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Asthma

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A chronic inflammatory disease of the airways characterized by recurrent episodes of wheezing, shortness of breath, chest tightness, and cough.

Affects an estimated 300 million individuals worldwide.

Estimated approximately 250,000 asthma-related deaths occur yearly, many of which are avoidable.

Pulmonary CD4+ cells produce type 2 helper (Th2) cytokines interleukin 4, interleukin 5 and interleukin 13, which enhance the growth, differentiation and recruitment of IgE producing B cells, eosinophils, basophils and mast cells which induce airway hyperactivity.

Biologic therapies targeting IgE , interleukin4 come interleukin13, and interleukin5 are effective in treating moderate to severe type two asthma.

Severe asthma affects less than 10% of patients with asthma, and is associated with substantial morbidity and mortality.

Up to 10% of adults and 2.5% of children with asthma have severe asthma, with reduce quality of life, increased risk of fixed airflow limitation, exacerbations, hospitalization and death.

In severe asthma persistent symptoms or frequent exacerbations required repetitive glucocorticoid bursts, steroid maintenance, or both and despite adequate treatment with high-dose inhaled steroids, long acting beta2 agonists, long-acting muscarinic antagonists, these patients need an add-on treatment which may include biologic therapies.

Patients with the asthma have increased susceptibility to streptococcal infections, increased bacterial pathogens, Interferon and type 1T helper cell responses to bacterial polysaccharides.

A clinical diagnosis based on medical history, physical examination, determination of airway obstruction reversibility and exclusion of diseases that mimic asthma.

No single diagnostic test exists for asthma.

Asthma should be suspected in the presence of episodic wheezing, shortness of breath, cough, and tightness of the chest, especially if more than one symptom is worse at night or precipitated by an upper airway infection.

Cause is multifactorial and is influenced by genetic and environmental mechanisms.

Allergic asthma results from maladaptive inflammatory responses the environmental proteins in genetically susceptible people.

Genome studies indicate the genetic association between interleukin 33 and asthma susceptibility.

Environmental allergens important cause.

All individuals with asthma of all severities should be assessed for exposure to allergens at home and at work, for symptoms on exposure, and for  sensitization  either by allergy skin testing or allergen specific IgE.

Characterized clinically by an excess tendency toward reversible airway narrowing.

May arise from environmental exposures and is worsened by intercurrent infections, and in sensitized persons, by exposure to allergens.

Aeroallergens are important in the pathogenesis of asthma, with allergic sensitization as a major component and risk factor for disease severity.
Aeroallergens provoke inflammation of the airways, cause outflow obstruction and exacerbation of asthma.
Aeroallergens oh cockroach and mouse allergen are associated with increased number of days of asthma symptoms in children.

A significant proportion of severe cases are related to allergic IgE mediated mechanisms.

Allergic asthma is a chronic inflammatory process of the airways mediated by CD4+T cells polarized to a type 2 helper (Th2) phenotype.

The dysregulation of innate and adaptive immune responses plays a central role in the development of asthma.

Allergic response type 2 helper T cell (Th2), also termed Th2 molecular endotype is characteristic of allergic asthma.

Approximately half the patients with asthma, exhibit Th2 endotype.

Th2 to endotype is characterized by predominate activation to Th2 cells that produce cytokines such as interleukins 4,5, and 13.

Class II major histocompatibility complex (MHC)-restricted CD4+Th2 T cells detected in the airways of almost all patients with asthma.

Major histocompatibility-complex (MHC) class II-dependent CD4+ T lymphocytes respond to environmental allergens and are key to initiation of asthma.

Chronic goblet cell metaplasia and airway hyperreactivity, changes which are dependent on the secretion of interleukin 13 by lung macrophages and subgroup CD4-CD8 T lymphocytes, called invariant natural killer T cells-concluding that chronic airway disease may occur in the absence of MHC class II dependent CD4+ T cells (Kim).

A helper Tcell type 2-predominant condition.

Increases the risks of helper T cell type-1 polarized pro inflammatory conditions such as coronary heart disease and diabetes mellitus.

Thymic stromal lymphopoietin (TSLP), an epithelial cell derived cytokine produced by proinflammatory stimuli driving allergic inflammatory responses via activity on innate immune cells, including mast cells, dendritic cells and CD34 positive progenitor cells.

Pathologically epithelial goblet-cell hyperplasia, subepithelial collagen deposition, and smooth muscle hypertrophy are referred to as airway remodeling.

