Thematic plan of practical classes

Acute and chronic bronchitis. Etiology and pathogenesis. Clinical pattern, diagnostics. Treatment. Complications. Prognosis. Syndrome of respiratory insufficiency.

Bronchial asthma. Clinical pattern. Diagnostics. Treatment. Complications. Syndrome of air hyperinflation of the lungs. Clinical pattern of bronchial asthma attack. Emergency care. The role of a doctor-dentist in prophylaxis of chronic bronchitis and bronchial asthma

 

 

  Chronic Bronchitis.  Chronic obstructive pulmonary disease (COPD)

 

 

·        

Chronic bronchitis

Chronic bronchitis is defined as the presence of chronic cough and sputum production for at least three months of two consecutive years in the absence of other diseases recognised to cause sputum production. In chronic bronchitis, epidemiologically the bronchial epithelium becomes chronically inflamed with hypertrophy of the mucus glands and an increased number of goblet cells. The cilia are also destroyed and the efficiency of the mucociliary escalator is greatly impaired. Mucus viscosity and mucus production are  increased, leading to difficulty in expectorating. Pooling of the mucus leads to increased susceptibility to infection. Repeated infections and infl ammation over time leads to irreversible structural damage to the walls of the airways  and to scarring, with narrowing and distortion of the smaller peripheral airways.

The vast majority of smokers will eventually fulfll the above epidemiology definition. However, only 20% of this group will develop significant airflow obstruction (i.e. COPD). In the past these individuals have received the label ‘chronic obstructive bronchitis’ as opposed to ‘chronic simple bronchitis’.

 

Ciliated epithelia are found in bronchi. It is the main factor of bronchial clerarnce.

Lung damage and inflammation in the large airways results in chronic bronchitis. Chronic bronchitis is defined in clinical terms as a cough with sputum production on most days for 3 months of a year, for 2 consecutive years. In the airways of the lung, the hallmark of chronic bronchitis is an increased number (hyperplasia) and increased size (hypertrophy) of the goblet cells and mucous glands of the airway. As a result, there is more mucus than usual in the airways, contributing to narrowing of the airways and causing a cough with sputum. Microscopically there is infiltration of the airway walls with inflammatory cells. Inflammation is followed by scarring and remodeling that thickens the walls and also results iarrowing of the airways. As chronic bronchitis progresses, there is squamous metaplasia (an abnormal change in the tissue lining the inside of the airway) and fibrosis (further thickening and scarring of the airway wall). The consequence of these changes is a limitation of airflow.

Patients with advanced COPD that have primarily chronic bronchitis rather than emphysema were commonly referred to as “Blue Bloaters” because of the bluish color of the skin and lips (cyanosis) along with hypoxia and fluid retention seen in them.

 

Inflammed bronchial mucosa. Secretion of purulent sputum in exacerbation of bronchitis

 

Leading syndromes in COPD and bronchial asthma are respiratory insufficiency and pulmonary emphysema

Respiratory insufficiency syndrome

Respiratory failure is inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial carbon dioxide levels is called hypercapnia. The normal reference values are: oxygen PaO₂ greater than 80 mmHg (11 kPa), and carbon dioxide PaCO₂ less than 45 mmHg (6.0 kPa). Classification into type I or type II relates to the absence or presence of hypercapnia respectively.

Respiratory failure is a syndrome in which the respiratory system fails in one or both of its gas exchange functions: oxygenation and carbon dioxide elimination. In practice, it may be classified as either hypoxemic or hypercapnic.

Hypoxemic respiratory failure (type I) is characterized by an arterial oxygen tension (P_a O₂) lower than 60 mm Hg with a normal or low arterial carbon dioxide tension (P_a CO₂). This is the most common form of respiratory failure, and it can be associated with virtually all acute diseases of the lung, which generally involve fluid filling or collapse of alveolar units. Some examples of type I respiratory failure are cardiogenic or noncardiogenic pulmonary edema, pneumonia, and pulmonary hemorrhage.

Hypercapnic respiratory failure (type II) is characterized by a PaCO₂ higher than 50 mm Hg. Hypoxemia is common in patients with hypercapnic respiratory failure who are breathing room air. The pH depends on the level of bicarbonate, which, in turn, is dependent on the duration of hypercapnia. Common etiologies include drug overdose, neuromuscular disease, chest wall abnormalities, and severe airway disorders (eg, asthma and chronic obstructive pulmonary disease [COPD]).

Respiratory failure may be further classified as either acute or chronic. Although acute respiratory failure is characterized by life-threatening derangements in arterial blood gases and acid-base status, the manifestations of chronic respiratory failure are less dramatic and may not be as readily apparent.

Acute hypercapnic respiratory failure develops over minutes to hours; therefore, pH is less than 7.3. Chronic respiratory failure develops over several days or longer, allowing time for renal compensation and an increase in bicarbonate concentration. Therefore, the pH usually is only slightly decreased.

The distinction between acute and chronic hypoxemic respiratory failure cannot readily be made on the basis of arterial blood gases. The clinical markers of chronic hypoxemia, such as polycythemia or cor pulmonale, suggest a long-standing disorder.

Arterial blood gases should be evaluated in all patients who are seriously ill or in whom respiratory failure is suspected. Chest radiography is essential. Echocardiography is not routine but is sometimes useful. Pulmonary functions tests (PFTs) may be helpful. Electrocardiography (ECG) should be performed to assess the possibility of a cardiovascular cause of respiratory failure; it also may detect dysrhythmias resulting from severe hypoxemia or acidosis. Right-heart catheterization is controversial (see Workup).

Hypoxemia is the major immediate threat to organ function. After the patient’s hypoxemia is corrected and the ventilatory and hemodynamic status have stabilized, every attempt should be made to identify and correct the underlying pathophysiologic process that led to respiratory failure in the first place. The specific treatment depends on the etiology of respiratory failure

 

Emphysema

 

                 

 

Emphysema is defined in terms of its pathological features, characterised by abnormal dilatation of the terminal air spaces distal to the terminal bronchioles, with destruction of their wall and loss of lung elasticity  Bullae may develop as a result of overdistention if areas of emphysema are larger than 1 cm in diameter. The distribution of the abnormal air spaces allows for the classifi cation of the two patterns of emphysema: panacinar (panlobular) emphysema, which results in distension, and destruction of the whole of the acinus, particularly the lower half of the lungs.

Centriacinar (centrilobular) emphysema involves damage around the respiratory bronchioles affecting the upper lobes and upper parts of the lower lobes of the lung.

The destructive process of emphysema is predominately associated with cigarette smoking. Cigarette smoke is an irritant and results in low-grade infl ammation of the airways and alveoli. It is known that cigarettes contain over 4000 toxic chemicals, which affect the balance between the antiprotease and proteases within the lungs, causing permanent damage. The inflmmatory cells (macrophages and neutrophils) produce a proteolytic enzyme known as elastases, which destroys elastin, an important component of lung tissue.

Lung damage and inflammation of the air sacs (alveoli) causes emphysema. Emphysema is an enlargement of the air spaces distal to the terminal bronchioles, with destruction of their walls. The destruction of air space walls reduces the surface area available for the exchange of oxygen and carbon dioxide during breathing. It also reduces the elasticity of the lung itself, which results in a loss of support for the airways that are embedded in the lung. These airways are more likely to collapse causing further limitation to airflow.

Emphysematous chest

 

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Chronic obstructive pulmonary disease (COPD), also known as chronic obstructive lung disease (COLD), chronic obstructive airway disease (COAD), chronic airflow limitation (CAL) and chronic obstructive respiratory disease (CORD), is clinically significant, irreversible, generalized airways obstruction associated with varying degrees of chronic bronchitis, abnormalities in small airways, and emphysema. The designation was introduced because chronic bronchitis, small airways abnormalities, and emphysema often coexist and it may be difficult in an individual case to decide which is the major factor producing the airways obstruction. In contrast to asthma, this limitation is poorly reversible and usually gets progressively worse over time.

When it is clear that the patient’s entire disease can be explained by emphysematous changes in the lung, the diagnosis “chronic obstructive emphysema” is preferred to the more general designation COPD. Similarly, the diagnosis “chronic obstructive bronchitis” should be used when the obstructive abnormality is a direct result of an inflammatory process in the airways.

 

Etiology

To avoid the semantic confusion often encountered in discussions of these disorders, the following definitions are provided. Chronic bronchitis, when unqualified, is defined as a condition associated with prolonged exposure to nonspecific bronchial irritants and accompanied by mucus hypersecretion and certain structural alterations in the bronchi. Clinically, it is characterized by chronic productive cough and is usually associated with cigarette smoking. Pulmonary emphysema is defined as enlargement of the air spaces distal to the terminal nonrespiratory bronchioles, accompanied by destructive changes of the alveolar walls. Airways obstruction is defined as increased resistance to air flow during forced expiration. It may result from narrowing or obliteration of the airways secondary to intrinsic bronchial disease or from excessive collapse of airways during forced expiration secondary to pulmonary emphysema.

Some degree of emphysematous change is extremely common in the general population, but not all patients with emphysema have sufficient airways obstructive problems to be considered as having COPD. Similarly, many cigarette smokers have evidence of chronic bronchitis, but only a minority have clinically significant airways obstruction, usually associated with marked changes in the small airways of the lung. As noted, most patients with clinically significant irreversible airways obstruction (COPD) have some combination of chronic bronchitis and emphysema. It is uncertain, however, whether this overlap results from a common causal factor or whether emphysema and chronic bronchitis predispose to one another.

 

 Smoking and COPD

Smoking

The primary risk factor for COPD is chronic tobacco smoking. In the United States, 80 to 90% of cases of COPD are due to smoking. Exposure to cigarette smoke is measured in pack-years, the average number of packages of cigarettes smoked daily multiplied by the number of years of smoking. The likelihood of developing COPD increases with age and cumulative smoke exposure, and almost all lifelong smokers will develop COPD, provided that smoking-related, extrapulmonary diseases (cardiovascular, diabetes, cancer) do not claim their lives beforehand.

Occupational exposures

Intense and prolonged exposure to workplace dusts found in coal mining, gold mining, and the cotton textile industry and chemicals such as cadmium, isocyanates, and fumes from welding have been implicated in the development of airflow obstruction, even ionsmokers. Workers who smoke and are exposed to these particles and gases are even more likely to develop COPD. Intense silica dust exposure causes silicosis, a restrictive lung disease distinct from COPD; however, less intense silica dust exposures have been linked to a COPD-like condition. The effect of occupational pollutants on the lungs appears substantially less important than the effect of cigarette smoking.

Air pollution

Studies in many countries have found people who live in large cities have a higher rate of COPD compared to people who live in rural areas. Urban air pollution may be a contributing factor for COPD, as it is thought to slow the normal growth of the lungs, although the long-term research needed to confirm the link has not been done. Studies of the industrial waste gas and COPD/asthma-aggravating compound, sulfur dioxide, and the inverse relation to the presence of the blue lichen Xanthoria (usually found abundantly in the countryside, but never in towns or cities) have been seen to suggest combustive industrial processes do not aid COPD sufferers. In many developing countries, indoor air pollution from cooking fire smoke (often using biomass fuels such as wood and animal dung) is a common cause of COPD, especially in women.

Genetics

Some factor in addition to heavy smoke exposure is required for a person to develop COPD. This factor is probably a genetic susceptibility. COPD is more common among relatives of COPD patients who smoke than unrelated smokers. The genetic differences that make some peoples’ lungs susceptible to the effects of tobacco smoke are mostly unknown. Alpha 1-antitrypsin deficiency is a genetic condition that is responsible for about 2% of cases of COPD. In this condition, the body does not make enough of a protein, alpha 1-antitrypsin. Alpha 1-antitrypsin protects the lungs from damage caused by protease enzymes, such as elastase and trypsin, that can be released as a result of an inflammatory response to tobacco smoke.

 Autoimmune disease

There is mounting evidence that there may be an autoimmune component to COPD, triggered by lifelong smoking. Many individuals with COPD who have stopped smoking have active inflammation in the lungs. The disease may continue to get worse for many years after stopping smoking due to this ongoing inflammation. This sustained inflammation is thought to be mediated by autoantibodies and autoreactive T cells.

