Asthma

Asthma is a heterogeneous disease with multiple clinical phenotypes. Both genetic and environmental factors contribute to the pathogenesis of asthma. Several risk factors have been implicated. Asthma is said to be

"extrinsic" or "atopic" if allergy to exogenous substances is recognized and "intrinsic" (or nonallergic) if no such exogenous factors can be identified.

Arterial blood gas (ABG) values are important to help determine the severity of the asthma attack. The four stages of arterial blood gas values progression in persons with status asthmaticus are as follows.

1. First stage. The first stage is characterized by hyperventilation with a normal partial pressure of oxygen (PO2). 2. Second stage. The second stage is characterized by hyperventilation accompanied by hypoxemia (low PO2), and hypocapnia or decreased partial pressure of carbon dioxide (low PCO2). The decrease in PCO2 increases the bicarbonate (HCO3)/PCO2 ratio and, thereby, increases the pH level; thus the descriptive term respiratory alkalosis. It takes several days for kidney to compensate by decreasing bicarbonate reabsorption, which decreases serum level of HCO3 and return pH to normal range. 3. Third stage. In the third stage patients are hypoxemic (low PO2) but they are not hyperventilating because of the respiratory muscle fatigue. They have normal PCO2 which is considered false-normal. This is an extremely serious sign of respiratory muscle fatigue that mandates admission to ICU. 12 4. Last stage. As the severity of airflow obstruction increases, hypoxia (low PO2) becomes more severe, PCO2 subsequently increases due to respiratory muscle insufficiency followed by respiratory acidosis. This is an even more serious sign that mandates intubation and mechanical ventilation.

BRONCHIAL EOSINOPHILIC INFILTRATION.

A characteristic feature of the airways in status asthmaticus is infiltration of the walls of bronchi and proximal bronchioles by eosinophils, T lymphocytes and mast cells. The eosinophils are activated to secrete major basic protein. T lymphocytes are as numerous as eosinophils, making up half the inflammatory cells. Mast cells are increased within the smooth muscle layer. The bronchial inflammatory infiltration is accompanied by marked congestion and edema.

Typical asthma attack.

A typical attack of asthma begins with a feeling of tightness in the chest and nonproductive cough. Both inspiratory and expiratory wheezes appear, the respiratory rate increases, and the patient becomes dyspneic. Characteristically, the expiratory phase is particularly prolonged. The end of the attack is often heralded by severe coughing and expectoration of thick, mucus containing Curschmann spirals, eosinophils, and Charcot-Leyden crystals.

LABORATORY STUDIES.

Blood eosinophilia greater than 4% (normal: 1-4%) supports the diagnosis of asthma, but an absence of this finding does not exclude the diagnosis of asthma. This finding is not specific for asthma may be observed in patients with atopic dermatitis, eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Elevated total serum IgE levels (normal: 0-380 IU/mL) are frequently observed in allergic patients, but this finding is not specific for asthma and may be observed in patients with allergic bronchopulmonary aspergillosis, and eosinophilic granulomatosis with polyangiitis. A normal total serum immunoglobulin E level does not exclude the diagnosis of asthma

Immunologically mediated sub-phenotype.

High molecular weight agents (e.g., latex, animal proteins, and flour) act as complete antigens and induce the production of specific IgE antibodies. Reactions between specific IgE antibodies and antigens lead to a cascade of events that results in an influx of inflammatory cells into the airway and the release of inflammatory mediators. An asthmatic reaction occurs early (during the first 90 minutes after the exposure) of late (during the first two days after the challenge). Immunologically mediated sub-phenotype is seen in animal handlers, bakers, and workers exposed to wood and vegetable dusts.

Cytokines produced by Th2 lymphocytes play critical roles in asthma.

IL-3 is a survival factor for eosinophils and basophils. IL-4 helps in the differentiation of uncommitted T cells into Th2 cells, switch of B-lymphocyte immunoglobulin synthesis to IgE production, and selective endothelial cell expression of vascular cell adhesion molecule-1 (VCAM-1) that mediates eosinophil, basophil, and T cell specific recruitment. IL-5 is the major hematopoietic cytokine regulating eosinophil production and survival. IL-13 appears to contribute to airway eosinophilia, mucous gland hyperplasia, airway fibrosis, and remodeling. GM-CSF is also a survival factor for eosinophils.