Bronchoconstriction increases mechanical forces within airways distorting tissue cells causing airway remodeling.

Phenotypic features of the disease correlates with the age at the onset in children and adults.

Asthma associated phenotypes vary over time.

Atopy and the family history of asthma are more common in patients with early onset asthma, whereas current smoking is more common with late-onset disease.

Patients with late onset asthma are likely to report nighttime awakenings due to their asthma symptoms.

A new diagnosis of asthma is unusual after 40 years of age.

Adult onset asthma is associated with obesity, asthma with fixed airflow limitation, smoking, and perhaps COPD.

Associated with an increased risk of new onset of obstructive sleep apnea.

Asthma and obstructive sleep apnea deleteriously influence each other.

In elderly patients with asthma lung function usually decreases with the longer duration of the process, increasing age and stiffness of the chest wall, reduced respiratory muscle function, loss of elastic recoil, and airway wall remodeling.

In patients with difficult to control asthma there is a high prevalence of obstructive sleep apnea up to 90%,of cases.

50% to 90% of total pulmonary resistance in asthma resides in the peripheral airways or in the small airways.

?49% of total pulmonary resistance in asthma is due to central airway resistance or large airway obstruction.

Age at onset correlated with asthma phenotypes, such as wheezing.

Single nucleotide polymorphisms on chromosome 17q21 associated with the risk of disease and regulates the expression of at least one gene, ORMDL3.

17q21 locus is associated with early onset asthma before the age of four years.

In children of African ancestry , and of northern European ancestry have association of asthma at the 1q31 locus containing DENND1B gene, and this gene expressed by natural killer cells and dendritic cells and encodes a protein that interacts with TNF-alpha receptor. (Sleighman P).

Environmental exposure to tobacco smoke in early life interacts with genetic susceptibility to asthma-17q21.

Single nucleotide polymorphism rs37972, which maps glucocorticoid-induced transcript 1 gene (GLCC11), is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma (Tantisira KG et al).

Association between 17q21 markers and early onset asthma may indicate a different biologic process from later onset asthma.

Prevalence of asthma among children increase form 3.6% in 1980 to 5.8% in 2003.

4-17% children, 7.3%-10.1% adults in the US.

Prevalence in children and adolescents range from 6.9-19% by high school graduation.

There is a disproportionate representation among women, ethnic minorities and people who are economically disadvantaged.

Asthma control usually improves after menopause in women who don’t take hormone therapy.

 

 

In general, estrogens increase asthmatic inflammation, whereas androgens reduce it.

Prevalence in US adults aged 65 years or older is similar to that in children.

Asthma prevalence in the u.s. population age 65 years or older is 6.9% and increasing, and is similar to that in Children of about 8.6%.

In the U.S. 24 million people with 5000 deaths annually.

Results in roughly 500,000 hospitalizations annually.

Annual economic burden $56 billion per year.

One in every nine U.S. adults has asthma, accounting for an estimated 1 million hospital visits and 1.6 million ED visits each year.

Asthma prevalence is 39% higher in African Americans than in Europeans.

Treatment costs totaling more than $30 billion/yr.

In 2010 the number of people reported to have asthma was 25.7 million.

National rate is 1 in 12 adults have asthma.

300 million person affected worldwide, with 250,000 deaths annually.

Third leading cause of hospitalization among individuals under 18 years of age, behind pneumonia and injuries.

Severe disease occurs in less than 10% of patients with asthma and is associated with substantial morbidity and mortality.

Most cases present in childhood or young adulthood.

Nine people die from asthma daily, and the prevalence continues to increase.

Age specific mortality associated with asthma in older patients.

Hospitalizations for older patients remain lower than that for younger patients.

Asthma in older patients divided into patients with long standing disease from childhood, and late onset disease following sixth decade of life.

Diagnosis in older patients difficult reflecting other diagnoses such as COPD, or CHF.

In older asthmatic patients eosinophilic inflammation is associated with airway hyperresponsiveness, and neutrophils determine airflow limitation at rest and during bronchoconstriction.

Aging decreases lung capacity over time, and leads to obstruction defect on PFTs, making it difficult to distinguish from active disease such as asthma.

Associated with increased risk of serious pneumococcal disease ,Streptococcus pyrogenes, otitis media, and Bordetella pertussis infections.

Patients with asthma have an impaired innate and adaptive immunity which results in increased risk of microbial infection.