 Acute exacerbations

An acute exacerbation of COPD is a sudden worsening of COPD symptoms (shortness of breath, quantity and color of phlegm) that typically lasts for several days. It may be triggered by an infection with bacteria or viruses or by environmental pollutants. Typically, infections cause 75% or more of the exacerbations; bacteria can be found in roughly 25% of cases, viruses in another 25%, and both viruses and bacteria in another 25%. Pulmonary emboli can also cause exacerbations of COPD. Airway inflammation is increased during the exacerbation, resulting in increased hyperinflation, reduced expiratory air flow and worsening of gas transfer. This can also lead to hypoventilation and eventually hypoxia, insufficient tissue perfusion, and then cell necrosis.

Other risk factors

Bronchial hyperresponsiveness, is a characteristic of asthma and refers to the increased sensitivity of the airways in response to an inhaled constrictor agonist. Many people with COPD also have this tendency. In COPD, the presence of bronchial hyperresponsiveness predicts a worse course of the disease.It is not known if bronchial hyperresponsiveness is a cause or a consequence of COPD. Other risk factors such as repeated lung infection and possibly a diet high in cured meats (possibly due to the preservative sodium nitrite) may be related to the development of COPD.

 

Worldwide, COPD ranked as the sixth leading cause of death in 1990. It is projected to become the fourth leading cause of death worldwide by 2030, due to an increase in smoking rates and demographic changes in many countries. COPD is the third leading cause of death in the U.S. and the economic burden of COPD in the U.S. in 2007 was $42.6 billion in health care costs and lost productivity.

The development of chronic bronchitis, emphysema, and chronic airways obstruction appears to be determined by a balance between individual susceptibility and exposure to provocative agents.

COPD is caused by noxious particles or gas, most commonly from tobacco smoking, which triggers an abnormal inflammatory response in the lung.

 

Pathology

The basic lesion of emphysema apparently results from the effect of proteolytic enzymes on the alveolar wall. Such enzymes can be released from leukocytes participating in an inflammatory process. Thus, any factor leading to a chronic inflammatory reaction at the alveolar level encourages development of emphysematous lesions. Smoking presumably plays a role due to its adverse effects on lung defense mechanisms (particularly by impairing the function of the alveolar macrophage) permitting low-grade inflammatory reactions to develop with consequent recurrent or chronic release of leukocytic proteolytic enzymes. Fortunately, most people caeutralize such enzymes as a result of antiproteolytic activity of the «i-globulin fraction of their sera. In a rare condition known as homozygotic antitrypsin deficiency, however, the serum antiproteolytic activity is markedly diminished. In such patients, emphysema may develop by middle age even in the absence of exposure to substances that interfere with lung defense mechanisms. In the absence of severe deficiency of ai-globulin in the serum, however, the factors which make some cigarette smokers more susceptible to develop­ment of emphysema than others remain uncertain. It is also uncertain why persons with similar degrees of emphysema may have considerably varying degrees of severity of airways obstruction.

With sufficient exposure to bronchial irritants, particularly cigarette smoke, most persons develop some degree of chronic bronchitis. The lesion essential to development of severe airways obstruction is apparently located in the small airways and may be basically different from the ordinary large airways abnormality which leads to hypersecretion of mucus in most smokers. The reason why small airways abnormalities develop in some patients with chronic bronchitis is uncertain, but viral or bacterial pulmonary infections in childhood, an unidentified immunologic mechanism, a mildly impaired ability to inactivate proteolytic enzymes (as in heterozygotic antitrypsin deficiency), or unidentified genetic characteristics could be predisposing factors. While typical allergic bronchial asthma is not a common precursor of COPD, the exact interrelationships of these disorders are not known.

COPD is a major cause of disability and death. In the USA, it is second to heart disease as a cause of disability in Social Security statistics, and reported mortality rates have been doubling about every 5 yr. Its true mortality probably exceeds that from lung cancer. Some of this increase reflects the longer survival of patients who previously would have died of bacterial pneumonia before their COPD became known. Overall, it has been estimated that COPD affects as many as 15% of older men. Symptomatic COPD affects men 8 to 10 times more often than women, presumably as a result of the more frequent, prolonged, and heavier smoking in men; however, the incidence in women is now increasing.

 

        

 

Changes in lungs in COPD

 

In patients with severe emphysema, the lungs are large and pale and often fail to collapse when the thorax is opened. Microscopic examination reveals “departitioning” of the lung due to loss of alveolar walls. Large bullae may be present in advanced disease. Changes may be most marked in the center of the secondary lobule (centrilobular emphysema) or more diffusely scattered throughout the lobule (panacinar emphysema). In all forms, the normal architecture is destroyed; rupture of septa results in air sacs of various sizes. The number of capillaries in the remaining alveolar walls is reduced, and the pulmonary arterial vessels may show sclerotic changes. These abnormalities lead not only to a reduction in the area of alveolar membrane available for gas exchange, but also to the perfusion of non-ventilated areas and to the ventilation of nonperfused parts of the lung; i.e., ventilation/perfusion abnormalities. They also lead to poor support of the airways of the lung, accounting for excessive collapse of airways on expiration.

In chronic bronchitis, the bronchial walls are thickened, there is mucus in the lumen, and the number of goblet cells and mucous glands is increased. There may be purulent secretions and inflammatory changes in bronchial walls and surrounding lung parenchyma if infection is present. Such large airways changes do not account for severe airways obstruction, however, and in patients dying of COPD, narrowing or obliteration, or both, of small airways may be observed.

Right ventricular hypertrophy (cor pulmonale) is common in patients with advanced respiratory insufficiency.

Location of the lungs and airways in the body. The inset image shows a detailed cross-section of the bronchioles and alveoli. Figure B shows lungs damaged by COPD. The inset image shows a detailed cross-section of the damaged bronchioles and alveolar walls.

It is not fully understood how tobacco smoke and other inhaled particles damage the lungs to cause COPD. The most important processes causing lung damage are:

·         Oxidative stress produced by the high concentrations of free radicals in tobacco smoke

·         Cytokine release due to inflammation as the body responds to irritant particles such as tobacco smoke in the airway

·         Tobacco smoke and free radicals impair the activity of antiprotease enzymes such as alpha 1-antitrypsin, allowing protease enzymes to damage the lung

Potential role of coagulation and the complement system in COPD; a complex cascade of blood plasma proteins and platelet activation as molecular perturbations associated with patients suffering from COPD

Narrowing of the airways reduces the airflow rate to and from the air sacs (alveoli) and limits effectiveness of the lungs. In COPD, the greatest reduction in air flow occurs when breathing out (during expiration) because the pressure in the chest tends to compress rather than expand the airways. In theory, air flow could be increased by breathing more forcefully, increasing the pressure in the chest during expiration. In COPD, there is often a limit to how much this can actually increase air flow, a situation known as expiratory flow limitation.

If the rate of airflow is too low, a person with COPD may not be able to completely finish breathing out (expiration) before he or she needs to take another breath. This is particularly common during exercise, when breathing must be faster. A little of the air of the previous breath remains within the lungs when the next breath is started, resulting in an increase in the volume of air in the lungs, a process called dynamic hyperinflation.

Dynamic hyperinflation is closely linked to dyspnea in COPD. It is less comfortable to breathe with hyperinflation because it takes more effort to move the lungs and chest wall when they are already stretched by hyperinflation.

Another factor contributing to shortness of breath in COPD is the loss of the surface area available for the exchange of oxygen and carbon dioxide with emphysema. This reduces the rate of transfer of these gases between the body and the atmosphere and can lead to low oxygen and high carbon dioxide levels in the body. A person with emphysema may have to breathe faster or more deeply to compensate, which can be difficult to do if there is also flow limitation or hyperinflation.

Some people with advanced COPD do manage to breathe fast to compensate, but usually have dyspnea as a result. Others, who may be less short of breath, tolerate low oxygen and high carbon dioxide levels in their bodies, but this can eventually lead to headaches, drowsiness and heart failure.

Advanced COPD can lead to complications beyond the lungs, such as weight loss (cachexia), pulmonary hypertension and right-sided heart failure (cor  pulmonale). Osteoporosis, heart disease, muscle wasting and depression are all more common in people with COPD. 

 

 

Several molecular signatures associated to lung function decline and corollaries of disease severity have been proposed, a majority of which are characterized in easily accessible surrogate tissue, including blood derivatives such as serum and plasma. A recent 2010 clinical study proposes alpha 1B-glycoprotein precursor/A1BG, alpha 2-antiplasmin, apolipoprotein A-IV precursor/APOA4, and complement component 3 precursor, among other coagulation and complement system proteins as corollaries of lung function decline, although ambiguity between cause and effect is unresolved.

COPD is thought to begin early in life, though significant symptoms and disability usually do not occur until middle age. Mild ventilatory abnormalities may be discernible long before the onset of significant clinical symptoms. A mild “smoker’s cough” is often present many years before onset of exertional dyspnea.

Gradually progressive exertional dyspnea is the most common presenting complaint. Patients may date the onset of dyspnea to an acute respiratory illness, but the acute infection may only unmask a preexisting subclinical chronic respiratory disorder. Cough, wheezing, recurrent respiratory infections, or, occasionally, weakness, weight loss, or lack of libido may also be initial manifestations. Rarely, initial complaints are related to congestive heart failure secondary to cor pulmonale, patients with such complaints apparently ignoring their cough and dyspnea prior to the onset of dependent edema and severe cyanosis.

Cough and sputum production are extremely variable. The patient may admit only to “clearing his chest” on awakening in the morning or after smoking the first cigarette of the day. Other patients may have severe disabling cough. Sputum varies from a few ml of clear viscid mucus to large bronchiectasis-like quantities of purulent material.

Wheezing also varies in character and intensity. Asthma-like episodes may occur with acute infections. A mild chronic wheeze that is most obvious on reclining may be noted. Many patients deny having any wheeze.

The physical findings in COPD are notoriously variable, especially in early cases. A consistent abnormality is obstruction to expiratory air flow manifested by a slowing of forced expiration. To demonstrate this, the patient is asked to take a deep breath and then empty his lungs as quickly and completely as possible. Forced expiration is normally virtually complete in < 4 seconds. This test, which should be part of every routine physical examination, may be abnormal even though the patient does not complain of dyspnea.

 

Other findings, including bronchi, diminished vesicular breath sounds, tachycardia, distant heart tones, and decreased diaphragmatic motion, are not consistently present. The typical findings of gross pulmonary hyperinflation, prolonged expiration during quiet breathing, depressed diaphragm, pursed-lip breathing, stooped posture, calloused elbows from repeated assumption of the “tripod position,” and marked use of accessory muscles of respiration are seen only in later stages of COPD. A barrel-chested appearance is an unreliable finding since it is ofteoted in elderly patients without significant respiratory problems. Late in the disease, there may be frank cyanosis from hypoxemia, a plethoric appearance associated with secondary erythrocytosis, and, in patients with severe cor pulmonale, signs of congestive heart failure. Mild, chronic, dependent edema is quite common and does not necessarily indicate heart failure. It may result from prolonged sitting, elevated intrathoracic pressures, and renal retention of salt secondary to blood gas abnormalities even in the absence of cor pulmonale.

X-ray findings are also variable. In early stages of the disease, the x-ray is ofteormal. Changes indicative of hyperinflation (e.g , depressed diaphragm, generalized radiolucency of the lung fields, increased retrosternal air space, and tenting of the diaphragm at the insertions to the ribs) are common and suggestive of emphysematous disease, but are not diagnostic. They may also be found in pa dents with asthma and occasionally m healthy persons Localized radioluceno with attenuation of vascular markings is a more reliable indicator of emphysema.

Symptoms and Signs

 

 

X-ray in chronic bronchitis shows pneumofibrosis (pointed lung pattern)

 

These radiographs of a patient with chronic obstructive pulmonary disease (COPD) reveal pulmonary hyperinflation.

In the PA projection above the diaphragms are at the level of the eleventh posterior ribs and appear flat.

The lateral radiograph below demonstrates the prominence of the anterior clear-space and of the AP diameter of the chest as well as the flat diaphragms.

