will be suppressed by the use of steroids resulting in anti-inflammatory effect.

o    At the same time steroids reduce the recruitment of the inflammatory cells (Eiosinophils, Macrophages, Lymphocytes and so on).

o    They also manage to reduce the cytokines which are also involved in the pathogenesis of the bronchial asthma.

o    And again they increase the responsiveness of the β2 receptors as we have already mentioned.

·         adverse effects

o    With the inhalational steroids are very limited if we compare them with the adverse effects of the prolonged systemic use of steroids.

o    With inhalational steroids we have two possible mild adverse effects:

o    Patients taking steroids by inhalation usually suffer from horsiness of the voice, and this is due to the precipitation of the drug particles on the vocal cords. This horsiness can be overcome by just washing the mouth following the inhalation of the drug.

o    And the other possible adverse reaction is that the patient may develop oral candidiasis (a fungal infection of the oral cavity), and again this can also be avoided by just washing the mouth following inhalation.

 

Cromolyn Sodium:

 

·         It’s another anti-inflammatory agent without bronchodilation effect.

·         It’s very insoluble (again here the doctor didn’t mention where it's insoluble, but because its poorly absorbed I think that its lipid insoluble).

·         Rout of administration: It's also given by inhalation either in the form of powder for adults or as a solution for children.

·         Indications: It's indicated for allergen and exercise induced asthma particularly in children, and it can be given during pregnancy as it is poorly absorbed and almost devoid from adverse effects.

·         We have talked about the drug MOA when we discussed the anti-histamines, and we said that it prevents the release of the bronchoconstricting substances from the mast cells, and therefore in some old books the drug is called mast cell stabilizer, as it stabilizes the mast cells preventing the release of their contents.

·         Adverse Effects:

o    The drug may cause bronchial irritation especially when taken as a fine powder, it may also cause dry cough.

o    and it also has bitter taste like Ipratropium

 

Leukotriene Antagonists:

We all know that Leukotrienes are potent bronchoconstrictors; therefore inhibition of their synthesis or blocking their action will minimize the possibility of developing an attack.

 

Leukotriene antagonists nowadays are not considered as first or second line therapy, they are referred to as an add on therapy , meaning that an asthmatic patient who is under β2 agonist treatment may receive Leukotriene antagonists, but he cant depend on them alone for treatment.

 

Note that all the previously mentioned drugs are additive, meaning that we may combine them together depending on the severity of the disease, so a patient with β2 agonist therapy he may receive Ipratropium as well (of course in addition to steroids), or he may get Cromolyn Sodium or Theophylline and so on, so the idea is that we may combine these drugs depending on the severity of the disease.

We have two main examples of Leukotriene antagonists:

 

Zileuton and Zafirlukast or Montelukast.

·         Zileuton inhibits the synthesis of Leukotrienes by inhibiting the Lipoxygenase enzyme.

·         Zafirlukast and Montelukast block the action of Leukotrienes on their receptors.

·         A very important point related to these drugs is that they are quite useful in aspirin induced asthma:

·         With aspirin there is an inhibition of Cyclooxygenase enzyme, (both Cox-1 & Cox-2 will be inhibited) inhibiting the synthesis of the prostaglandins, so consequently most of the arachidonic acid formed by phospholipase A2 will be shifted toward Leukotriene synthesis via lipoxygenase pathway, so the level of the Leukotrienes will increase and therefore they will precipitate an acute attack in patient who is potentially asthmatic, and therefore the use of the Leukotriene antagonists is quite useful in aspirin induced asthma.

·         Both drugs inhibit the CYT P450 enzyme system, so there is a possible interaction with other drugs.

• Patients with acute severe asthma should receive supplemental oxygen therapy by mask or nasal cannulae titrated to maintain Sao₂ normal for altitude (greater than 95% at sea level). Significant dehydration should be corrected; urine specific gravity may help guide therapy in young children, in whom assessment of hydration status may be difficult.

