Asthma Etiology Diagnosis and Treatment

In order to better understand asthma, one must first go back to the basic fundamentals and etiology as well as pathophysiology of asthma in order to gain useful perspective. Asthma is one of the most common chronic conditions affecting both children and adults, yet much remains to be learned of its etiology.?? Asthma is a chronic, persistent inflammatory disease of the airways characterized by exacerbations of coughing, wheezing, chest tightness, and difficult breathing that are usually reversible, but that can be severe and sometimes fatal.?? Well controlled asthma consists of regular use of maintenance corticosteroids in order to reduce the number of exacerbations over time. Exacerbation of asthma is characterized by the worsening of symptoms with increase in dyspnoea, cough and wheeze.?? Many treatments are available to asthma patients yet the most popular is the use of corticosteroid therapy by way of inhalers. This route is easy and simple and provides relief to the targeted area if administered correctly. Introducing inhalers to the newly diagnosed asthmatic, with proper training and compliance, can assist with the reduction of asthma exacerbations and the rate of severity. Using something as simple as a peak flow which will measure peak expiratory flow (PEF) can help the patient categorize themselves as having a non-severe or severe asthma exacerbation. Severe asthma exacerbations can be serious and if left untreated fatal. Patients have been found to have similar symptoms consisting of dyspnoea, unable to complete full sentences, increased heart rate and respiratory rate, wheezing and chest tightness, possible blue lips and agitation is also noted. If an asthma exacerbation is caught in the early stages administration of inhaled agonists consistently over the first hour, will show improvement and an increase in airflow.

The pathophysiologic features of asthma can be broken down into three separate sections consisting of smooth muscle spasm, mucus plugging of the airways, inflammation of the airways, and biomarkers. The nervous system plays a large role in the control of the smooth muscle that is in the airways. The cholinergic system controls the smooth bronchial muscle while the beta-adrenergic system is consisting of a system of nerves in charge of the relaxing the smooth bronchial muscle. There is also the alpha-adrenergic system, which has fewer nerves in the airways, but still plays a role in the smooth bronchial muscle. All three systems must work together to provide a response that circulates the mediators that ultimately act as alpha-adrenergic receptors in the smooth muscle. Many theories have surfaced in reference to the difference between a non-asthmatic versus an asthmatic patient's smooth muscle in the airways. One theory has stressed the possibility of a partial beta blockade, another abnormal cholinergic mechanism, and a third theory has suggested a basic abnormality of the non-adrenergic inhibitory system.

Airway inflammation is a common symptom of asthma and if not controlled quickly can lead to constriction. Assessing epithelial changes due to airway inflammation is important as the reaction caused by the inflammation is responsible for the damage therefore leading to a hyperreactive airway. Uncontrolled inflammation in the upper and lower airways and in the systemic circulation may compromise the control of allergic rhinitis and asthma, with subsequent disease progression.

Mucus plugging can create respiratory distress for many a patient and research is still being conducted on whether or not findings of mucus plugging in asthmatic patients are more significant than that of the non-asthmatic patient. Researchers have used the study of an asthmatic's sputum with plugs to further their knowledge in asthma etiology yet they cannot rely on this alone for diagnosing the severity of asthma.

It is important to detect and monitor inflammatory occurrences by way of a variety of simple tests and procedures. There are many tried and true tests available in order to properly diagnosis asthma. Tests and procedures can include; blood panel, nasal wash, sputum sample, possibly an induced sputum, exhaled breath condensate and fractional exhaled nitric oxide. A large number of molecules measured in EBC, including LTB4, prostaglandin E2 and 8-isoprostane, are considered useful markers of airway inflammation and oxidative stress in the airways.??µ Bonsignore et al. completed a study on pediatric patients in order to better understand the significance of biomarkers in induced sputum. Many biomarkers were found to be significantly higher in patients with moderate asthma versus healthy patients. These biomarkers include; interluekon-8 precursor (IL-8), matrix metalloproteinase (MMP-9), tissue inhibitor of metalloproteinase (TIMP)-1 and number of eosinophils. Fractional exhaled nitric oxide assessment was also completed as this is a reliable marker for airway inflammation.

Mucus plugging can create respiratory distress for many a patient and research is still being conducted on whether or not findings of mucus plugging in asthmatic patients are more significant than that of the non-asthmatic patient. Researchers have used the study of an asthmatic's sputum with plugs to further their knowledge in asthma etiology yet they cannot rely on this alone for diagnosing the severity of asthma.