 

 

Bullae are seen occasionally with COPD. Large bullae are generally well seen on ordinary x-rays, but small ones are more reliably detected with planograms. They may occur as part of a diffuse emphysematous process or as isolated phenomena and thus do not necessarily indicate a generalized lung disease.

Bronchitis itself does not have a characteristic appearance on ordinary chest x-ray, but bronchograms may reveal cylindrical dilation of bronchi on inspiration bronchial collapse on forced expiration, and enlarged mucous ducts Prank: saccular bronchiectasis is unusual and generally occurs only in patients who have had a previous severe respiratory infection.

In patients with recurrent chest infections, a variety of nondescript postinflammatory abnormalities may be noted, such as localized fibrotic changes, hone combing, or contraction atelectasis of a segment or lobe.

Spirometric testing reveals characteristic obstruction to expiratory air flow with slowing of forced expiration as manifested by a reduced 1-second forced expiratory volume (FEV1) and a low maximum mid-expiratory flow. Slowing of forced expiration is also evident on flow-volume curves. The vital capacity (VC) and forced vital capacity (FVC) are somewhat impaired in patients with severe disease but are better maintained than the measures of the speed of expiration. For this reason, the FEV1/VC and FEV1/FVC ratios are regularly reduced to < 60% with clinically significant COPD. This degree of abnormality should persist despite prolonged, maximal therapy before a diagnosis of COPD is considered confirmed

Maldistribution of ventilation and perfusion occurs in COPD and is manifested m several ways. An excessive physiologic dead space ventilation indicates that there are areas of the lung in which ventilation is high relative to blood flow (a high ventilation/perfusion ratio), resulting in “wasted” ventilation. Physiologic shunting indicates the presence of alveoli with reduced ventilation in relation to blood flow (a low ventilation/perfusion ratio) which allows some of the pulmonary blood flow to reach the left heart without becoming fully oxygenated, resulting in hypoxemia. In late stages of the disease, overall alveolar underventilation with hypercapnia occurs, aggravating any hypoxemia present due to physiologic shunting. Chronic hypercapnia is usually well compensated, and pH levels are close to normal.

The pattern of physiologic abnormality in an individual case depends to some extent on the relative severity of intrinsic bronchial disease and anatomic emphysema. Diffusing capacity is regularly reduced in patients with severe anatomic emphysema, but is more variable in patients with airways obstruction associated with predominant intrinsic bronchial disease. In patients with severe emphysema. resting hypoxemia is usually mild and hypercapnia does not occur until terminal stages of the illness. In these patients, cardiac output may be quite low, but frank pulmonary hypertension and cor pulmonale are usually late developments. In patients with airways obstruction associated primarily with an intrinsic bronchial disorder, severe hypoxemia and hypercapnia may be noted relatively early. Such patients usually have a well-maintained cardiac output and tend to develop severe pulmonary hypertension with chronic cor pulmonale. The residual volume (RV) and total lung capacity (TLC) are markedly elevated in emphysematous patients, while pulmonary hyperinflation may be relatively slight in bronchitic COPD, but the ratio of RV to TLC tends to be elevated in both types of disease.

Detailed lung function measurements help to determine the severity of emphysema and intrinsic bronchial disease in an individual case, but are rarely needed for ordinary clinical evaluation. With severe emphysema, pressure-volume curves show a characteristic loss of recoil and increased compliance. Airways resistance measurements made in the body plethysmograph tend to reflect the severity of intrinsic bronchial narrowing.

In a few cases with severe emphysema but little bronchitis or with severe obstructive bronchitis but little, if any, emphysema, it is possible to distinguish emphysematous type (Type A) disease from bronchial type (Type B) disease on the basis of clinical and physiologic findings. Unfortunately, most patients appear to have a “mixed” syndrome.

Specific parenchymal lung diseases which may lead to airways obstruction can usually be excluded by chest x-ray. Upper airway lesions (generally associated with stridor) and localized bronchial obstructions (often associated with a localized wheeze) must also be excluded. It is particularly important to exclude primary cardiac disease with congestive failure as a cause of the patient’s respiratory insufficiency. A normal or small cardiac silhouette on chest x-ray is characteristic of COPD prior to development of frank cor pulmonale, but is most unusual in patients who are dyspneic as a result of a cardiac disorder.

Homozygotic antitrypsin deficiency should be suspected when there is a family history of obstructive airways disease, or when emphysema occurs in a woman, a relatively young man, or a nonsmoker. The diagnosis may be confirmed by measuring serum antitrypsin levels or by specific phenotyping.

 

 

 

	Wheezing Menu 0:00 The sound of wheezing as heard with a stethoscope.

 

Pulseoxymetry

A chest X-ray demonstrating severe COPD. Note the small size of the heart in comparison to the lungs.

 

The diagnosis of COPD should be considered in anyone who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease such as regular tobacco smoking. No single symptom or sign can adequately confirm or exclude the diagnosis of COPD, although COPD is uncommon under the age of 40 years.

 

Spirometry

 

The diagnosis of COPD is confirmed by spirometry, a test that measures the forced expiratory volume in one second (FEV1), which is the greatest volume of air that can be breathed out in the first second of a large breath. Spirometry also measures the forced vital capacity (FVC), which is the greatest volume of air that can be breathed out in a whole large breath. Normally, at least 70% of the FVC comes out in the first second (i.e. the FEV1/FVC ratio is >70%). A ratio less thaormal defines the patient as having COPD. More specifically, the diagnosis of COPD is made when the FEV1/FVC ratio is <70%. The GOLD criteria (Global Initiative for Chronic Obstructive Lung Disease) also require that values are after bronchodilator medication has been given to make the diagnosis, and the NICE criteria also require FEV1%. According to the ERS criteria, it is FEV1% predicted that defines when a patient has COPD, that is, when FEV1% predicted is < 88% for men, or < 89% for women.

Spirometry can help to determine the severity of COPD. The FEV1 (measured after bronchodilator medication) is expressed as a percentage of a predicted “normal” value based on a person’s age, gender, height and weight:

 

 

Severity of COPD (GOLD scale)	FEV1 % predicted
Mild (GOLD 1)	≥80
Moderate (GOLD 2)	50-79
Severe (GOLD 3)	30-49
Very severe (GOLD 4)	<30 or chronic respiratory failure symptoms

 

The severity of COPD also depends on the severity of dyspnea and exercise limitation. These and other factors can be combined with spirometry results to obtain a COPD severity score that takes multiple dimensions of the disease into account.

Other tests

On chest x-ray, the classic signs of COPD are overexpanded lung (hyperinflation), a flattened diaphragm, increased retrosternal airspace, and bullae.It can be useful to help exclude other lung diseases, such as pneumonia, pulmonary edema or a pneumothorax. Complete pulmonary function tests with measurements of lung volumes and gas transfer may also show hyperinflation and can discriminate between COPD with emphysema and COPD without emphysema. A high-resolution computed tomography scan of the chest may show the distribution of emphysema throughout the lungs and can also be useful to exclude other lung diseases.

A blood sample taken from an artery, i.e. Arterial Blood Gas (ABG), can be tested for blood gas levels which may show low oxygen (hypoxaemia) and/or high carbon dioxide (respiratory acidosis if pH is also decreased). A blood sample taken from a vein may show a high blood count (reactive polycythemia), a reaction to long-term hypoxemia.

Diagnosis

Diagnosis of COPD should be considered in any patient who has the following:

• symptoms of cough

• sputum production or

• dyspnoea or

• history of exposure to risk factors for the disease.

The diagnosis requires spirometry; post-bronchodilator FEV1/forced vital capacity <0.7 confirms the presence of airflow limitation that is not fully reversible.

 

Spirometric classification

Spirometric classification has proved useful in predicting health status, utilisation of healthcare resources, development of exacerbation  and mortality in COPD. It is intended to be applicable to populations and not to substitute clinical judgment in the evaluation of the severity of disease in individual patients.

Assessment of severity: staging

It is accepted that a single measurement of FEV1 incompletely represents the complex clinical consequences of COPD because: 1) many patients are practically asymptomatic; 2) persistant cough and sputum production often precede the development of airflow limitation and, in others, the first symptom may be the development of dyspnoea with previously tolerated activities; and 3) in the clinical course of the disease, systemic consequences, such as weight loss, and peripheral muscle wasting and dysfunction, may develop. Due to these and other factors, a staging system that could offer a composite picture of disease severity is highly desirable, although it is currently unavailable. However, spirometric classification is useful in predicting outcomes such as health status and mortality, and should be evaluated. In addition to the FEV1, the BMI and dyspnoea have proved useful in predicting outcomes such as survival and this document recommends that they be evaluated in all patients.BMI is easily obtained by dividing the weight (in kg) over the height (in m2).

Values <21 kg•m-2 are associated with increased mortality.

Functional dyspnoea can be assessed by the Medical Research Council dyspnoea scale.

0 not troubled with breathlessness except with strenuous exercise.

1 troubled by shortness of breath when hurrying or walking up a slight hill.

2 walks slower than people of the same age due to breathlessness or has to stop for breath when walking at own pace on the level.

3 stops for breath after walking ~100 m or after a few minutes on the level.

4 too breathless to leave the house or breathless when dressing or undressing.

 

Course and Prognosis

Some reversal of airways obstruction and considerable symptomatic improve¬ment can often be obtained initially, but the long-term prognosis is less favorable in patients with persistent obstructive abnormality. After initial improvement, the FEV1 generally falls 50 to 75 ml/yr, which is 2 to 3 times the rate of decline expected from aging alone. There is a concomitant slow progression of exertional dyspnea and disability. The course is punctuated by acute symptomatic exacerbations, generally related to superimposed bronchial infections.

Prognosis is closely related to the severity of expiratory slowing. When the FEV1 exceeds 1.25 L, the 10-yr survival rate is about 50%; when the FEV, is 1 L, the average patient survives about 5 yr; when there is very severe expiratory slowing (FEV1 about 0.5 L), survival for > 2 yr is unusual, particularly if the patient also has chronic hypercapnia or demonstrable cor pulmonale.

 

Treatment

Important management strategies are smoking cessation, vaccinations, rehabilitation, and drug therapy (often using inhalers). Some patients go on to require long-term oxygen therapy or lung transplantation.

Therapy does not result in cure, but provides symptomatic relief and controls potentially fatal exacerbations. It may also slow progression of the disorder, though this is unproved. Treatment is directed at alleviating conditions which cause symptoms and excessive disability (e.g., infection, bronchospasm, bronchial hypersecretion, hypoxemia, and unnecessary limitation of physical activity).

Infection: An attempt should be made to clear purulent sputum with a broad-spectrum antibiotic, the course repeated promptly at the first sign of recurrent bronchial infection or sputum purulence. Ampicillin or cephalothin may be used to treat severe exacerbations Regular courses of a broad-spectrum antibiotic are indicated in patients with frequent infectious exacerbations.

Bronchospasm:

Corticosteroids have a very limited role in treating COPD, but a trial of these agents may be required to prove conclusively that the airways obstruction is not a result of potentially reversible bronchospasm. This is especially true when there is a past history suggesting asthma, eosinophilia, fluctuations in the severity of airways obstruction, or a good immediate response to inhalation of a bronchodilator. If a corticosteroid trial (e.g., prednisone 30 to 40 mg every morning for 3 wk) is undertaken, its usefulness should be documented by objective improvement w spirometric tests before long-term corticosteroid therapy is recommended, al which time the lowest maintenance dose which sustains improvement is used. In some patients, alternate-day therapy can be used for maintenance.

Bronchial secretions: Adequate systemic hydration is essential to prevent 10-spissation of secretions. In some patients bronchial hygiene may also be improved by inhalation of mist, postural drainage, and chest physical therapy, particularly following bronchodilator inhalation. Saturated solution of potassium iodide 10 drops in H20 t.i.d. is used by some physicians in an attempt to thin bronchial secretions. Despite their wide use, IPPB machines have not been shown to improve the patient’s ability to raise secretions or to affect favorably the overall condition of ambulatory patients with COPD.