 

Combination Controller Therapy

o    The 2002 NAEPP guidelines recommend that the combination of inhaled corticosteroids and long-acting inhaled ß₂ agonists is the preferred treatment for step 3 moderate persistent asthma. This combination is superior to doubling the dose of inhaled corticosteroids or adding leukotriene antagonists to inhaled corticosteroids.

o    Advair is a combination product that treats both the inflammatory and bronchoconstrictive components of moderate to severe persistent asthma by delivering a dose of fluticasone (100, 250, or 500 mcg) with a fixed dose of salmeterol (50 mcg). It has a rapid onset (within 1 week), and the salmeterol component may allow reduction in inhaled corticosteroid dosage by 50% in patients with persistent asthma.

Omalizumab

o    Omalizumab (Xolair) is an anti-IgE antibody approved for the treatment of asthma not well controlled by high doses of inhaled corticosteroids. It is only indicated for corticosteroid-dependent atopic patients requiring oral corticosteroids
or receiving high-dose inhaled corticosteroids with continued symptoms and high IgE levels. The dosage is determined by the patient's baseline total serum IgE (IU/mL) and body weight (kg). Doses range from 150 to 375 mg given subcutaneously at either 2- or 4-week intervals.

Methotrexate

o    Methotrexate in low doses (15 mg/wk) has been used to reduce the systemic corticosteroid dose in patients with severe steroid-dependent asthma. It results in a moderate reduction in systemic steroid dosage (approximately 23%) in some patients, but some studies have shown no beneficial effect. Methotrexate should be considered experimental and reserved for severe steroid-dependent asthmatics under the care of specialists, with careful monitoring of hepatic and pulmonary function.

EVALUATION OF THERAPEUTIC OUTCOMES

o    Chronic Asthma

§  Control of asthma is defined as achieving minimal need for rescue short-acting ß₂agonists (ideally none), no acute episodes, no limitation of activity, no emergency care visits, no nocturnal symptoms, normal pulmonary function, minimal or no medication side effects, and satisfaction of the patient and family with care.

§  Monitoring consists of quantitating the use of inhaled short-acting inhaled ß₂agonists, days of limited activity, and number of symptoms (especially nocturnal).

§  In moderate to severe persistent asthma, once-daily (on awakening) peak flow monitoring is recommended. The NAEPP recommends yearly spirometric studies.

§  Patients should also be asked about exercise tolerance and nocturnal symptoms.

§  All patients on inhaled drugs should have their inhalation technique evaluated monthly initially and then every 3 to 6 months.

§  After initiation of anti-inflammatory therapy or an increase in dosage, most patients should begin experiencing a decrease in symptoms within 1 to 2 weeks and achieve maximum symptomatic improvement within 4 to 8 weeks. Improvement in baseline FEV1 or peak expiratory flow (PEF) should follow a similar time frame, but a decrease in BHR as measured by morning PEF, PEF variability, and exercise tolerance may take longer and improve over 1 to 3 months.

o    Acute Severe Asthma

§  Patients at risk for acute severe exacerbations should monitor morning peak flows at home.

§  In young children, increased respiratory rate and heart rate and inability to speak more than one or two words between breaths are signs of severe obstruction.

§  Lung function, either spirometry or peak flows, should be monitored 5 to 10 minutes after each treatment.

§  Oxygen saturation by pulse oximetry and peak flows should be measured in all patients not completely responding to initial intensive inhaled ß₂-agonist therapy.

 

 

 

 

Occupational Asthma

o    This form of asthma is stimulated by fumes (epoxy resins, plastics), organic and chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals.

o    Asthma attacks usually develop after repeated exposure to the inciting antigen(s).

o    Sensitizers are Classified as:

§  Fibrogenic: like silica, asbestos.

§  Non-fibrogenic: Iron, Nickel, any other metal.

o    Criteria for occupational asthma which include the following points:

§  A sensitizing agent should be present in the work place; we have more than 250 sensitizers in the work place, the most important one is HDI, and also we have Chromium Cr, Steel, formaldehyde (mainly in hospitals), natural rubber (in gloves), pesticides, chlorine, wood dusts.

§  The worker will be symptom-less on holidays and weekends.

o    Most important sensitizer is TDI which we call Toluene Di-Isocyanate which we can find in the painting industry, mainly car paintings.

o    Diagnosis:

§  Is it asthma?

·         We look on physical spirometry, metacholine hypersensitivity test, history…

§  Is it occupational asthma?

·         We look at history…

§  What is causing it?