Emotion-induced asthma.

Psychological stress can aggravate or precipitate an attack of bronchospasm in as many as half of all asthmatics. It is believed that vagal efferent stimulation is the underlying mechanism.

9 HYPERTROPHY OF BRONCHIAL TUNICA MUSCULARIS PROPRIA.

The thickness of the smooth muscle layer in bronchi is increased in individuals with asthma, compared with nonasthmatic control subjects. The increase involves bronchi of all sizes but is most apparent in small bronchi of about 0.5 cm diameter. It is attributable to smooth muscle cell hyperplasia as well as hypertrophy. The excess of bronchial smooth muscle mass in patients with asthma is associated with airway hyperresponsiveness.

Non-immunologically mediated sub-phenotype.

This is a rapid response to irritant chemicals, such as smoke, ammonia or chlorine exposure. This sub-phenotype is referred to as reactive airways dysfunction syndrome (RADS). It is postulated that RADS is due to that extensive denudation of the epithelium resulting in airway inflammation.

BRONCHIAL PLUGGING BY MUCUS. The bronchial lumen is compromised by the accumulation of mucus which has a concentric or spiral pattern in cross-section. Numerous eosinophils are present within the mucus admixed with desquamated epithelial cells. The excessive mucus is produced by hyperplastic goblet cells in the surface epithelium and enlarged submucosal mucinous glands (similar to chronic bronchitis) present in large and small bronchi and bronchioles. These changes result in

abnormalities in the viscoelastic and rheologic characteristics of airway mucus and in abnormalities in mucociliary clearance. The cellular and biochemical composition of airway secretions in asthma is abnormal in several respects. The numbers of eosinophils are increased, accounting for the presence of Charcot-Leyden crystals. In addition, concentrations of mucin in airway secretions are higher than normal in asthma; this finding accounts for the occasional finding of corkscrew-shaped twists of inspissated mucus (Curschmann spirals) in sputum from asthmatic patients. Clumps of sloughed epithelial cells (Creola bodies) are seen occasionally in sputum also. Further, concentrations of albumin and DNA are increased in sputum from asthmatic patients, reflecting abnormal vascular permeability and increased inflammatory cells, respectively. The accumulation of abnormal mucus in the airways worsens airway obstruction and provokes the symptoms of cough and sputum production. In addition, mucus accumulation in the airway contributes importantly to airway obstruction during fatal attacks of asthma.

Exercise can precipitate some bronchospasm in more than half of

all asthmatics. In some patients, exercise is the only inciting factor. Exercise-induced asthma is related to the magnitude of heat or water loss from the airway epithelium. The more rapid the ventilation (severity of exercise) and the colder and drier the air breathed, the more likely is an attack of asthma. Thus, an asthmatic playing hockey on an outdoor rink in Canada in winter is more likely to have an attack than one swimming slowly in Texas during the summer. The mechanisms underlying exercise-induced asthma are unclear. The condition may be the consequence of mediator release or vascular congestion in the bronchi secondary to rewarming of the airways after the exertion.

Aspirin-induced asthma is characterized by the triad of

aspirin intolerance, sinusitis with nasal polyps, and asthma. The prevalence of aspirin-induced asthma in adult asthmatics is 3-5% when based on patient history alone but is 21% when oral aspirin challenge is prospectively performed. Rhinorrhea and nasal congestion generally precede onset of asthma and aspirin sensitivity by 1-5 years in aspirin-induced asthma. Ingestion of aspirin or certain NSAIDs will result in an acute asthma attack accompanied by rhinitis and conjunctival injection within 3 hours of drug ingestion. The asthma associated with this phenotype is often severe and poorly responsive to corticosteroids. The mechanism of aspirin-induced asthma is believed to be "shunting" of arachidonic acid metabolism away from prostanoid production, leading to increased leukotriene production and resultant bronchoconstriction. Genetics studies have identified mutations in the leukotriene pathway in patients with aspirin-induced asthma, although these mutations alone do not explain the adult onset of disease. It is likely that an environmental factor is required to activate the pathologic response in aspirin-induced asthma.