Hypoxemia: Severe chronic hypoxemia, often associated with hypercapnia, accentuates pulmonary hypertension and leads to development of cor pulmonale in patients with COPD. Recurrent cardiac failure may develop and necessitate long-term 02 therapy. Low flow (1 to 2 L/min) 02 therapy via nasal prongs for 15 h or more/day (including sleeping hours) may be effective in reversing pulmonary hy¬pertension and improving cardiac status. Around-the-clock 02 supplementation has been shown to be preferable for patients with severe chronic hypoxemia (arterial O2 tensions consistently < 55 mm Hg at rest) and appears to prolong survival. When instituting long-term O2 therapy, it is important to monitor the blood gas responses. No more O2 should be given than is needed to raise the arterial 02 tension to 55 mm Hg. One should also be sure that chronic 02 therapy does not lead to a progressive rise in C02 tension as a consequence of removing hypoxic ventilatory drive; in fact, this has rarely proved to be an important problem.

Even in patients without severe cor pulmonale, O2 may be needed to correct severe exertional hypoxemia when the patient is started on a graded exercise program. Use of 02 for symptomatic relief of dyspnea without verification of severe hypoxemia, however, is unjustified and potentially dangerous.

Hypercapnia: Patients with rapidly developing or worsening hypercapnia require immediate hospitalization and intensive therapy, but chronic well-compen¬sated hypercapnia is generally well tolerated and requires no specific therapy.

Heart failure: The most important measure for controlling heart failure second¬ary to cor pulmonale is correction of excessive hypoxemia. Diuretic therapy and controlled sodium intake are important adjuncts. Digitalis must be used cautiously, if at all, since digitalis intoxication readily occurs in patients with COPD, probably as a result of fluctuating blood gas and electrolyte abnormalities.

Exercise tolerance: Prolonged inactivity leads to excessive disability in patients with COPD. As long as there is no severe cardiac disease, it is important to maintain a regular exercise program. This can usually be prescribed directly by the physician. If the patient is severely disabled, however, the program may be more effective if supervised by a trained physical therapist. The exercise program should have a specific meaningful goal (e.g., walking to the store, golfing) and should train those muscles needed for this specific activity. Breathing “exercises” (breathing training) may have a place in treating anxious patients who develop an excessively rapid ventilatory rate during exertion, but such exercises have not been shown to improve ventilatory capacity.

Depression: Periods of severe depression or marked anxiety are frequent in patients with COPD. A vigorous therapeutic program and an enthusiastic physician are most helpful. A nihilistic attitude toward management of this disease is inexcusable. The patient must understand the nature of the disease and the goals and expectations of therapy.

Exacerbations: Treat promptly; e.g., if sputum becomes purulent, prescribe a course of broad-spectrum antibiotics and a more intensive program of bronchodilation and bronchial hygiene (see above). Patients with increasing hypoxemia or hypercapnia should be hospitalized promptly for intensive therapy. Sedatives and hypnotics should always be avoided in patients with COPD, particularly during exacerbations, since they increase the risk of acute ventilatory failure.

 

Management

There is currently no cure for COPD; however, COPD is both preventable and treatable.Clinical practice guidelines for the management of COPD are available from the Global Initiative for Chronic Obstructive Lung Disease (GOLD), a collaboration that includes the World Health Organization and the U.S. National Heart, Lung, and Blood Institute. The major current directions of COPD management are to assess and monitor the disease, reduce the risk factors, manage stable COPD, prevent and treat acute exacerbations and manage comorbidity.

The only measures that have been shown to reduce mortality is smoking cessation and supplemental oxygen.

Bronchodilators

 

Bronchodilators are medicines that relax smooth muscle around the airways, increasing the calibre of the airways and improving air flow. They can reduce the symptoms of shortness of breath, wheeze and exercise limitation, resulting in an improved quality of life for people with COPD. They do not slow down the rate of progression of the underlying disease. Bronchodilators are usually administered with an inhaler or via a nebulizer.

There are two major types of bronchodilator, β2 agonists and anticholinergics. Anticholinergics appear superior to β2 agonists in COPD. Anticholinergics reduce respiratory deaths while β2 agonists have no effect on respiratory deaths. Each type may be either long-acting (with an effect lasting 12 hours or more) or short-acting (with a rapid onset of effect that does not last as long).

 Β2 AGONISTS

β2 agonists stimulate β2 receptors on airway smooth muscles, causing them to relax. There are several β2 agonists available. Salbutamol(common brand name: Ventolin) and terbutaline are widely used short acting β2 agonists and provide rapid relief of COPD symptoms. Long acting β2 agonists (LABAs) such as salmeterol and formoterol are used as maintenance therapy and lead to improved airflow, exercise capacity, and quality of life.

 ANTICHOLINERGICS

Anticholinergic drugs cause airway smooth muscles to relax by blocking stimulation from cholinergic nerves. Ipratropium provides short-acting rapid relief of COPD symptoms. Tiotropium is a long-acting anticholinergic whose regular use is associated with improvements in airflow, exercise capacity, and quality of life. Ipratropium is associated with increased cardiovascularmorbidity.

While tiotropium in pill form reduces the risk of all cause mortality, cardiovascular mortality and cardiovascular events hat in mist form increases mortality.

 Corticosteroids

Corticosteroids are used in tablet or inhaled form to treat and prevent acute exacerbations of COPD. Well-inhaled corticosteroids (ICS) have not shown benefit for people with mild COPD, however, they have been shown to decrease acute exacerbations in those with either moderate or severe COPD.They however have no effect on overall one-year mortality and are associated with increased rates of pneumonia.

 Other medication

Antibiotics specifically macrolides such as azithromycin reduce the number of exacerbations in those who have two or more a year.

Theophylline is a bronchodilator and phosphodiesterase inhibitor that in high doses can reduce symptoms for some people who have COPD. More often, side effects such as nausea and stimulation of the heart limit its use.

Prevention

Annual influenza vaccinations and pneumococcal vaccinations may be beneficial.

 Smoking cessation

Smoking cessation is one of the most important factors in slowing down the progression of COPD. Once COPD has been diagnosed, stopping smoking slows down the rate of progression of the disease. Even at a late stage of the disease, it can significantly reduce the rate of deterioration in lung function and delay the onset of disability and death. It is the only standard intervention that can improve the rate of progression of COPD.

Smoking cessation starts with an individual decision to stop smoking that leads to an attempt at quitting. Often several attempts are required before long-term smoking cessation is achieved. Some smokers can achieve long-term smoking cessation through “willpower” alone. However, smoking is highly addictive, and many smokers need further support to quit. The chance of successfully stopping smoking can be greatly improved through social support, engagement in a smoking cessation programme and the use of drugs such as nicotine replacement therapy, bupropion and varenicline.

 Occupational health

Measures can be taken to reduce the likelihood that workers in at-risk industries—such as coal mining, construction and stonemasonry-will develop COPD. Examples of these measures include: education of workers and management about the risks, promoting smoking cessation, surveillance of workers for early signs of COPD, use of personal dust monitors, use of respirators, and dust control. Dust control can be achieved by improving ventilation, using water sprays and by using mining techniques that minimize dust generation. If a worker develops COPD, further lung damage can be reduced by avoiding ongoing dust exposure, for example by changing the work role. Air pollution

Air quality can be improved by pollution reduction efforts, which should lead to health gains for people with COPD. A person who has COPD may experience fewer symptoms if they stay indoors on days when air quality is poor. 

Bronchial asthma

Asthma (from the Greek ἅσθμα, ásthma, “panting”) is a common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Common symptoms include wheezing, coughing, chest tightness, and shortness of breath. The prevalence of asthma has increased significantly since the 1970s. Worldwide as of 2011, 235-300 million people were affected with about 250,000 deaths.

Asthma is defi ned as a chronic infl ammatory condition of the airways, leading to widespread, variable airways obstruction that is reversible spontaneously or with treatment (Bellamy and Booker, 2003). In some patients with chronic asthma the disease progresses, leading to irreversible airways obstruction, particularly if the asthma is untreated, either because it has not been diagnosed or mismanaged, or if it is particularly severe. Children with asthma have a one in ten chance of developing irreversible asthma (Rasmussen et al., 2002), while the risk for adult-onset asthmatics is one in four (Ulrik and Lange, 1994). Studies by Agertoft and Pedersen (1994) and Haahtela et al. (1991) demonstrated in both children and adults how asthma might lead to irreversible deterioration in lung function if their asthma was not treated appropriately, particularly with corticosteroid therapy. The airway infl ammation in asthma over time can lead to remodelling of the airways through increased smooth muscle, disruption of the surface epithelium, increased collagen deposition and thickening of the basement membrane (Reed, 1999). This highlights the importance of patients being correctly diagnosed and treated to reduce the risk of long-term chronic obstructive pulmonary disease.

Asthma (from the Greek ἅσθμα, ásthma, “panting”) is a common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Common symptoms include wheezing, coughing, chest tightness, and shortness of breath. The prevalence of asthma has increased significantly since the 1970s. Worldwide as of 2011, 235-300 million people were affected with about 250,000 deaths.

Asthma is defi ned as a chronic infl ammatory condition of the airways, leading to widespread, variable airways obstruction that is reversible spontaneously or with treatment (Bellamy and Booker, 2003). In some patients with chronic asthma the disease progresses, leading to irreversible airways obstruction, particularly if the asthma is untreated, either because it has not been diagnosed or mismanaged, or if it is particularly severe. Children with asthma have a one in ten chance of developing irreversible asthma (Rasmussen et al., 2002), while the risk for adult-onset asthmatics is one in four (Ulrik and Lange, 1994). Studies by Agertoft and Pedersen (1994) and Haahtela et al. (1991) demonstrated in both children and adults how asthma might lead to irreversible deterioration in lung function if their asthma was not treated appropriately, particularly with corticosteroid therapy. The airway infl ammation in asthma over time can lead to remodelling of the airways through increased smooth muscle, disruption of the surface epithelium, increased collagen deposition and thickening of the basement membrane (Reed, 1999). This highlights the importance of patients being correctly diagnosed and treated to reduce the risk of long-term chronic obstructive pulmonary disease.Asthma is a bronchial hypersensitivity disorder characterized by reversible airway obstruction, produced by a combination of mucosal edema, constriction of the bronchial musculature, and excessive secretion of viscid mucus, causing mucous plugs.

Atopic, or “extrinsic,” asthma has been thought to result from sensitization of the bronchial mucosa by tissue-specific antibodies. The antibodies produced are specific immunoglobulins of the IgE (type I) class, and the total serum IgE concentration is usually elevated. Exposure to the appropriate allergens by inhala-tion results in an antigen-antibody reaction, that releases vasoactive bronchoconstrictive chemical mediators, causing the characteristic tissue changes (picture 1). More recent work suggests that immunoglobulin G (IgG) may play a role similar to that of IgE in some cases.

Approximately 50% of asthmatics are of the nonatopic (“intrinsic”) type in which the bronchial reaction occurs in response to nonimmunologic stimuli such as infection, irritating inhalants, cold air, exercise, and emotional upset. These patients do not demonstrate elevated IgE antibodies in their serum, and the history does not suggest hypersensitivity to specific allergens, although there may be other immunologic mechanisms that have not yet been demon strated.  Agrowing list of agents encountered in the work place have been shown to cause asthma. Some organic materials such as wood dust act through an immunologic mechanism, whereas certain chemicals and metal dusts apparently cause direct irritation or protein denaturation in low concentrations. Susceptible individuals may be affected by concentrations well below those allowed by US government standards. Occupational asthma should be suspected when symptoms occur repeatedly at work or within several hours there after and improve away from work. Improvement may require several days Beta-adrenergic blocking agents such as propranolol cause intense bronchial constriction in patients with asthma, apparently due to parasympathetic nerve stimulation. Aspirin and nonsteroidal antiinflammatory agents may cause severe asthma in some patients.

As of 2011, 235-300 million people worldwide are affected by asthma, and approximately 250,000 people die per year from the disease. Rates vary between countries with prevalences between 1 and 18%.It is more common indeveloped than developing countries. One thus sees lower rates in Asia, Eastern Europe and Africa. Within developed countries it is more common in those who are economically disadvantage while in contrast in developing countries it is more common in the affluent. The reason for these differences is not well know. Low and middle income countries make up more than 80% of the mortality.