·         Any allergic test that we have.

o    It can occur in 2 forms:

§  With latency.

§  Without latency.

o    With latency

§  Which is of immunological pattern, sometimes takes from months to years to develop until the worker is sensitized, so the worker start using the material but nothing happens at first, but after months to years asthma will happen depending on threshold of pain.

§  So the accumulative dose will be exist until it reaches the threshold of pain then worker will start to have the urticaria and dermatitis and go to the doctor, and tells the doctor that “doctor I’m sure it’s not from this material, I have been using it for years”, but in fact it is. Because the accumulative dose was not enough to trigger the pain until it reaches the threshold then the pain comes.

§  Same thing happens when we have the sensitizing agent, it should reach its threshold to trigger the allergy and this threshold is different from patient to patient.

§  These things are more common in atopics; atopy literally means that we have higher levels of IgE in the blood.

§  No if we classify ourselves into atopics and non-atopics, we will find that atopy is 20-40% in the Jordanian people, most people who have conjunctivitis or runny nose or hay fever or any sort of eczema, those entire if you test their IgE you will find high IgE, you will find atopy, so they are atopics.

§  Now in case of atopy lower concentration of the sensitizer can trigger asthma in the work place.

§  There were studies on platinum industries and they have seen that most atopics develop asthma at platinum industries, so they started examining them and screening them, comparing atopics with non-atopics, and comparing smokers with non-smokers, they conclude that you must have a worker that is not smoker and non-atopic (super worker) in order not to have asthma among your employees, super worker who is not atopic and non-smoker and not exist, but at last they said just control your exposure and don’t care about the workers!!!!!!

o    without latency

§  That when we have a massive exposure, usually this form is due to disasters at the work place, and it doesn’t take time to make asthma with breathlessness, tightness, cough, dyspnea, wheezing…

§  Here we have a case of occupational asthma:

·         Someone who wakes up at night twice daily having breathlessness and cough for 4 years, his history: non-smoker, no childhood asthma, but he works as painter using 2 main components which are HDI (HydroxyDi-Isocyanate) and another.

·         On physical examination he has prolonged expiratory phase

·         Doing spirometry he is within his normal limits, because asthmatic patients are completely normal between attacks.

§  And it’s very difficult to diagnose and show that symptoms of asthma when he is on attack, if we suspect that the worker is sensitized from certain substance in the work place we bring this substance to the lab, and put it in a chamber, and we try to make the same factory environment in this chamber, then we do the lung function test or take a bronchial biopsy after making the patient inhale this substance.

§  We do the spirometry and we start measuring their forced expiratory volume in one second FEV₁, then after 24-48 hours we will see that every thing will get back to normal because now he is away from the substance, away from the work place.

§  On biopsy we will see thickening in the basement membrane and increased total inflammatory cells.

§  Immuno-histo-chemical tests will show increased in T lymphocytes and deposits of HDI on the apical surfaces of airways epithelium.

§  That was in patients without latency, in disasters, what we call that reactive airway dysfunction syndrome, immediate developing asthma.

§  So it’s an asthma like illness, after a single exposure to high concentration of a sensitizer (vapor, fume or smoke), often occurring after work place accidents.

§  What’s the difference between vapor and fume and smoke?

·         Vapor is simply gaseous H₂O.

·         Fume should contain metals, so it’s of metallic component.

·         Smoke when it’s of hydrocarbon component.

§  Certain USA society one day examines 1100 workers for work-related asthmas to find that:

·         70% were new cases of asthma.

·         19% work-aggravated asthma.

·         11% reactive airway dysfunction syndrome, which is occupational without latency.

o    You have to know that occupational asthma does not affect all workers, only some of the workers will be affected, and most of these affected workers are atopics as we said, because atopics are more vulnerable to occupational asthma, because they need less concentration of the sensitizer to cause asthmatic attack, and symptoms will develop in either of the 2 forms, with latency (months to years) or without latency (immediately due to disaster).

o    On weekends and holidays they will be symptom-less, there is something called metacholine hypersensitivity test used to diagnose asthma, and the most difficult among these asthmas is the wheat farmers-asthma or bread workers-asthma, because it doesn’t show any abnormality in any test.

o    Risk factors for developing occupational asthma include:

§  Atopy.