There are a multitude of causes of asthma and many of which start in childhood and can endure throughout a patient's lifetime. Studies have found that genetics plays a large role in the predisposition for asthma. Some patients do not have a choice for the predisposition to have asthma as prenatal risk factors play a large role in the occurrence of asthma. Prenatal risk factors include prenatal smoking, diet and nutrition, stress, antibiotic use, mode of delivery. Risk factors can continue into childhood with many not by choice. Parents are encouraged to monitor transient wheezing, late or acute onset wheezing, and persistent wheezing as additional testing may need to be completed. Another risk factor is that of maternal diet restrictions which in turn can cause an allergy for the pediatric patient. Still a controversial subject, but the idea of not breastfeeding has been discussed and thought to deprive the infant of certain antibiotics which are necessary for future growth and deflection of disease. Decreased airway calibre in infancy has been reported as a risk factor for transient wheezing, perhaps related to prenatal and postnatal exposure to environmental tobacco smoke.?? Lastly, sex, gender, allergy sensitization, family structure, socio-economic status, reoccurring infections with use of antibiotics, exposure to smoke and animals are all considered significant risk factors that may make controlling childhood asthma a challenge.

Many adults are diagnosed with asthma later on in life. This new onset asthma in adulthood could be caused by a series of occupational and environmental sources. Many occupations can have a number of chemicals and irritants in which repeated exposure can lead to airway inflammation. Many individuals start smoking, whether cigarettes or marijuana, in adulthood and for some the repeated exposure can cause airway inflammation. Some individuals have repeated respiratory sicknesses such as bronchitis, which when chronic, due to increased cough and sputum production can cause a rise in airway inflammation.

Asthma is a manageable disease that is chronic with no cure but when properly treated and controlled exacerbations can be kept to a minimum. Asthma exacerbations can be traced back to two categories; viral infections and bacterial infections. Approximately 80% of exacerbations are associated with respiratory tract viral infections, with rhinoviral infection responsible for about two thirds of cases. Asthmatic patients may be more vulnerable to rhinovirus due to the lack of interferon productions. Interferons are antiviral proteins that play a role in fighting off viral infections. Asthmatics with an exacerbation with a viral component are mainly characterized by neutrophilic inflammation. Evidence of neutrophil degranulation and increased lactate dehydrogenase levels are independent predictors of severity, and increased levels of the potent neutrophil chemokine IL-8 are found in exacerbations. Researchers have mainly relied on viral infection components in order to better understand asthma but recognition and studies have been expanded to better understand the bacterial infection component and it's relationship to asthma. Some studies have shown results that indicate that asthmatics are more likely to be affected by bacterial infections due to the increase risk of invasive pneumococcal disease. C pneumoniae, an atypical bacterium, has also been found to be significant yet more research needs to be conducted as results from current studies show bacterial components are secondary to viral infection.

Diagnosis and Classification

Classification of asthma is important as the different categories relate to the level of severity as well as recommended treatment. Classification starts with obtaining a detailed medical history as well as a detailed description of symptoms associated with asthma exacerbations. This medical history enables the physician to categorize the patient according to severity of symptoms. Patients are asked about their day and night symptoms, the frequency of asthma exacerbations and results from a lung function test can help categorize the patient as mild, moderate or severe in order for the physician to appropriate recommend the correct course of treatment.

Physicians rely on many indicators and markers in order to clinical diagnosis asthma. Most asthmatics have chronic airway inflammation but the level of inflammation varies among patients and plays role in correctly diagnosing asthma. The most studied marker in exhaled breath is nitric oxide (NO). Elevated levels of fractional exhaled NO (FeNO) are found in both adults and children with asthma, as a consequence of up regulation of the enzyme iNOS.??· Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose.

Airway inflammation and hyperresponsiveness are used in characterizing asthma and research has been conducted in order to differentiate between the correlation of using inhaled corticosteroids and inflammatory cells in the airway. Crimi et al. researched and studied by using a methacholine challenge, with modifications for two study groups, bronchoalveolar lavage and biopsy, and eosinophil cationic protein assay in order better understand the relationship between airway inflammation and hyperresponsiveness. The study took a closer look at the airway lumen and mucosa and the relationship between inflammatory cells and hyperresponsiveness. Inhaled steroids caused a decrease of airway responsiveness that was paralleled by a decrease of eosinophils and other inflammatory cells in bronchial mucosa in only one uncontrolled study. Crimi et al. concluded, through their research, that a true perennial allergic asthmatic's hyperresponsiveness is not directly related with the presence of eosinophils, neutrophils, lymphocytes, or macrophages.