Air pollution-induced asthma. Massive air pollution, usually in episodes associated with temperature inversions, is

associated with bronchospasm in patients with asthma and other preexisting lung diseases. SO2, oxides of nitrogen, and ozone are the commonly implicated environmental pollutants.

AUTOIMMUNE HYPOTHESIS. One hypothesis assumes that intrinsic asthma may represent a form of

autoimmunity possibly triggered by a viral infection like influenza which often precedes its onset. This is further supported by the recent observation that intrinsic asthmatics frequently demonstrate positive autologous serum skin tests (ASST) and positive antinuclear (ANA) autoantibodies. The ASST consists of intradermal injection of autologous serum. A weal and flare response indicates a positive test. This test detects basophil histamine releasing activity due to presence of autoantibodies against the high-affinity IgE receptor on mast cells.

After allergen specific IgE antibodies are synthesized and secreted by plasma cells, they bind to high-affinity receptors on mast cells (and basophils). When an allergen is subsequently inhaled and comes into contact with mucosal mast cells, it cross links allergen-specific IgE antibodies on the mast cell surface; rapid degranulation and mediator release follow, leading to

bronchoconstriction within several minutes. This is known as the early or immediate phase reaction. The mast cell mediators, including histamine, prostaglandin D2, and cysteinyl leukotrienes (LTC4, D4, and E4), contract bronchial smooth muscle directly, and may also stimulate reflex neural pathways. This early phase reaction is sometimes followed by a late phase recurrence of bronchoconstriction several hours later. The late phase response coincides with an influx of inflammatory cells, including Th2 lymphocytes, eosinophils, neutrophils, basophils. The mediators released by these cells also cause bronchial smooth muscle contraction that is largely reversible by beta-agonist administration. The T cell population infiltrating the asthmatic airway is characterized by the Th2 lymphocytes that produce a restricted panel of cytokines, including IL-3, IL-4, IL-5, IL-13, and GM-CSF, but not interferon-γ, when stimulated with antigen. Th2 lymphocytes also express the chemokine receptors (CCR4 and CCR8) and the chemoattractant receptor (CR)-like molecule (CRTH2), a receptor for prostaglandin D2 (PGD2).

Atopic asthma phenotype. This is the most common form of asthma and is usually seen in

children and in a large proportion of adult asthmatics. About 30% to 50% of all patients with asthma have known or suspected reactions to such allergens as pollens, animal hair or fur, and house dust contaminated with mites. Allergic asthma is strongly correlated with skin-test reactivity.

hypothesis. The hygiene hypothesis states that a lack of early childhood exposure to infectious agents and parasites increases susceptibility to allergic disease by modulating immune system development, e.g. favoring Th2 differentiation of naive T cells, increasing the probability of an IgE response to allergens. First proposed by Strachan in 1989, the hygiene hypothesis was developed to explain the observation that atopic diseases were less common in

children from larger families, which were presumably exposed to more infectious agents through their siblings, than in children from families with only one child. The hygiene hypothesis has been extensively investigated and has become an important theoretical framework for the study of allergic disorders. It is used to explain the increase in allergic diseases that has been seen since industrialization, and the higher incidence of allergic diseases in more developed countries. he global microbial burden in early life, including exposure to nonpathogenic microbes, which could deviate the immune responses away from those associated with allergic responses. It thus made sense to suspect that polymorphisms in CD14, a major player in the biological process leading to the detection of and development of biological responses against environmental microbial products, could be involved in a mechanism that resulted in protection against asthma and allergies in people with at high levels of exposure