While asthma is twice as common in boys as girls, severe asthma occurs at equal rates. In contrast adult women have a higher rate of asthma than men and it is more common in the young than the old.

Global rates of asthma have increased significantly between the 1960s and 2008 with it being recognized as a major public health problem since the 1970s. Rates of asthma have plateaued in the developed world since the mid 1990s with recent increases primarily in the developing world. Asthma affects approximately 7% of the population of the United States and 5% of people in the United Kingdom. Canada, Australia and New Zealand have rates of about 14-15%.

Development of Asthma. Asthma is thought to be caused by a combination of genetic and environmental factors.

Asthma is caused by a combination of environmental and genetic factors. These factors influence both its severity and how responsive it is to treatment. The interaction between environmental and genetic factors is complex and not fully understood. It is believed that the recent increased rates of asthma are due to a combination of these environmental and epigenetic changes.

Environmental

Many environmental factors have been associated with asthma’s development and exacerbation including: allergens, air pollution, and other environmental chemicals.

There is a relationship between exposure to air pollutants and the development of asthma. Smoking during pregnancy and after delivery is associated with a greater risk of asthma-like symptoms. Low air quality, from traffic pollution or high ozone levels, has been associated with both asthma development and increase asthma severity.

Exposure to indoor volatile organic compounds may be a trigger for asthma; formaldehyde exposure, for example, has a positive association. Also, phthalates in PVC are associated with asthma in children and adults as are high levels of endotoxin exposure.  Asthma is associated with exposure to indoor allergens. Common indoor allergens include: dust mites, cockroaches, animal dander, and mold. Efforts to decrease dust mites have been found to be ineffective. Certain viral respiratory infections may increase the risk of developing asthma when acquired as a young children including: respiratory syncytial virus and rhinovirus. Certain other infections however may decrease the risk.

HYGIENE HYPOTHESIS

The hygiene hypothesis is a theory which attempts to explain the increase rates of asthma worldwide—increased rates of asthma are a direct and unintended result of reduced exposure, during childhood, to non infectious bacteria and viruses in modern societies. It has been proposed that the reduced exposure to bacteria and viruses is due, in part, to increased cleanliness and decreased family size.[Evidence supporting the hygiene hypothesis includes observations of lower rates of asthma seen on farms and in households with pets; however, there are still many uncertainties.

Antibiotic use early in life has been linked to the development of asthma. Also, delivery via caesarean sections is associated with an increased risk (estimated at 20-80%) of asthma—this increased risk is attributed to the lack of healthy bacterial colonization that the newborn would have acquired from passage through the birth canal. There is a link between asthma and the degree of affluence.

Family history is a risk factor for asthma with many different genes being implicated. If one identical twin is affected, the probability of the other having the disease is ~25%. By the end of 2005, 25 genes had been associated with asthma in six or more separate populations including: GSTM1, IL10,CTLA-4, SPINK5, LTC4S, IL4R and ADAM33 among others. Many of these genes are related to the immune system or to modulating inflammation. Even among this list of genes supported by highly replicated studies, results have not been consistent among all populations tested. In 2006 over 100 geneswere associated with asthma in one genetic association study alone; more continue to be found.

Some genetic variants may only cause asthma when they are combined with specific environmental exposures. The genetic trait CD14 single nucleotide polymorphism (SNP) C-159T and exposure to endotoxin (a bacterial product) is an example. Endotoxin exposure can come from several environmental sources including tobacco smoke, dogs, and farms. Risk for asthma, then, is determined by both a persons genotype and the level of endotoxin exposure.

Medical conditions

A triad of atopic eczema, allergic rhinitis, and asthma is called atopy. The strongest risk factor for developing asthma is a history of atopic disease; with asthma occuring at a much greater rate in those who have either eczema or hay fever. Asthma has been associated with the autoimmune disease vasculitis, Churg–Strauss syndrome. Individuals with certain types of urticaria may also experience symptoms of asthma.

There is a correlation between obesity and the risk of asthma with both having increased in recent years. Several factors may be at play including decreased respiratory function due to a buildup of fat and the fact that adipose tissue leads to a pro-inflammatory state.

Beta blocker medications such as propranolol may trigger asthma in those who are susceptible. Cardioselective beta-blockers, however, appear safe in those with mild or moderate disease. Other medications that can cause problems include: ASA, NSAIDs, and angiotensin-converting enzyme inhibitors.

Exacerbation

Some individuals will have stable asthma for weeks or months and then suddenly develop an episode of acute asthma. Different individuals react differently to various factors. Most individuals can develop severe exacerbation from a number of triggering agents.

Home factors that can lead to exacerbation of asthma include dust, animal dander (especially cat and dog hair), cockroach allergens and mold. Perfumes are a common cause of acute attacks in women and children. Both virus and bacterial infections of the upper respiratory tract infection can worsen the disease. Psychological stress may worsen symptoms—it’s thought that stress alters the immune system and thus increases the airway inflammatory response to allergens and irritants

Airway Inflammation

Infectious agents constantly enter the body via the respiratory system. The bronchi have several protective methods against these invaders. These include:

recruitment of inflammatory cells from the bloodstream into the bronchial wall, where they directly attack the invading organisms and secrete inflammatory chemicals that are toxic to the organisms

swelling of the bronchial wall

mucus secretion

constriction of the airway.

The fundamental defect in asthma is that, for reasons that are unclear, these inflammatory actions occur in the bronchi when no serious infection, toxin, or other inhaled threat to the body exists.

Airway inflammation in asthma is:

a direct response of the immune system to a trigger

a cascade of immunologic events that includes inflammatory cells and mediators

an immune-mediated process that leads to inflammatory changes in the airway, including eosinophil recruitment and airway edema.

 

Bronchial hyperreactivity

Hyperreactivity of the airways to several stimuli is a hallmark of clinical asthma, and it appears bronchial hyperreactivity (BHR) is caused by airway inflammation. Studies have shown that the degree of BHR correlates, for instance, with the number of inflammatory cells recovered in BAL fluid from the airways of asthmatic patients.

Clinically, the degree of BHR (measured in research studies by methacholine challenge) has been shown to correlate with general asthma severity, with morning peak expiratory flow rate (PEFR), with the degree of diurnal variation of PEFR, and with the frequency of inhaled beta-agonist use (when taken by patients as needed for symptoms). The degree of BHR appears to decrease when asthma is well controlled with medication. The ultimate result and significance of BHR is the airflow obstruction that occurs when an asthmatic is exposed to a trigger.

Aeroallergens as a risk factor for asthma

There are no reliable tests to detect which infants are at risk of developing allergic disease and asthma. A positive skin-prick test for egg protein, as a marker of specific immunoglobulin (Ig) E antibody, at 6 months of age in a group of high-risk children (i.e., with a family history of atopy) was associated with development of atopic dermatitis, wheezy illness and asthma by age 7 years 8 and was consistent with earlier studies.9–11 In a community study12 of 360 children, the cumulative incidence of newly diagnosed asthma from 6 to 11 years of age was 12%. Bronchial hyperresponsiveness to cold air at age 6 years was associated with a 2.6-fold increase in risk (95% CI 1.25–5.4). However, after adjusting for mild wheezing at age 6 years, which is associated with an increased risk of 7.5-fold (95% CI 3.6–15.0, p < 0.001), and for positive skin-test reaction to inhalant allergens at age 6 years, which is associated with an increased risk of 3.6-fold (95% CI 1.5–9.5, p < 0.01), the response to cold air was no longer a significant predictor. Therefore, hyperresponsiveness to cold air is associated with a subsequent diagnosis of asthma, but depends on the presence of atopy and prior mild wheezing. Earlier studies, as indicated in the 1995 consensus statement, 13 identified exposure to household dust mites and indoor animals, especially cats, as risk factors for asthma. A recent 12-month study of 476 children with asthma, aged 4–9 years, living in inner city communities in the UnitedStates found that 36.8% of the children were allergic to cockroach allergen, 34.9% to dust-mite allergen and 22.7% to cat allergen. Analyses of dust showed that 50.2% of bedrooms contained high concentrations of cockroach allergen, 9.7% contained dust-mite allergen and 12.6% contained cat allergen. Adjusted rates of hospital admission were 0.37 a year for those who were allergic to and exposed to high concentrations of cockroach allergen compared with 0.11 for those allergic to other allergens (p < 0.001) and 2.56 unscheduled medical visits for asthma compared

with 1.43 (p < 0.001). Those allergic to cockroach allergens experienced more days of wheezing, missed school days, night sleep loss and changes in activities than those allergic to dust-mite and cat allergens. This suggests that exposure to high concentrations of allergen in those allergic to a specific allergen is likely to enhance asthma morbidity. In a higher socioeconomic group,15 135 of 1054 adolescents in 2 high schools were identified with asthma; 48 who were symptomatic and responded to histamine challenge and 123 controls were studied. Analysis of total IgE, dust-mite, cat and cockroach sensitization found only allergy to dustmite allergen to be independently associated with asthma (odds ratio [OR] 6.6, p < 0.0001). Dust from 81% of the houses contained more than 2 μg/g of class-I allergen from 2 common species of dust mites, Dermatophagoides pteronissinus (Der P1) and D. farinae (Der F1); 40% contained cat allergens and 17% contained cockroach allergens. Asthma was not associated with race, socioeconomic status, smoking in the home, sensitization to outdoor allergens or indoor allergen concentration. When asthma is prevalent and high concentrations of dust-mite allergen are present, sensitization is the prime risk factor for symptomatic asthma. Nevertheless, the importance of the environment is dependent on the predominant exposures in that environment, which are influenced by cultural and geographic factors. Seasonal changes in indoor allergen levels have been associated with changes in bronchial responsiveness.  In 32 people with asthma, who were allergic to dust mites, the provocative concentration of histamine giving a 20% fall in FEV1 (PC20) increased from 2.05 mg/mL in autumn to 4.51 mg/mL in spring (p < 0.001), indicating a reduction in airway responsiveness. In 11 control subjects, who were allergic but not sensitized to dust mites, there was no significant change (PC20 of 3.44 mg/mL in autumn and 4.52 mg/mL in spring). Increased bronchial responsiveness in autumn was associated with higher levels of Der P1 in floor dust in homes. Most indoor aeroallergens have been measured in terms of the amount per gram of dust, but, as they must be inhaled to have an effect, ambient airborne concentrations are likely to be much more important. In a recent placebo-controlled, double-blind study17 using an allergen exposure chamber, 15 people with asthma, who were allergic to dust mites (as evidenced by both skin tests and conventional bronchial-inhalation challenge) were exposed to 1200 μg of the class-I allergen of a common dust mite and to a placebo. Symptoms, PEF and medication use were assessed before and after challenge: 12 reacted with symptoms and a median decrease in FEV1 of 16.4% when exposed to allergen but not placebo; the other 3 had only minor symptoms during both active and placebo exposure and had no change in lung function. Late-phase reactions occurred in 1 person exposed to allergen, and in 3 given the conventional challenge. No healthy subjects reacted to any challenge. The authors concluded that asthma symptoms in allergic people were elicited by minor amounts of airborne allergen. Another marker of the role of allergy in asthma is its association with acute asthma that is severe enough to require hospital admission. In a retrospective study involving 138 children aged 5–18 years seen consecutively in a specialized clinic,18 admission to hospital was associated with age (OR 0.8), allergy to cockroach (OR 2.2) and cat (OR 2.9). Based on a stepwise, multiple logistic regression analysis, only cat allergen (OR 3.8), age (OR 0.8) and race (OR 3.2) were independent predictors. In a prospective, single-blind, randomized controlled study of house-dust avoidance measures in 23 children aged 5–18 years who had been admitted to hospital with acute severe asthma,19 the 13 children in the experimental group had improved PEF at 3 and 6 months after intervention. The demographics and use of medication were the same in both the experimental and control groups. Improved PEF at 3 months was found in 6 of 7 children sensitized and exposed to dust-mite allergen when allergen concentrations in both bedding and bedroom floors fell. There was no difference in FEV1. During the study, 4 of the children in the experimental group and 2 of the 10 in the control group were readmitted to hospital with episodes provoked by viral respiratory infections. Exposure to high concentrations of outdoor allergens has been associated with provocation of severe acute asthma and asthma deaths in subjects allergic to specific allergens, most clearly Alternaria spores. Neither exposure to lower concentrations of allergeor concomitant exposure to air pollutants has been consistently associated with symptoms.