Treatment of Asthma

There is no known cure for asthma so early diagnosis and treatment will encourage maintenance and control with reduction in asthma exacerbations. A diagnosing physician will do a thorough physical exam as well as document a detailed medical history in order to correctly diagnosis a patient. Spirometry is also a helpful tool as it is a common medical office test used to assess how well the lungs work by measuring how much air is inhaled as well as how much air can be exhaled and how quickly. Spirometry is used to diagnosis asthma as well as several other respiratory diseases such as chronic obstructive pulmonary disease. Bateman et al. states, Asthma treatment for adults can be administered in different ways: inhaled, orally or parenterally (by subcutaneous, intramuscular or intravenous injection). The major advantage of inhaled therapy is that drugs are delivered directly into the airways, producing higher local concentrations with significantly lower risk of systemic side effects. Inhaled glucocorticosteroids, leukotriene modifiers, theophylline, omalizumab, systemic glucocorticosteroids, and short and long acting inhaled and oral B?‚‚ agonists are some of more popular treatments available for all age groups. For pediatric patients ease of administration is key. Inhalers have been the most popular route of administration of treatment as they are the easy to use as well as the fastest route for dispensing medication. Naturally each patient is different and customizing what works best for each individual is crucial in managing asthma.

Patients with mild asthma or non-severe exacerbations can usually manage their asthma at home, or in the outpatient setting, utilizing fast acting inhaled B?‚‚ agonists in which using the rescue inhaler every twenty minutes for the first hour should produce positive results and relief in airway inflammation. Oral glucocorticoids can be used for mild exacerbations if the inhaler has seems to have no effect after one hour. Severe asthma exacerbations can be life threatening and knowing when hospital intervention is needed is key to survival. Urgent care centers have gained in popularity and if the mild asthma exacerbations require medical intervention, centers such as these might provide additional inhaled nebulizers, supplemental oxygen and a dose of steroids. This course of treatment usually can revise an asthma exacerbation but sometimes a higher level of care is needed in the emergency room. In the emergency room immediate intervention is needed in order to stop the progression of the exacerbation. Within the first hour emergency room staff may provide a higher level of oxygen, if needed, intravenous fluids to fight dehydration, a significantly higher dose of albuterol and ipratropium bromide nebulizer, and an aggressive dose of steroids. After the first hour a physician will reassess the patient and at that time significant improvement has been made or an additional round of treatment may be needed.

Leukotrienes made of three separate molecules that, when together, create a powerful effect by stimulating smooth muscle contraction. Leukotrienes are known for their powerful bronchoconstrictor properties. Leukotrienes, in addition to other products in the 5-lipoxygenasse pathway, have been proven to be associated with asthma by way of the pathophysiologic responses they create. Drazen et al. explains the 5 lipoxygenase pathway as such; Leukotriene A?‚„ is unstable and is quickly converted to leukotriene C?‚„ or leukotriene B?‚„. In three cell types associated with asthma-eosinophils, mast cells, and alveolar macrophages-leukotriene A?‚„ is converted to leukotriene C?‚„ by the addition of glutathione at the C position of leukotriene A?‚„, a reaction catalyzed by leukotriene C?‚„ synthase. Leukotriene C?‚„ is then exported to the extracellular space through a specific transmembrane transporter. In the extracellular space, the glutamic acid moiety is cleaved from leukotriene C?‚„ to form leukotriene D?‚„, which in turn is cleaved by extracellular dipeptidases to form the 6-cysteinyl analogue of leukotriene C?‚„, known as leukotriene E?‚„. Because leukotriene C?‚„, leukotriene D?‚„, and leukotriene E?‚„ all contain the amino acid cysteine, they are collectively referred to as cysteinyl leukotrienes. The cysteinyl leukotrienes are degraded rapidly in the extracellular space and the liver to inactive products.