The nascent gut microbiota of infants is essential in establishing proper immune function and that disruptions to this community results in early dysfunction and subsequent development of asthma.

Patients with asthma aremore likely to have a diagnosis of selective IGA deficiency or common variable immunodeficiency than non-asthmatic individuals, accounting for their increased risk of bacterial infections in some individuals with asthma.

Acute asthma exacerbations result in 1.8 million hospitalizations per year, with an estimated mortality rate of 13.3 deaths per million per year in US adults.

Children and adults with asthma with a serum vitamin D level of this than 30 ng/mL have been linked to airway hyperresponsiveness, impaired lung function, increased exacerbations and reduce corticosteroids responsiveness.

Vitamin D supplementation during the prenatal period does not influence the six-year incidence of asthma and recurrent wheeze among children who were at risk for asthma.

Slightly more boys than girls are affected and after puberty more women affected than men.

Twenty percent develop in patients over the age of 45 years.

Most common chronic illness in childhood in the U.S.

Increasing prevalence and the increase is more among women and minorities.

After age 17 women had to have a 40% higher asthma prevalence than men, they experiencesignificantly more asthma attacks, and require hospitalization more often with exacerbations.

Peak incidence is in the first to fourth years of life.

Genetically complex process with high interindividual repeatability and high individual variability.

Up to 40% of patients have no response to therapy (Szefler SJ et al).

Poor control of asthma is associated with environmental factors such as air pollution and cockroach feces, lower socioeconomic status, and ow level of literacy.

Asthma uncontrolled in 58.8% of adults and 49.7% of pediatric patients.

Uncontrolled asthma defined as occurring in patients who are symptomatic and experience rescue medication administration >2 times/week: nocturnal symptoms, limited activities, lung function obstruction with <80% predicted on Spirometry; or daytime symptoms >2 times/week (Global Initiative for Asthma).

Anti-inflammatory medications for long-term control of childhood asthma require inhaled corticosteroids or nedocromil.

Recurrent episodes of asthmatic wheezing in pre-school age children are usually triggered by respiratory tract infections, which may progress to severe exacerbation requiring systemic glucocorticoids.

In children under age 5 with at least four wheezing episodes in the previous year and a positive value on the modified asthma predictive Index, long-term daily inhaled glucocorticoid therapy is recommended.

The Childhood Asthma Research and Education(CARE) Network Prevention of Early Asthma in Kids (PEAK) trial found daily inhaled glucocorticoids benefited children with at least one exacerbation requiring emergency or hospital care during the previous year.

Daily use of inhaled glucocorticoids in children less than five years of age was associated with a small but significant reduction in height, a reduction that was only partially reversed during a one-year observation after discontinuance in treatments.

The use of chronic proton pump Inhibitors does not improve symptom control in children with asthma, and may be associated with adverse effects.

Prevalence of 1% in pregnancy.

34-89% of asthmatics have GERD and up to 40% have peptic esophagitis.

GERD postulated to cause bronchoconstriction by microaspiration into the airways directly, and indirectly via vagal mediated effects of acid on the upper airway or esophagus.

GERD associated with adult onset asthma.

Asthma may lead to the development of GERD by changing the pressure gradient between the thorax and the abdomen causing displacement of the lower esophageal sphincter into the chest, by induction of pulmonary hyperinflation exacerbating diaphragmatic dysfunction, and by lowered esophageal sphincter tone decreased by use of bronchodilators.

In pregnancy associated with increased maternal morbidity, especially for those women requiring oral corticosteroids.

24-85% of all asthma attacks in children are associated with a viral respiratory tract infection.

Atypical bacterial infection and or a reactivation is associated with serologic positivity rates of 40 to 60% of asthma exacerbations, indicating that viral and atypical bacterial infections may interact in increasing exacerbation risk.

Annual influenza vaccination for protects against acute asthma exacerbations in children.

24% increase in asthma-related mortality for those >65 years of age between 1984-94 with no increase in other age groups.

Patients with difficult to manage asthma should not be given beta-blockers.

Self-management plan is a process whereby the patient modifies their treatment in response to the severity of their asthma in accordance with predetermined severity.

Self-monitoring of peak flow and key symptoms with regular medical review represents the optimal management of asthma and should be offered to most adults with asthma.

Use of inhaled steroid therapy decreases the rate of hospitalization by approximately 50% and mortality up to 90%.