§  Smoking.

§  Long period of exposure (the longer the more dangerous).

o    In epidemiological studies we see that most causes of asthma is exposure to high molecular weight antigens rather than low molecular weight antigens, when we talk about low molecular we talk about metals mainly.

o    An important thing to mention is that reactive airway dysfunction syndrome which is occupational asthma without latency is of unknown mechanism.

o    High Molecular & Low Molecular Antigens

§  As we said we have more than 250 sensitizers classified to high molecular weight antigens and low molecular weight antigens, the high molecular weight antigens are more commonly exist and more common causes and associated with PRIC test, or we can do patch test.

§  The PRIC test is: some place on the dermal skin we make it touch the antigen and then we wait for 20 minutes, and see if there is a reaction so it’s a +ve sensitizer, so there is a high IgE level, and to be more specific we put also –ve control and +ve control, the best +ve control to use is histamine, and the best –ve control to use is normal saline water, to exclude any false –ve or false +ve results.

§  Or we can do Patch test: dermatologists put a patch containing the expected substance for 48-72 hours in according to make absorption of the material of the allergen, the ratio between concentration in PRIC test to the concentration in patch test is 1:1000, so in patch testing we are using 1000 larger dose than what we use in PRIC test, that’s why PRIC test is safer.

§  According to the high molecular weight antigens we can store them, and use them one time after another because they are storable, but low molecular weight antigens are un-storable, so if we want to use them in a test we have to prepare them from the beginning and use them immediately.

o    Peak Flow Method:

§  When we want to diagnose a patient with occupational asthma we use the peak flow method, it’s a device that will measure the output in one second, and it’s small and cheap and easy to use by the worker himself.

§  He do only one fast puff because we only measuring one second, not like the lung function spirometry test that we have to do more than one fast puff to reach the platue, no here in the peak flow one fast puff is enough.

§  And we order the patient to do this puff every 2-4 hours, then we got the results and then we plot them on a curve by ourselves.

§  As a conclusion the diagnosis of occupational asthma becomes easy, we have only to follow the criteria that I told you about and then do any skin test in the lab…

§  There is 2 terms in our concern, specificity and sensitivity, the lower the sensitivity the higher the specificity and vise versa, the higher the sensitivity the lower the specificity.

§  Asthmatic patients need steroids for treatment and you know the side effects of steroids, we don’t want them to take steroids more than necessary, so we control their steroids by this peak flow meter, how?

§  We give the worker 20 mg as a starting dose for asthma, and we ask him to record breathing by the peak flow method, then if he is Ok we drop the dose to 15 mg, and we monitor his peak flow again, if he is Ok we drop the dose to 10 mg and monitor again, if he is Ok so we can drop it to 5 mg, so we want to make sure that the worker is doing Ok with the minimal steroidal dose, and the only method to control this is by doing this peak flow…

§  So we order the patient to make this peak flow at least twice or four times daily:

·         Peak flow will be more after work.

·         Peak flow is higher on weekends and holidays.

·         Peak flow is higher away from work place.

§  In all previous cases if we don’t have occupational asthma the differential diagnosis will be:

·         Non-occupational asthma.

·         Industrial bronchitis.

·         Airway irritation without asthma.

·         Hypersensitivity pneumonitis.

·         Bronchiolitis obletirans.

·         Chromium fever.

·         Fume fever.

§   We do after the classical criteria some skin tests, blood tests which is available for high molecular weight antigens as we said, but the low molecular weight antigens (Al, Br, Ni…) we have to prepare them because they are un-storable due to their un-stability, and the +ve skin or blood test show high IgE but not necessarily airway sensitization.

o    Treatment

§  The most important issue is how we are treating these patients, we use inhaled B-agonists for occasional therapy, inhaled corticosteroids, inhaled Salbutamol, oral B-agonists, oral Theophylline, Theophylline intravenously, but never Theophylline intramuscularly, and this Theophylline by the way has many many problems because it’s difficult to monitor and has very narrow therapeutic index.

§  Sometimes we can change the HDI,TDI to MDI (Meta Di-Isocyanate) because it’s less allergic.

§  Protective equipments should be used at work, and we of course can ask the patient to leave his job but we don’t do this because by this we save only one worker and not the others.