In neutrophils, leukotriene A?‚„ is converted to leukotriene B?‚„, which is a dihydroxy as opposed to a cysteinyl leukotriene, by the action of leukotriene A?‚„ epoxide hydrolase. Leukotriene B?‚„ is degraded by multiple pathways, including cytochrome P-450 (CYP4F4, CYP4F5) and 12-hydroxyeicosanoid dehydrogenase in multiple tissues. Cysteinyl leukotrienes are a subtype of the leukotriene receptor and mediate the tightening of pulmonary vascular smooth muscle. Leukotrienes have been proven to play a key role is asthma and the reaction to the airway as there is an increase in production during a reaction.Allergy induced asthma has an immediate reaction to the body as well as a delayed reaction of the leukotrienes. Regular use of leukotriene modifier and an antihistamine have been found to significantly reduce the allergic reaction as well as eliminate early indication of an allergen asthma attack. Chronic asthma can be determined by a patient having ongoing symptoms and a variance in the peak flow of 20% throughout a twenty-four-hour period. Many leukotriene modifiers are available to asthma patients. One such modifier was found to have a significant effect on leukotriene production. Zileuton inhibits leukotriene synthesis by inhibiting 5-lipoxygenase; clinical doses of zileuton reduce the synthesis of leukotrienes by 70 to 90 percent.

Recently, the concentration of nitric oxide present in exhaled breath (FeNO) has been evaluated as a tool for assessing asthma. FeNO is elevated in patients with asthma, is reduced by treatment with inhaled corticosteroids, and correlates with eosinophilic airway inflammation measured using bronchial biopsies and induced sputum. Shaw et al. study researched the effectiveness of utilizing nitric oxide with standard asthma treatments versus no nitric oxide with treatment. There is a continuing discussion on whether or not FeNO is accurate in managing asthma. One research group completed a study that tested the theory that titrating corticosteroid dose using the concentration of FeNO results in fewer asthma exacerbations and more efficient use of corticosteroids, when compared with traditional management. Shaw et al. research indicated that there is no correlation between reduction in corticosteroid use and the reduction of exacerbation frequency. Though this study did find the participants ended the study on a lower dose of inhaled corticosteroids with no increase in exacerbations.

With advances in technology throughout the medical field comes advancements in therapy for severe asthma. Omalizumab, a humanised anti-IgE monoclonal antibody specifically binding free IgE, has been introduced in asthma treatment.??µ Omalizumab has been found to be very effective in reducing asthma exacerbations as well as reduce inflammation. Several other new drugs are on the market but additional research needed to be conducted as some have severe side effects. Nonpharmacological approaches, such as diet and exercise, have also become a trend in treatment recommendation in order to control asthma exacerbations.

Asthma Disease Management

Although pharmacologic intervention to treat established asthma is highly effective in controlling symptoms and improving quality of life, measures to prevent the development of asthma, including avoiding or reducing exposure to risk factors, should be implemented wherever possible. Asthma patients should participate in an allergy test as the results would assist with pinpointing certain allergens that could trigger asthma symptoms and exacerbations.

Many patients seen in emergencies rooms during active asthma exacerbations have been found to have noted serum IgE antibodies in relation to common allergens. Chapman et al. states, Although an association between inhalant allergy and asthma has been recognized for over 50 years, in many cases it has been difficult to demonstrate cause and effect. This is because in part some asthmatic patients are nonallergic, and even in allergic patients many other factors are known to trigger asthma attacks, including viral infections, chemical exposure and nonspecific irritants. Likewise, patients are often not aware of a direct association between exposure to a specific allergen (dust mite) and the development of respiratory symptoms. As a result, the role of allergy is often hidden from the patient and many physicians regard allergic reactions as factors likely to exacerbate asthma, rather than a primary cause.

Asthma self-management education encompasses a collaborative partnership between the clinician, the patient, and the patient's caregiver. Education plays a key role in the patient having controlled asthma versus uncontrolled asthma. Utilizing something as simple as a peak flow will allow the patient to understand what the results mean and what the next step is if an asthma exacerbation is starting to happen. Myers et al., suggests, A written asthma action plan is the most appropriate method to provide concise instructions on managing ambulatory asthma symptoms and exacerbations. This written plan should include relevant information regarding triggers, medications, and emergency contacts. The patient should be familiar with and able to use a peak flow meter, and to know his or her personal best peak flow. When identifying triggers, it is important to consider the patient's home life and what the child may be exposed to on a daily basis. Understanding what led to the most recent exacerbation can also help pinpoint what factors could be contributing. Education should also include a detailed written plan that the patient and others are aware of that explains the timeline for home treatment as well as when emergent intervention is needed by way of the emergency room. Continuing education has a direct relation with compliance amongst patients which ultimately has an impact on the global burden with healthcare costs in relation to asthma.