Asthma is a polygenic disease. Asthma is not a disorder with simple Mendelian mode of inheritance, but a multifactorial disorder of the airways brought about by complex interaction between genetic and environmental factors. Genetic screens with classical linkage analysis and single nucleotide polymorphisms of various candidate genes indicate that asthma is polygenic, with each gene identified having a small effect that is often not replicated in different populations. This observation suggests that the interaction of many genes is important, and these may differ in different populations. The most consistent findings have been association of asthma and atopy with polymorphisms of genes on

chromosome 5q. The 5q region contains genes like IL-3, IL-4, IL-5, IL-9, IL-12b, and IL-13 which are associated with atopy. Most of these influence the T cell development and polarization towards TH2 besides modulating other features like recruitment of eosinophils, mast cells, and neutrophils to the site of inflammation. Novel genes that have been associated with asthma, including ADAM-33, DPP-10, and SPINK5, have also been identified by positional cloning, but their function in disease pathogenesis is thus far obscure. ADAM33 encodes disintegrin and metalloproteinase domain-containing protein 33 and is associated with airway remodeling events. DPP-10 is associated with bronchial hyperresponsiveness and IgE. SPINK5 is associated with airway remodeling.

SUPERANTIGEN HYPOTHESIS. This hypothesis states that individuals with intrinsic asthma are susceptible to

colonization of the airway epithelium with S. aureus. S. aureus produces several exotoxins that function as superantigens. Superantigens are so-called because they have the capacity to stimulate polyclonal T and B cell proliferation directly, independently of antigen presentation by antigen-presenting cells. Proliferation and activation of CD4 T lymphocytes result in production of staphylococcal superantigen-specific IgE antibodies, and sensitization of mast cells. Inhaled staphylococcal exotoxins can induce eosinophilic airway inflammation with increased production of IL-4, and airway hyperresponsiveness independent of any allergen.

Atopic asthma is the commonest form of asthma. Atopic asthma is a type of asthma that occurs in individuals with atopy. Atopy is a genetic predisposition to

develop immediate hypersensitivity reactions with production of IgE in response to common environmental proteins such as house dustmite, grass pollen, and food allergens. Atopic individuals produce abnormally high levels of the antibody IgE in response to these allergens, express more high affinity IgE receptors than normal individuals, and have more of these receptors occupied by IgE.

Bronchial asthma is an example of type I hypersensitivity reaction. Type 2 helper T cells (Th2) play a triggering role in the activation/recruitment of IgE antibody producing B cells, mast cells and eosinophils. The consequences of mast cell activation by allergen are key to the

development of clinical asthma. The following sequence of events explains how inhalation of allergen leads to the early, or immediate, phase of airway inflammation, which is followed about six hours later by a late phase reaction. Initial allergen exposure is followed by elaboration of specific IgE antibodies. Regulation of specific IgE production appears related to an overexpression of Th2 cell responses relative to the Th1 type; this overexpression is likely due to a combination of genetic and environmental influences. In contrast, type 1 helper T (Th1) cells, another class of CD4 T cells, produce interferon-γ and interleukin-2, which initiate the killing of viruses and other intracellular organisms by activating macrophages and cytotoxic T cells. These two subgroups of helper T cells arise in response to different immunogenic stimuli and cytokines, and they constitute an immunoregulatory loop: cytokines from Th1 cells inhibit Th2 cells, and vice versa.

Atopic asthma usually begins in childhood and is paroxysmal, the attack starting suddenly and lasting a few hours or days. Atopic asthma is triggered by

environmental allergens, such as dusts, pollens, roach or animal dander, and foods. Serum IgE is increased and skin tests against the offending antigens are positive, i.e. result in an immediate wheal-and-flare reaction. Atopic asthma tends to become less severe as the child grows older and often ceases during adolescence. Atopic asthma has a familial tendency and some of the genes responsible have been identified. Patients with asthma commonly suffer from other atopic diseases, particularly allergic rhinitis, which may be found in over 80% of asthmatic patients, and atopic dermatitis. Atopy may be found in 40-50% of the population in affluent countries. Only a proportion of atopic individuals become asthmatic . This observation suggests that some other environmental or genetic factor(s) predispose to the development of asthma in atopic individuals. The allergens that lead to sensitization are usually proteins that have protease activity, and the commonest allergens are derived from house dust mites, cat and dog fur, cockroaches, grass and tree pollens.