Respiratory infections

 

Viral respiratory infection is a well known provocative factor for episodes of asthma. As well, specific agents, including respiratory syncytial virus (RSV), adenovirus, mycoplasma and pertussis, can provoke episodes of wheezing illness and, in a few cases, prolonged bronchial hyperresponsiveness. Recent studies using polymerase chain reaction (PCR) have implicated human rhinoviruses (HRV) as important agents in all age groups, and 1 study using this technique suggested a high prevalence of chronic Chlamydia infection in asthmatic children. How viruses or other agents provoke asthma is not clear. There is evidence of increased IgE production during viral infection. A recent study23 using a human B-cell culture system found that HRV-induced, double-stranded RNA activates an antiviral protein kinase that can induce Ig class switching to IgE, suggesting a mechanism for viral provocation of allergy and asthma.

This is consistent with a study of experimental HRV infection in asthmatic adults, which resulted in augmented eosinophilic inflammation (assessed in sputum) and enhanced bronchial responsiveness. In another controlled study of experimental HRV infection in people with allergic rhinitis (but no asthma) and a nonallergic control group, there was a significant increase in bronchial responsiveness to histamine in the allergic group. Rhinovirus infection of cultured human tracheal epithelium, confirmed by PCR, resulted in increased expression (upregulation) of messenger RNA for intercellular adhesion molecule-1 (ICAM-1) mRNA (the major HRV receptor on epithelial cells) and increased secretion of IL-1b, which itself up-regulates ICAM-1. Because ICAM-1 has important eosinophil attractant properties, this may be an important way in which the bronchial airway inflammatory response may be increased by HRV infection in asthma. RSV infection accompanying bronchiolitis is associated with persistent bronchial  hyperresponsiveness in some children, but its role in causing asthma is unclear. Recent animal studies suggest that RSV infection in mice followed by aeroallergen exposure results in pulmonary inflammation with eosinophilic infiltration; in guinea pigs, prior sensitization to allergen followed by infection with RSV results in much more severe mucosal damage.

 

Occupational and irritant-induced asthma

Occupational asthma (OA), defined as asthma induced by exposure to a specific agent in the workplace,32 is the most common occupational lung disease in developed countries. Occupational exposure has been estimated to cause 5%–15% of adult-onset asthma. The prevalence of OA due to agents with high molecular weight is generally < 5%; prevalence due to low molecular weight agents is 5%–10%. In 1 series, reactive airways dysfunction syndrome (RADS) or irritant-induced asthma accounted for 17% of 154 consecutive cases of OA. Many agents can cause OA. Those that cause immunologically mediated OA include a broad spectrum of protein-derived as well as natural and synthetic chemicals used in various workplaces. Extensive lists of causative agents and workplaces have been published and a computerized database is available. These agents can be classified according to whether their pathogenic mechanism is immunologically mediated. An occupational cause should be suspected for all new cases of asthma in adults. A detailed occupational history of past and current exposure to possible causal agents in the workplace, work processes and specific job duties should be obtained. Information can be requested from the work site, including material safety data sheets. Walk-through visits of the workplace may be necessary. Industrial hygiene data and employee health records can also be obtained. Temporal associations are not sufficient to diagnose work-related asthma, and objective tests are necessary to confirm the diagnosis. Workers with asthma symptoms should not be told to leave their job until the diagnosis is proven because part of the diagnostic work-up of OA may involve a trial return to the work site by the worker. Challenge testing with the specific suspected agent has been used to confirm the work relationship. These tests can be falsely negative if a wrong agent is used for testing or if the patient has been away from work for too long. Another method to confirm the work relationship is serial monitoring of PEF for a period at work and a similar period away from work. Computerized peak-flow meters are helpful in overcoming some of the problems of PEF monitoring.  When the results of PEF monitoring suggest OA and specific inhalation challenges in the laboratory are not possible or negative, it is advisable to confirm OA by serial spirometry throughout a work shift. Combining PEF monitoring with serial assessments of nonallergic bronchial responsiveness can provide further objective evidence. Identification of those with OA is important because progressive deterioration and permanent disability may occur if exposure continues after onset of symptoms. Early removal from exposure may be associated with disappearance of symptoms and airway hyperresponsiveness. The ideal treatment is the permanent removal of patients with OA from exposure to the causal agent; some workers who have continued in the same job after diagnosis have died. Any patient with OA who remains in the same job should have respiratory protection and close medical follow-up. Worsening of asthma should lead to immediate removal from exposure. Irritant-induced asthma is caused by single or multiple exposures to high concentrations of an irritant vapour, fume or smoke in previously normal people. The term “reactive airways dysfunction syndrome” or RADS is used when the condition is caused by a single exposure. A patient’s pre-existing asthma may be aggravated by exposure to low levels of irritants, such as fumes, vapours or dust. However, the presence of asthma before being exposed to a sensitizing agent in the workplace does not preclude the development of true OA. People with asthma should not be exposed to concentrations of irritant higher than permissible (the airborne concentration to which nearly all workers may be exposed repeatedly without ill effects), although even this level may not be safe in those with airway hyperresponsiveness. For further information, readers should consult the full text of the Canadian Thoracic Society Guidelines on occupational asthma.

Frequent Chest Infections

Patients with COPD, particularly when severe or end stage, may present with frequent chest infections, especially in the winter. Symptoms of a chest infection consist of increased breathlessness, usually with a productive cough of  yellow or green sputum. Wheeze may be evident in some patients at rest. Patients generally feel unwell, lethargic and have little appetite.

Exercise-induced

Exercise can trigger bronchoconstriction in both people with and without asthma. It occurs in most people with asthma and up to 20% of people without asthma.In athletes it occurs more common in elite athletes with rates varying from 3% for bobsled racer to 50% for cycling and 60% for cross-country skiing. Inhaled beta2-agonists do not appear to improve athletic performance among those without asthma however oral doses may improve endurance and strength.

Occupational

Asthma as a result of (or worsened by) workplace exposures is a commonly reported occupational disease. Many cases however are not reported or recognized as such. It is estimated that 5–25% of asthma cases in adults are work related. A few hundred different agents have been implicated with the most common being: isocyanates, grain and wood dust, colophony, soldering flux, latex, animals, andaldehydes. The employment associated with the highest risk of problems include: those who spray paint, bakers and those who process food, nurses, chemical workers, those who work with animals,welders, hairdressers and timber workers.

Pathology

Obstruction of the lumen of a bronchiole by mucoid exudate, goblet cell metaplasia, and epithelial basement membrane thickening in a person with asthma.

Asthma is the result of chronic inflammation of the airways which subsequently results in increased contractability of the surrounding smooth muscles. This among other factors leads to bouts of narrowing of the airway and the classic symptoms of wheezing. The narrowing is typically reversible with or without treatment. Occasionally the airways themselves change. The typical changes in the airway include an increase in eosinophils and thickening of the lamina reticularis. Chronically airway smooth muscle may increase in size along with an increase in the numbers of mucous glands in the airways. Other cell types involved include: T lymphocytes, macrophages, and neutrophils. There may also be involvement of other components of the immune system including: cytokines, chemokines,histamine, and leukotrienes among others.

Bronchoconstriction

Inhalation of an allergen solution by a patient with allergic asthma causes prompt and significant bronchoconstriction. After this bronchial allergen challenge, there is a rapid decline in forced expiratory volume in 1 second (FEV1) that begins within 15 minutes and generally subsides within the first hour (see figure below). This bronchial manifestation of immediate hypersensitivity has been termed an early asthmatic reaction (EAR), or the early phase response. After this phase resolves (spontaneously or with a beta-agonist, if needed), the FEV1 reaches a level that is at or close to the pre-challenge baseline.

In about 50% of patients, there can be a spontaneous return of bronchoconstriction that occurs several hours after the allergen challenge (and after the EAR has resolved) (see figure above). This late phase response usually occurs 6-24 hours after exposure to the allergen and is termed the late asthmatic response (LAR). This late decline in FEV1 may be less severe than during the EAR but is generally more prolonged, lasting several hours (see figure above).

The EAR results from binding of inhaled allergen to mast cell membrane-bound IgE with subsequent release of mediators (e.g., histamine, leukotrienes, and prostaglandins). Among these mediators, the cysteinyl leukotrienes appear to account for a significant part of the early bronchoconstrictor response.

Inflammatory and Bronchoconstriction Events of the Early Phase of an Acute

The LAR to an allergen is typified not only by a decline in FEV1 but also by the influx of inflammatory cells, most notably eosinophils, and airway edema. The intensity of LAR inflammation correlates with the degree of airflow obstruction that occurs during the LAR. Note that the airflow obstruction of the LAR usually lasts longer, as much as several hours or more.

Inflammatory and Bronchoconstriction Events of the Late Phase of an Acute The LAR often resembles asthma, which is a chronic inflammatory disease. It is possible that repeated or prolonged episodes of LAR may approximate the events in the airways in both chronic allergic and nonallergic asthma.

    

CLINICAL SYMPTOMS

Asthma is characterized by recurrent attacks of dyspnea, cough, and expectoration of tenacious mucoid sputum, and usually wheezing. Symptoms may be mild and may occur only in association with respiratory infection, or they may occur in various degrees of severity to the point of being life-threatening.

Asthma is characterized by recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing. Symptoms are often worse at night and in the early morning or in response to exercise or cold air. Some people with asthma rarely experience symptoms, usually in response to triggers, whereas others may have marked and persistent symptoms.

Associated conditions

A number of other health conditions occur more frequently in those with asthma including: gastro-esophageal reflux disease (GERD), rhinosinusitis, andobstructive sleep apnea. Psychological disorders are also more common.

Classic allergic (atopic) asthma usually begins in childhood and becomes progressively more severe throughout life, although spontaneous remissions may occur in adulthood. Hay fever often accompanies atopic asthma.

The acute attack is characterized by dyspnea usually associated with expiratory wheezing that may be heard without a stethoscope. Cough may be present but is usually not the predominant symptom. There is a small group of patients with asthma in whom paroxysmal cough may be the predominant symptom.

When asthma becomes prolonged, with severe intractable wheezing, it is known as status asthmaticus.

Inquiry

Complaints

             

Common symptoms of asthma include wheezing, chest tightness, dyspnea and cough. The characteristics of these symptoms, which are variable, often paroxysmal and provoked by allergic or nonallergic stimuli such as cold air and irritants, are useful in diagnosis. Nocturnal occurrence is common. Measuring the patient’s response to a therapeutic trial may be helpful in diagnosis. Nonpulmonary symptoms that suggest a  predisposition to allergy—rhinitis, conjunctivitis and eczema—are also common in, but not specific to, asthma patients. In patients with symptoms that are persistent or that do not respond to simple treatment, objective confirmation of variable airflow obstruction is required.

Breathlessness

Breathlessness is the most common and troublesome symptom of COPD. It is subjective and is defi ned as an abnormal awareness of, or diffi culty with, breathing (Bourke and Brewis, 1998). There are various terms used to describe types of breathlessness.

Cough and Sputum Production

In most patients with COPD, a productive cough often precedes the onset of breathlessness. The cough is usually caused by either irritation of the airway nerves due to release of compounds from infl ammatory cells or by the presence of increased sputum production. Usually cough and sputum production in individuals who smoke is reversed once they stop. The cough is usually worse in the morning and is associated with chest tightness, which is usually relieved by expectorating. Sputum in such patients will usually be white and in smokers grey.

However, not all patients with COPD will have a cough and produce sputum routinely, except when they develop an exacerbation of COPD, which may become mucopurulent, yellow or green. Excessive production of sputum (more than an eggcup full) and frequent infective episodes may indicate a diagnosis of bronchiectasis and referral to a respiratory consultant for further investigations should be made.