For patients with mild persistent disease regular treatment with inhaled corticosteroids is recommended.

The doubling of the dose of inhaled corticosteroids reported to be ineffective in preventing exacerbation of asthma, but high dose inhaled corticosteroids administered at the time of exacerbation can improve control of the disease.

When asthma control has been achieved with inhaled corticosteroids it is recommended that stepping down of therapy to minimize adverse effects of medications, especially for those with moderate to severe disease.

Long acting beta agonists, formoterol and salmeterol associated with more deaths when used alone in the treatment of asthma.

Long acting beta agonists should not be used in the management of asthma without corticosteroids or other asthma controller, to reduce rare, but serious, adverse events (FDA).

The use of long-acting beta agonists increases the risk of severe exacerbations of asthma, hospitalization, and death compared to asthma controller therapes alone.

Meta-analysis of 110 clinical trials of long-acting beta agonists involving 60,000 patients taking formoterol, salmeterol, formoterol plus budesonide, and salmeterol plus fluticasone: the long-acting beta agonists (LABA). were associated with a greater risk of asthma related death, asthma related intubation or asthma related hospitalization, 16 deaths occurred in the salmeterol group and only 4 deaths in the non-long acting beta agonist group (Rappley).

A systemic analysis and meta analysis of randomized controlled studies of stepping off long- acting bronchodilators in asthmatic patients controlled by combination of inhaled corticosteroids and long- acting bronchodilator therapy: discontinuing LABA in patients with asthma results in increased asthma associated impairment compared with continued use of LABA and inhalation all corticosteroids (Borzek JL et al).

Treatment with mepolizumab, which is a monoclonal antibody against interleukin-5, a pro eosinophilic cytokine, significantly reduced the number of lung and blood eosinophils in a small group of patients with severe corticosteroid resistant asthma.

Monoclonal antibodies against interleukin- 5, when administered intravenously is effective in decreasing both the rate of asthma exacerbations and the maintenance dose of systemic glucocorticoids in the control of asthma in patients with sputum eosinophilia of more than 3%.

In a three way double-blind study of 210 patients with asthma the addition of tiotropium bromide, a long-acting anti-cholinergic agent, was added to an inhaled glucocorticoid, as compared with doubling of the dose of the inhaled glucocorticoid or the addition of the long acting beta agonist salmeterol: the addition of tiotropium two inhaled glucocorticoids improves symptoms and lung function in patients with inadequately controlled asthma and its effects appear to be equivalent to those with the addition of salmeterol (Peters SP et al).

Use of mepolizumab was associated with significant reduction in asthma exacerbations suggesting that eosinophils play a central role in asthma and its outcome.

Mepolizumab administered intravenously was subcutaneously reduces asthma exacerbations and is associated with improvements in the markers of asthma control.

Accumulation of eosinophils predicts a good response to inhaled corticosteroids.

Anti-IgE in treatment with omalizumab is a recumbent humanized monoclonal used for patients with uncontrolled moderate or severe allergic asthma and is effective and safe.

Unhygienic contact with other children or animals decreases significantly the risk of asthma.

Patients with asthma more likely to be obese than non-asthmatics.

Patients with asthma should be encouraged to improve physical fitness to gain general health benefits.

Measurement of the fraction of exhaled nitric oxide is a noninvasive marker that is useful to adjust the doses of inhaled corticosteroids.

Expert panel of the National Asthma Education recommends hospitalization for patients with peak flow of <50% of predicted after emergency department treatment.

Airways in refractory asthma have more heterogeneous inflammatory response, increased involvement of neutrophils, increased involvement of the distal lung and airway remodeling than in mild to moderate asthma.

All adult asthmatic patients should receive a single dose of 23-valent pneumococcal vaccine to prevent pneumococcal disease.

Recommending a daily oral magnesium supplement could help prevent asthma flare ups and reduce inhaler use.

It is known to relax smooth muscle cells by reducing intracellular calcium and exhibits an anti-inflammatory effect by balancing T-cells and suppressing mast cells.

It also inhibits acetylcholine release and nitric acid and prostacyclin synthesis to decrease muscle fiber excitability.

A systemic literature review to assess magnesium supplementation as a nonpharmacological treatment for asthma management in both oral and intravenous formulations.:

Magnesium Improves pulmonary function on the FEVI and FVC

Itepekimab, a IgG4P monoclonal antibody against interleukin 33 leads to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate to severe asthma.

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