In the severe episode, the respiratory rate is often

greater than 30/min. Accessory muscles of respiration are usually used, and suprasternal retractions are commonly present. The heart rate is more than 120 beats per minute. Loud biphasic (expiratory and inspiratory) wheezing can be heard. Pulsus paradoxus is often present (pulsus paradoxus is an exaggeration of the normal variation in the pulse during the inspiratory phase of respiration, in which the pulse becomes weaker as one inhales and stronger as one exhales. Pulsus paradoxus differs from a normal pulse in that the inspiratory diminution in arterial pressure exceeds 10 mm Hg; under normal conditions of rest, an inspiratory fall of arterial systolic pressure less than 10 mm Hg occurs). Oxygen saturation of hemoglobin with room air is < 91%.

The gross appearances are characteristic. When the chest is opened in cases of death in status asthmaticus, the lungs are found to be

greatly distended (lung overinflation); they fail to retract as normal lungs do when the negative intrapleural pressure is replaced by atmospheric pressure on opening the pleural cavities. Lungs take over as much space of the chest cavity possible, covering the heart. Contrasting with the general distension, small areas of atelectasis may be seen as dark, airless, firm areas, depressed below the level of the surrounding lung. The most striking macroscopic finding is occlusion of bronchi and bronchioles by thick, tenacious mucus plugs. Plugs of thick, tenacious mucus are found in airways of all sizes beyond the second-order bronchi but the most striking changes are seen in airways of about 5 mm diameter. When the cut surface of the lung is exposed, the bronchi of this size are seen to be filled with grey plugs of viscous mucus that can be made to protrude from the lumen by compression of the lungs. Bronchography has shown that airway plugging is widespread between asthmatic attacks as well as being most prominent in patients dying of asthma. Bronchography has shown that air can pass the plugs only on inspiration.

Physical examination findings. Clinical signs of asthma on chest examination are more likely to be found during symptomatic periods. These include

hyperexpansion of the thorax (especially in children), use of accessory muscles, hyperresonance to percussion, diminished breath sounds, sounds of wheezing during normal breathing or a prolonged phase of forced exhalation (typical of airflow obstruction), and increased nasal secretion, mucosal swelling and nasal polyps. Chest examination may be normal on auscultation, particularly in asymptomatic patients. Wheezing may be absent in mild or intermittent asthma, between asthma exacerbations.

Abnormalities on plain chest X-ray examination of asthmatic patients include

hyperinflation of the lungs (increased lung lucency), increased anteroposterior diameter, diaphragm flattening (apex of diaphragm lying below the level of the 6th anterior rib), and slightly thickened bronchial walls. These abnormalities have been present only in 25% of patients examined during asthmatic attack. Plain films can be normal in up to 75% of patients with asthmatic attack. Usually, patients with intermittent asthma tend to have normal chest radiographs. For this reason, imaging studies are usually not necessary in an uncomplicated asthma attack. High-resolution computed tomography (HRCT) has allowed visualization of airways and parenchyma in much greater detail than conventional CT or plain radiography. HRCT scan abnormalities have been present in 80% of asthmatic subjects examined. HRCT findings include mucoid impaction, lobar atelectasis and bronchial wall thickening. Mucoid impaction has been reported in as many as 21% of cases, but this abnormality may disappear after treatment.

Spirometry assessments should be obtained as the primary test to establish the asthma diagnosis. Spirometry should be performed prior to initiating treatment. Optimally, the initial spirometry should also

include measurements before and after inhalation of a short-acting bronchodilator. Asthma attack is characterized by airflow obstruction. Airflow obstruction is defined as a reduced FEV1, normal FVC, and a reduced FEV1/FVC ratio, such that FEV1 is <80% of that predicted, and FEV1/FVC is <70% (normal: 70%). Reversibility is demonstrated by an increase of 12% and 200 mL after the administration of a short-acting bronchodilator. Asthma patients have normal or high values of diffusing capacity of the lungs for carbon monoxide (DLCO). The diagnosis of asthma cannot be based on spirometry findings alone because many other diseases are associated with obstructive spirometry indices.