Any patient with haemoptysis should be referred for a chest X-ray and a consultant’s opinion. Haemoptysis can develop as a result of a number of reasons, such as a pulmonary embolism, tuberculosis, pneumonia, infective bronchitis, left ventricular failure or mitral stenosis

Wheeze

Wheeze is caused by the sound generated by turbulent airfl ow through the airways. It is usually associated with asthma, particularly in patients with  atopy and exposure to a specifi c allergen. In some patients with COPD wheeze may be evident during an exacerbation as a result of bronchial constriction. COPD patients may experience wheeze post exertion or when going out in the cold air or during windy conditions. However, unlike patients with asthma, patients with COPD are rarely disturbed at night with a wheeze.

 

Wheezing MENU 0:00 The sound of wheezing as heard with a stethoscope.

OTHER SYMPTOMS

Chest Pain

Chest pain may be a feature of COPD related to intercostal muscular skeletal strain through coughing or intercostal muscle ischaemia. Other causes such as pleurisy, tumours or ischaemic heart disease should be excluded.

Ankle Oedema

Ankle oedema is often present during an exacerbation, particularly in severe COPD, usually as a result of the development of right-sided heart failure, therwise known as cor pulmonale (explained further in the section ‘Complications of COPD’).

Anorexia

Loss of appetite is relatively common in patients with COPD, particularly during an exacerbation. This is due to increased breathlessness, cough and sputum production, which makes eating diffi cult and requires a great deal of effort. Loss of taste is also often common in these patients as a result of medication, in particular antibiotics and nebuliser therapy.

Weight Loss

Weight loss is a common symptom in patients with advanced or end-stage COPD, particularly those predominantly with emphysema. This is often due to an increase in the number of exacerbations per year and reduction in appetite. However, it is also as a result of a combination of factors, not just reduced calorie intake, but also the increased work of breathing due to their increased breathlessness. Insuffi cient calories are consumed to match the energy demands or metabolic rate required to sustain a steady weight. Other diagnoses such as lung cancer may also need to be investigated, especially if associated with rapid weight loss and other symptoms, such as cough and haemoptysis.

A low body mass index (BMI) and loss of lean muscle mass are common in COPD, especially in patients with emphysema. Weight loss is a poor prognostic sign and a low BMI increases the risk of death from COPD.

Fatigue and Depression

Fatigue is a familiar symptom in patients with a chronic condition, particularly in COPD. In advanced COPD breathlessness is a contributing factor in that the least exertion results in patients struggling to breathe. Various studies have revealed a strong correlation between fatigue, breathlessness and physical activity (Small and Lamb, 1999; Woo, 2000). This eventually leads to frustration, increased dependence and social isolation, which can result in clinical depression.

Disability

All symptoms such as breathlessness, excessive coughing, frequent exacerbations, fatigue and depression can have a huge impact on the patient’s quality of life and daily activities of living, such as washing and dressing, household chores or shopping. These things are taken for granted when fi t and healthy, but for patients with a chronic disease such as COPD, the simplest of tasks can take several hours to complete. The assessment of such disabilities is important to measure in order to determine the impact that the disease has on the patient’s everyday life.

History

Provocative factors in asthma

Aeroallergens

Aeroallergens are ubiquitous, although quantitative and qualitative differences depend on geographic location, climate, degree of urbanization and specific conditions in the home, school and workplace. Almost all adults appear to have T lymphocytes that are sensitized to at least some aeroallergens; thus, development of allergic disease may depend on quantitative differences in T cells.

Several lines of evidence link aeroallergens to asthma:

• A total of 60% of adults and 80% of children with asthma have positive skin-prick tests for environmental allergens, and allergen-bronchial challenge tests are positive only in those with allergen-specific positive skin tests.

• Allergen sensitization is a risk factor for severe, acute asthma, especially if the patient is exposed to high concentrations of the specific allergen.

• In general, severity of symptoms and of bronchial responsiveness correlates with degree of sensitivity to allergens; in some patients, allergy does not play an important role.

• Symptoms, PEF and bronchial responsiveness usually improve when allergens to which the person is sensitized are avoided. Aeroallergens, which are carried on inhalable particles, are proteins that vary in molecular weight from 14 to 78 kilodaltons. Outdoor allergens arise from pollen or mold spores; indoor allergen sources include several species of dust mites, cats, dogs and other mammals, cockroaches and indoor mold spores. The molecular structure and functional properties of common and important indoor allergens, based on the World Health Organization’s nomenclature, have recently been summarized. Recombinant allergens with immunoreactivity comparable to that of the natural allergens are being produced and evaluated for allergen standardization, for diagnostic testing and for immunotherapy with specific epitopes and naked DNA vaccines. Infants are exposed and become sensitized to aeroallergens as well as food allergens in utero.4,5 In people who are genetically predisposed to allergy, antenatal factors, including maternal and, thus, fetal exposure to allergens and materno–placento– fetal immunologic interactions are important in determining whether the predisposition results in allergic disease.

 Exposure to low concentrations of indoor allergens in early childhood is associated with a low incidence of sensitization, but very low concentrations may be sufficient to sensitize children who are predisposed and have a family history of allergy, presumably after intrauterine priming.

Appearance of a patient during attack of asthma

Essentials of Diagnosis:

• Recurrent acute attacks of dyspnea, cough, and mucoid sputum, usually accompanied by wheezing.

• Prolonged expiration with generalized wheezing and musical rales.

• Bronchial obstruction reversible by drugs

Evaluation of asthma severity

There is no agreement about how best to assess overall asthma severity. Assessment of asthma severity before or without treatment usually takes into account 3 factors, including 2 considered in the diagnosis:  symptoms, physiologic indicators of airway disease and asthma morbidity. Thus, some algorithm based on frequency and severity of symptoms (including the need for inhaled β2- agonist rescue therapy), degree of airflow obstruction and indices of morbidity (admissions to hospital, need for intubation, emergency room visits, time away from work or school, etc.) can be used to classify asthma severity (Table 1). Because asthma is controllable, the factors that define its severity before treatment become markers of its control in the treated patient. The amount of anti-inflammatory medication required to control symptoms is often added to the severity algorithm. However, a case has been made that the primary measure of asthma severity in the treated patient should be the minimum anti-inflammatory medication required  to achieve ideal control.

Diagnosis is usually based on the pattern of symptoms, response to therapy over time, and spirometry. It is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. Asthma may also be classified as atopic (extrinsic) or non-atopic (intrinsic).

Laboratory Findings: The sputum is characteristically tenacious and mucoid, containing “plugs” and “spirals.” Eosinophils are seen microscopically. The differential blood count may show eosinophilia. In severe, acute bronchospasm, arterial hypoxemia may be present as a result of disturbed perfusion /ventilation relationships, alveolar hypoventilation, or functional right-to-left shunts.

X-Ray Findings: Chest films usually show no abnormalities. Reversible hyperexpansion may occur in severe paroxysms, or hyperexpansion may persist in long-standing cases. Transient, migratory pulmonary infiltrations may be present. Severe attacks are sometimes complicated by pneumothorax

 

Spirometry

Spirometry is  recommended to aid in diagnosis and management There is currently no precise test for asthma with the diagnosis typically based on the pattern of symptoms and response to therapy over time. A diagnosis of asthma should be suspected if there is a history of: recurrent wheezing, coughing or difficulty breathing and these symptoms occur or worsen due to exercise, viral infections, allergens or air pollution. Spirometry is then used to confirm the diagnosis. In children under the age of six the diagnosis is more difficult as they are too young for spirometry.

. It is the single best test for asthma. If the FEV1 measured by this technique improves more than 12% following administration of a brochodilator such as salbutamol this is supportive of the diagnosis. It however may be normal in those with a history of mild asthma, not currently acting up. Single-breath diffusing capacity can help differentiate asthma from COPD. It is reasonable to perform spirometry every 1 or 2 years to follow how well a person’s asthma is controlled.

 

   

 

Other

The methacholine challenge involves the inhalation of increasing concentrations of a substance that causes airway narrowing in those predisposed. If negative it means that a person does not have asthma; if positive, however, it is not specific for the disease.

Other supportive evidence includes: a ≥20% difference in peak expiratory flow rate on  at least three days in a week for at least two weeks, a ≥20% improvement of peak flow following treatment with either salbutamol, inhaled corticosteroids or prednisone, or a ≥20% decrease in peak flow following exposure to a trigger. Testing peak expiratory flow is more variable than spirometry, however, and thus not recommended for routine diagnosis. It may be useful for daily self-monitoring in those with moderate to severe disease and for checking the effectiveness of new medications. It may also be helpful in guiding treatment in those with acute exacerbations.

      

Skin allergy testing is a method for medical diagnosis of allergies that attempts to provoke a small, controlled, allergic response.

 

A microscopic amount of an allergen is introduced to a patient’s skin by various means:

•      Prick test or scratch test: pricking the skin with a needle or pin containing a small amount of the allergen.

•      Patch test: applying a patch to the skin, where the patch contains the allergen

If an immuno-response is seen in the form of a rash, urticaria (hives), or (worse) anaphylaxis it can be concluded that the patient has a hypersensitivity (or allergy) to that allergen. Further testing can be done to identify the particular allergen.

The “scratch test” as it’s called, is still very commonly used as an allergen test. A similar test involving injecting the allergen is also used, but is not quite as common due to increased likelihood of infection and general ineffectiveness by comparison. There are other methods available to test for allergy.

Some allergies are identified in a few minutes but others may take several days. In all cases where the test is positive, the skin will become raised, red and appear itchy. The results are recorded- larger wheals indicating that the subject is more sensitive to that particular allergen. A negative test does not mean that the subject is not allergic; simply that either the right concentration was not used or the body failed to elicit a response.

Prick test

In the prick (scratch) test, a few drops of the purified allergen are gently pricked on to the skin surface, usually the forearm. This test is usually done in order to identify allergies to pet dander, dust, pollen, foods or dust mites. Intradermal injections are done by injecting a small amount of allergen just beneath the skin surface. The test is done to assess allergies to drugs like penicillin or bee venom.

To ensure that the skin is reacting in the way it is supposed to, all skin allergy tests are also performed with proven allergens like histamine or glycerin. The majority of people do react to histamine and do not react to glycerin. If the skin does not react appropriately to these allergens then it most likely will not react to the other allergens. These results are interpreted as falsely negative.[1]

Patch test

The patch test simply uses a large patch which has different allergens on it. The patch is applied onto the skin, usually on the back. The allergens on the patch include latex, medications, preservatives, hair dyes, fragrances, resins and various metals. When a patch is applied the subject should avoid bathing or exercise for at least 48 hours.

 

Classification

Clinical classification (≥ 12 years old)[
Severity	Symptom frequency	Night time symptoms	%FEV1 of predicted	FEV1Variability	SABA use
Intermittent	≤2/week	≤2/month	≥80%	<20%	≤2 days/week
Mild persistent	>2/week	3–4/month	≥80%	20–30%	>2 days/week
Moderate persistent	Daily	>1/week	60–80%	>30%	daily
Severe persistent	Continuously	Frequent (7×/week)	<60%	>30%	≥twice/day

 

 

While asthma is a well recognized condition, there is not one universal agreed upon definition.[ It is defined by the Global Initiative for Asthma as “a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or in the early morning. These episodes are usually associated with widespread, but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment”.

Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. Asthma may also be classified as atopic (extrinsic) or non-atopic (intrinsic), based on whether symptoms are precipitated by allergens (atopic) or not (non-atopic).[7]While asthma is classified based on severity, at the moment there is no clear method for classifying different subgroups of asthma beyond this system. Finding ways to identify subgroups that respond well to different types of treatments is a current critical goal of asthma research.

Although asthma is a chronic obstructive condition, it is not considered as a part of chronic obstructive pulmonary disease as this term refers specifically to combinations of disease that are irreversible such as bronchiectasis, chronic bronchitis, and emphysema. Unlike these diseases, the airway obstruction in asthma is usually reversible; however, if left untreated, the chronic inflammation from asthma can lead the lungs to become irreversibly obstructed due to airway remodeling. In contrast to emphysema, asthma affects the bronchi, not the alveoli.