Economic Cost of Asthma

Considerable progress has been made in treating reversible airway disease, yet the prevalence and burden of asthma has increased in recent years. Smith et al. suggests, The appropriate use of maintenance medications and medical therapy allows many asthmatics to control their asthma, but the cost of treatment can be high. Treating acute attacks also consumes considerable medical resources. In addition, asthma symptoms often result in work and school absenteeism and lead to a decreased quality of life. Direct costs of asthma include diagnostic tests, prescribed medications, physician visits; which include office, clinic and emergency room visits, as well as inpatient hospital visits. The leading contributors to the direct medical cost of asthma in the United States are hospitalization costs and medication, representing approximately two thirds to three quarters of total direct costs. Indirect costs are sometimes called opportunity costs and are the value of resources lost as a result of time absent from work or other usual daily activity as a result of illness. Loss of work, loss of school, days spent in bed and restricted or loss of physical activity are all areas that have a direct impact on the economic burden of asthma. Both direct and indirect costs have an influence on costs as outcomes and total costs. For example, a study looking at the impact of an asthma intervention based on peak flow monitoring found a reduced emergency department use among members of the intervention group, resulting in a significant cost savings.

Global Burden of Asthma

It is estimated that as many as 300 million people of all ages, and all ethnic backgrounds, suffer from asthma and the burden of this disease to governments, health care systems, families, and patients is increasing worldwide. Masoli et al. states, With the projected increase in the proportion of the world's population that is urban from 45% to 59% in 2025, there is likely to be a marked increase in the number of asthmatics worldwide over the next two decades. It is estimated that there may be an additional 100 million persons with asthma by 2025. In order to better understand the global burden and costs of asthma one must understand the barriers worldwide. Genetics play a large role for the predisposition for asthma. Poverty and social class directly impact much of the population worldwide. Living situations and inaccessible medical assistance plague much of the third world countries. The inability to access proper medical care leaves many mothers unable to control the development of their children before birth. Even after birth, many factors still have a direct effect on a person with asthma. Air pollution, smoke, respiratory illnesses, such as tuberculosis, poor supply and cost of medication, as well as many more areas for concern, have a direct relation to the worldwide burden of asthma.

Many factors have been identified as possible causes of the increased morbidity and mortality, including poor patient understanding of the disease process and of appropriate medication use, noncompliance with prescribed medical regimens, and an inability to use medications properly, especially inhalers. Evidence of morbidity from asthma was found in many patients taking little or no prophylactic medication and this should be amenable to improved education. Ultimately, reducing economic and worldwide mortality and morbidity all comes back to the basics. Correctly diagnosing and classifying asthma leads right into proper and continuing education as well as reinforcing with the individual the importance of utilizing the tools they have in order to live a more productive life with a reduced risk of mortality from asthma.

Summary

While asthma management and treatment have made huge strides over the past few decades, many questions remain regarding epidemiology, pathophysiology, environmental control, disparities in care, diagnosis, assessment, monitoring, pharmacology, exacerbation management, and education, and many great mysteries have yet to be solved. This paper's purpose was to provide a definition and description of asthma and it's etiology and pathophysiology in order to better understand diagnosing and classifying asthma correctly in the patient. The treatment and management of asthma continues to be a hot topic for discussion as the economic and global impact of asthma is significant and will only get more complex in the near future. There will be a need for collaboration and standardization in regards to care and treatment of asthma patients. Research that addresses asthma prevention, disease modification, and reversal of underlying mechanisms, is of particular need and importance. Improve accessibility to essential drugs for the management of asthma in low? and middle?income countries. Adapt international asthma guidelines for developing countries to ensure they are practical and realistic in terms of different health care systems. Increasing the economic wealth and improving the distribution of resources between and within countries represent important priorities to enable better health care to be provided. Development of evidence-based interventions will also need to addressed in the future. Wider dissemination and implementation of evidence-based interventions that tailor care to individual risks and sensitivities, as well as to community-wide characteristics, must be investigated and deployed successfully across the continuum of care to ensure high standards of asthma care. Understanding asthma, it's etiology and pathophysiology, can directly affect global costs by way of correctly diagnosing and classifying asthma patients, as well as promoting correct treatment and management through education and compliance.

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