Mild episode. A mild episode is characterized by an

increased respiratory rate. Accessory muscles of respiration are not used. The heart rate is less than 100/min. Pulsus paradoxus is not present. Auscultation of chest reveals moderate wheezing, which is often end expiratory. Oxygen saturation of hemoglobin with room air is greater than 95%.

Bronchial asthma (or simply asthma), is a chronic lung condition in which breathing is periodically rendered difficult by widespread narrowing of the bronchi that changes in severity over short periods of time, either spontaneously or under treatment. Asthma is caused by

increased responsiveness of the airways to a variety of stimuli. Exposure to these stimuli leads to bronchiolar smooth muscle contraction (bronchospasm). The cause of increased responsiveness of the air passages is unknown but it is believed to be related to bronchial inflammation. Bronchospasm causes obstruction to air flow - maximal in expiration - and a high-pitched wheeze. The difficulty becomes particularly apparent during expiration because the airways normally collapse during that phase of respiration and because the expiratory muscles are less powerful than those that act during inspiration.

ALLERGY SKIN TESTING. Allergy skin testing is a useful adjunct in

individuals with atopy. Results help guide indoor allergen mitigation. The allergens that most commonly trigger asthma are aeroallergens such as house dust mites, animal danders, pollens, and mold spores. Two methods are available to test for allergic sensitivity to specific allergens in the environment: allergy skin test and blood radioallergosorbent test (RAST). Allergy immunotherapy may be beneficial in controlling allergic rhinitis and asthma symptoms for some patients.

Occupational asthma. Asthma is the most common occupational respiratory disorder in

industrialized nations, accounting for 9-20% of adult asthma cases. More than 80 different occupational exposures have been linked to the development of asthma. Occupational asthma has two distinct sub-phenotypes, defined by the underlying mechanism: non-immunologically mediated and immunologically mediated.

The pathology of intrinsic and extrinsic asthma is remarkably similar, with an increase in eosinophils, mucosal mast cells and T cells in the airways. (C) Immunopathologic features. The immunopathologic features are similar to those observed in allergic asthma: similar expression of Th2 cytokines, and a similar number of eosinophils in the mucosa. Intrinsic asthma is characterized by a

lack of circulating specific IgE, but IgE synthesis occurs in the airways, despite negative skin prick tests and normal serum IgE. (D) Pathogenesis. The pathogenesis of intrinsic asthma still remains incompletely resolved.

A functional polymorphism in the promoter region of the CD14 gene, which encodes the receptor for lipopolysaccharide and plays a role in innate immunity, may influence the risk for atopy and severity of asthma. The CD14 gene also maps on chromosome 5q. The CD14 receptor functions as a

multifunctional receptor for bacterial cell wall components including lipopolysaccharide and is likely to play a role in the polarization of T lymphocytes into Th1 and Th2 subsets, thereby influencing the cytokine profile and subsequent IgE production in response to antigen/allergen contact in allergic phenotypes. A functional single nucleotide polymorphism in the 5'flanking region of CD14 (CD14/−159) gene is one of the most widely tested genetic variations in relation to asthma and associated traits. CD14 is constitutively expressed primarily on the surface of monocytes, macrophages, and neutrophils as membrane CD14 (mCD14). A soluble form of CD14, sCD14, is abundant in serum. The CD14/−159 has two alleles (C and T) that are of similar frequency in the population. TT homozygotes have significantly higher levels of circulating sCD14 than CC homozygotes. Results of numerous studies indicate that TT homozygotes are less prone to develop atopic allergic responses because, having higher expression of CD14, they would be more sensitive to environmental microbial exposures that would deviate immune responses to allergens away from those of the T-helper-2 (Th2) type. On the other hand, at low levels of exposure, CC homozygotes are at the highest risk for allergic sensitization and serum IgE production.

Creola bodies are c

ompact clumps of columnar epithelial cells shed from the bronchial mucosa that are sometimes found in the sputum of asthmatics.