Diagnosis and evaluation of asthma in adults

Basic Recommendations

• Objective measurements are needed to confirm the diagnosis of asthma and to assess its severity in all symptomatic patients using:

Spirometry: A 12% (preferably 15%) or greater (at least 180 mL) improvement in FEV1 from the baseline 15 minutes after use of an inhaled short-acting β2-agonist, a 20% (250 mL) improvement after 10–14 days of inhaled glucocorticosteroid or ingested prednisone when symptoms are stable or a 20% (250 mL) or greater “spontaneous variability” is considered significant.

Peak expiratory flow (PEF): When spirometry and methacholine testing are unavailable, variable airflow obstruction (i.e., ideally 20% or greater diurnal variability) can be documented by home-measured PEF , although this method is not as sensitive or reliable as FEV1.

Airway hyperresponsiveness: Measurement of airway responsiveness to methacholine in specialized  pulmonary function laboratories may help to diagnose asthma.

• Appropriate allergy assessment is warranted in patients with asthma  and must be interpreted in light of the patient’s history.

• The primary measure of asthma severity in the treated patient should be the minimum therapy required

to achieve acceptable control Three main features must be considered in the diagnosis of asthma: symptoms, variable airflow obstruction and airway inflammation.  Airway inflammation is not yet readily

tested in routine clinical practice and will not be considered further here. However, skin testing may be an adjunct to diagnosis and is discussed in this section.

Variable airflow obstruction

Objective measurements are needed to confirm the diagnosis of asthma in all patients and to assess its  severity. Objective documentation of variable airflow obstruction can be obtained through measurement of FEV1, PEF or hyperresponsiveness to methacholine inhalation challenge.

Forced expiratory volume in 1 second

Variable airflow obstruction can be illustrated by improvement in FEV1 15 minutes after an inhaled β2-agonist

or after a 7- to 14-day course of inhaled glucocorticosteroid or ingested prednisone. A 12% or greater improvement in FEV1 (i.e., at least 180 mL) from the baseline after administration of a β2-agonist is considered significant (i.e., outside the 95% confidence interval (CI) for repeatability in people without asthma). However, there are no data to confirm that a bronchodilator response outside this 95% CI is indicative of asthma, and some suggest basing diagnosis on a greater than 15% increase in FEV1.

Because there is greater variability in FEV1 over a longer time interval (days or weeks v. minutes), longer-term changes in FEV1, either without any specific therapeutic intervention or after glucocorticosteroids, must be greater than 20% (at least 250 mL). A trial of glucocorticosteroid involves maximizing the patient’s response to a bronchodilator and obtaining a baseline FEV1, then carrying out a follow-up measurement after a 2-week course of prednisone (taken at the rate of 30 to 40 mg/d) to determine significant response.

Peak expiratory flow

Home measurement of PEF may also be used to document variable airflow obstruction. Variable airflow  bstruction is confirmed when the 95% CI of the mean percentage difference between the highest and lowest of 4 PEF values (morning and afternoon, before and after using a bronchodilator) is > 12%. However, some recommend a 20% variability to confirm the diagnosis of asthma. The importance of appropriate technique and the limitations of PEF are discussed further under “Home monitoring.”

 

Airway hyperresponsiveness

In patients with normal airflow while resting, excessive using a methacholine inhalation challenge.8 This test should be done when symptoms are present or have occurred within a few days. Usually the test is available only in specialized centres, which may limit its utility. This test should be made available to primary care  physicians who see most patients with mild asthma and where the measurement of responsiveness is most useful.9 Tests for airway responsiveness may give normal results in patients with glucocorticosteroid-responsive cough due to eosinophilic bronchitis.

Asthma exacerbation

Severity of an acute exacerbation
Near-fatal	High PaCO2 and/or requiring mechanical ventilation
Life threatening (any one of)
	Clinical signs	Measurements
	Altered level of consciousness	Peak flow < 33%
	Exhaustion	Oxygen saturation < 92%
	Arrhythmia	PaO2 < 8 kPa
	Low blood pressure	“Normal” PaCO2
	Cyanosis
	Silent chest
	Poor respiratory effort
Acute severe (any one of)
	Peak flow 33–50%
	Respiratory rate ≥ 25 breaths per minute
	Heart rate ≥ 110 beats per minute
	Unable to complete sentences in one breath
Moderate	Worsening symptoms
	Peak flow 50–80% best or predicted
	No features of acute severe asthma

 

An acute asthma exacerbation is commonly referred to as an asthma attack. The classic symptoms are shortness of breath,wheezing, and chest tightness. While these are the primary symptoms of asthma, some people present primarily withcoughing, and in severe cases, air motion may be significantly impaired such that no wheezing is heard.

Signs which occur during an asthma attack include the use of accessory muscles of respiration (sternocleidomastoid andscalene musclesof the neck), there may be a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest. A blue color of the skin and nails may occur from lack of oxygen.

In a mild exacerbation the peak expiratory flow rate (PEFR) is ≥200 L/min or ≥50% of the predicted best. Moderate is defined as between 80 and 200 L/min or 25% and 50% of the predicted best while severe is defined as ≤ 80 L/min or ≤25% of the predicted best.

Acute severe asthma, previously known as status asthmaticus, is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators and steroids. Half of cases are due to infections with others caused by allergen, air pollution, or insufficient or inappropriate medication use.

Brittle asthma is a kind of asthma distinguishable by recurrent, severe attacks. Type 1 brittle asthma is a disease with wide peak flow variability, despite intense medication. Type 2 brittle asthma is background well- controlled asthma with sudden severe exacerbations.

Differential diagnosis

Many other conditions can cause symptoms similar to those of asthma. In children other upper airway diseases such as allergic rhinitis and sinusitis should be considered as well as other causes of airway obstruction including: foreign body aspiration, tracheal stenosis or laryngotracheomalacia, vascular rings, enlarged lymph nodes or neck masses. In adults, COPD, congestive heart failure, airway masses, as well as drug induced coughing due to ACE inhibitors should be considered. In both populations vocal cord dysfunction may present similarly.[

Chronic obstructive pulmonary disease can coexist with asthma and can occur as a complication of chronic asthma. After the age of 65 most people with obstructive airway disease will have asthma and COPD. In this setting, COPD can be differentiated by increased airway neutrophils, abnormally increased wall thickness, and increased smooth muscle in the bronchi. However, this level of investigation is not performed due to COPD and asthma sharing similar principles of management: corticosteroids, long acting beta agonists, and smoking cessation. It closely resembles asthma in symptoms, is correlated with more exposure to cigarette smoke, an older age, less symptom reversibility after bronchodilator administration, and decreased likelihood of family history of atopy.

Treatment

Medications used to treat asthma are generally divided  into 2 main categories: relievers and controllers. Relievers are best represented by the inhaled short-acting β2-agonists. These quick-acting bronchodilators are used to relieve acute intercurrent asthma symptoms, only on demand and at the minimum required dose and frequency.

Inhaled ipratropium bromide is less effective, but is occasionally used as a reliever medication in patients intolerant of short-acting β2-agonists. Controllers (or preventers) include anti-inflammatory medications, such as inhaled (and oral) glucocorticosteroids, leukotriene-receptor antagonists, and anti-allergic or inhaled nonsteroidal agents, such as cromoglycate and nedocromil. These agents are  generally taken regularly to control asthma and prevent exacerbations. Inhaled glucocorticosteroids are the most effective agents in this category.

The controller group also includes some bronchodilators that are taken regularly in addition to inhaled glucocorticosteroids to help achieve and maintain asthma control.

These include the long-acting inhaled β2-agonists salmeterol and formoterol, which are the first choice in this category, as well as theophylline and ipratropium. The β2-agonists and ipratropium are considered of no significant benefit in reducing airway inflammation.

There is some evidence that theophylline may have immunomodulatory effects.

Asthma medications should be used at the minimum dose and frequency required to maintain acceptable asthma control; they should not be used as a substitute for proper control of the environment.

 

Complex nebulizer

 

Treatment of acute symptoms is usually with an inhaled short-acting beta-2 agonist (such as salbutamol). Symptoms can be prevented by avoiding triggers, such as allergens and irritants, and by the use of inhaled corticosteroids. Leukotriene antagonists are less effective than corticosteroids and thus less preferred.

While there is no cure for asthma, symptoms can typically be improved. A specific, customized plan for proactively monitoring and managing symptoms should be created. This plan should include the reduction of exposure to allergens, testing to assess the severity of symptoms, and the usage of medications. The treatment plan should be written down and advise adjustments to treament according to changes in symptoms.

The most effective treatment for asthma is identifying triggers, such as cigarette smoke, pets, or aspirin, and eliminating exposure to them. If trigger avoidance is insufficient, the use of medication is recommended. Pharmaceutical drugs are selected based on, among other things, the severity of illness and the frequency of symptoms. Specific medications for asthma are broadly classified into fast-acting and long-acting categories.

Bronchodilators are recommended for short-term relief of symptoms.> In those with occasional attacks, no other medication is needed. If mild persistent disease is present (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene antagonist or a mast cell stabilizer is recommended. For those who have daily attacks, a higher dose of inhaled glucocorticoid is used. In a moderate or severe exacerbation, oral glucocorticoids are added to these treatments.

Lifestyle modification

Avoidance of triggers is a key component of improving control and preventing attacks. The most common triggers include allergens, smoke (tobacco and other), air pollution, non selective beta-blockers, and sulfite-containing foods.Cigarette smoking and second-hand smoke (passive smoke) may reduce the effectiveness of medications such as steroids. Dust mite control measures, including air filtration, chemicals to kill mites, vacuuming, mattress covers and others methods had no effect on asthma symptoms.

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.

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 treatment for asthma 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.

•      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.

•      Glucocorticoids are generally considered the most effective treatment available for long term control. Inhaled forms are usually used except in the case of severe persistent disease, in which oral steroids 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) have at least a 12-hour effect. They however should not be used without an accompanying steroid due to an increased risk of severe symptoms, including exacerbation of asthma in both children and adults.

•      Leukotriene antagonists (such as zafirlukast) are an alternative to inhaled glucocorticoids, but are not preferred. They may also be used in addition to inhaled glucocorticoids but in this role are second line to LABA.

•      Mast cell stabilizers (such as cromolyn sodium) are another non-preferred alternative to glucocorticoids.

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 or not a difference exists in those severe symptomatology.

Adverse effects

Long-term use of inhaled glucocorticoids at conventional doses carries a minor risk of adverse effects. Risks include the development of cataracts and a mild regression in stature.

Other

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 is used to alleviate hypoxia if saturations fall below 92%.

•      Magnesium sulfate intravenous treatment has been shown to provide a bronchodilating effect when used in addition to other treatment in severe acute asthma attacks.

•      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.

•      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 can lead to clinical improvements. It involves the delivery of controlled thermal energy to the airway wall during a series of bronchoscopies and result in a prolonged reduction in airway smooth musclemass.

Alternative medicine

Many people with asthma, like those with other chronic disorders, use alternative treatments; surveys show that roughly 50% use some form of unconventional therapy. There is little data to support the effectiveness of most of these therapies. Evidence is insufficient to support the usage of Vitamin C. 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 medications use however does not have any effect on lung function. Thus an expert panel felt that evidence was insufficient to support its use.

 

Prognosis

The prognosis for asthma is generally good, especially for children with mild disease.Mortality has decreased over the last few decades due to better recognition and improvement in care. Globally it causes moderate or severe disability in 19.4 million people as of 2004 (16 million of which are in low and middle income countries). Of asthma diagnosed during childhood, half of cases will no longer carry the diagnosis after a decade. Airway remodeling is observed, but it is unknown whether these represent harmful or beneficial changes. Early treatment with glucocorticoids seems to prevent or ameliorates a decline in lung function.

Prevention

The evidence for the effectiveness of measures to prevent the development of asthma is weak. Some show promise including: limiting smoke exposure both in utero and after delivery, breastfeeding, and increased exposure to daycare or large families but none are well supported enough to be recommended for this indication. Early pet exposure may be useful. Results from exposure to pets at other times are inconclusive and it is only recommended that pets be removed from the home if a person has allergic symptoms to said pet Dietary restrictions during pregnancy or when breast feeding have not been found to be effective and thus are not recommended. Reducing or eliminating compounds known to sensitive people from the work place may be effective.