Status asthmaticus refers to

severe bronchoconstriction that does not respond to the drugs that usually abort the acute attack. In status asthmaticus, the severe acute paroxysm (tachypnea and wheezing) persists for days and even weeks, and under these circumstances airflow obstruction might be so extreme as to cause severe cyanosis and even death. Clinically, signs of respiratory distress develop, including retractions, use of abdominal muscles in exhalation, and inability to speak more than one or two words at a time. Use of accessory muscles correlates with severity of airflow obstruction. An abnormally prolonged expiratory phase with audible wheezing can be observed. The V/Q mismatch results in decreased oxygen saturation and hypoxia. Vital signs may show tachycardia and hypertension. Level of consciousness may progress from wide-awake to lethargic, agitated to comatose. As hypoxemia progresses, lethargy progresses to agitation caused by air hunger. As more lung units become obstructed, hypoxemia worsens and hypercapnia develops. Both hypoxemia and hypercapnia can lead to seizures and coma and are late signs of respiratory compromise.

Attacks of asthma are of

short duration and reverse completely. Patients typically have paroxysms of wheezing, dyspnea, and cough. Acute episodes of asthma may alternate with asymptomatic periods. Rarely, they may be severe and prolonged and unresponsive to therapy (status asthmaticus) and may lead to acute ventilator failure and even death. Bronchial asthma is to be distinguished from the etiologically distinct condition of cardiac asthma. The latter represents pulmonary edema consequent upon a failing left heart.

Moderately severe episode. In the moderately severe episode,

the respiratory rate is increased. Typically, accessory muscles of respiration are used, and suprasternal retractions are present. The heart rate is 100-120/min. Loud expiratory wheezing can be heard. Oxygen saturation of hemoglobin with room air is 91-95%.

Charcot-Leyden crystals have

the shape of a pair of long, narrow, six-sided pyramids placed base to base; their hexagonal shape can often be seen when they are cut across in histological preparations. The presence of these slender, dipyramidal crystals in human tissues and biologic fluids has become a hallmark of eosinophilic leukocyte infiltration, especially in association with allergic (asthma) and helminthic diseases. Charcot-Leyden crystals are composed of lysolecithin acylhydrolase. This protein comprises approximately 10% of the total cellular protein in eosinophils. Lysolecithin acylhydrolase is one of several eosinophil proteins involved in the eosinophil's antiparasitic and immune functions. This enzyme has cytotoxic properties and has been shown to damage the respiratory epithelium and increase vascular permeability.

Clinically, intrinsic asthma behaves very similar to allergic asthma, with

variable airflow obstruction and symptoms, symptom relief with bronchodilators and a good therapeutic response to corticosteroid therapy, even though higher doses may be needed. This strongly suggests that mast cell activation is similar between extrinsic and intrinsic asthma. As in extrinsic asthma, many patients with intrinsic asthma have concomitant perennial rhinitis and a high proportion also have nasal polyps and chronic rhinosinusitis. Patients with intrinsic asthma have negative skin test to common inhalant allergens and normal IgE serum concentrations. Intrinsic asthma begins suddenly in middle age, is chronic with exacerbations and remissions, and advances rapidly in its intensity. Intrinsic asthma has a female predominance, is often more severe than allergic asthma and may be less responsive to standard therapy. A lack of personal or family history of allergy is common, and seasonal or exposure-related triggers are absent.

Infectious asthma. A common precipitating factor in childhood asthma is a

viral respiratory tract infection rather than an allergic stimulus. In children under 2 years, respiratory syncytial virus is the usual agent; in older children, rhinovirus, influenza, and parainfluenza are common inciting organisms. The inflammatory response to viral infection in a susceptible person is believed to trigger the episode of bronchoconstriction. This hypothesis is supported by the demonstration that nonasthmatic persons also show bronchial hyperreactivity, which may persist for as long as 2 months after a viral infection.

Sputum. (A) Eosinophils. The sputum is

viscous and yellow in asthma. The color should not be taken as evidence that the sputum is infected. In asthma, the sputum is rich in eosinophils and the yellow characteristic color is due to myeloperoxidase, which is found in eosinophils. As well as eosinophils, microscopis studies of sputum show the presence of Charcot crystals, Curschmann spirals and Creola bodies.