Asthma

History

  • Historical Existence of Asthma: asthma has been known to exist for centuries
  • Derivation of the Term Asthma: the word asthma is derived from the Greek word for panting (lachániasma)

Definitions

  • Asthma: chronic inflammatory airway disorder (involving mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and epithelial cells), which is generally charecterized by the presence of reversible airway obstruction (either spontaneously or in response to treatment) and bronchial hyperresponsiveness (to various stimuli)
    • However, the above features are neither sensitive nor specific for the diagnosis of asthma
      • Bronchial hyperresponsiveness can be observed in allergic rhinitis without asthma
      • Some patients with recurrent wheezing/dyspnea associated with reversible airway obstruction/bronchial hyperresponsiveness do not have eosinophilic bronchial inflammation
        • Thickening of airway lamina reticularis (immediately under the supepithelial basement membrane) is a more consistent feature in asthma than eosinophilic airway inflammation -> this thickening reflects the presence of airway remodeling
      • Some patients have eosinophilic bronchial inflammation and chronic cough respond to inhaled steroids, but do not have reversible airway obstruction/bronchial hyperresponsiveness
      • Some patients with severe asthma have neutrophil-predominant (rather than eosinophil-predominant) airway inflammation
  • Bronchial Hyperresponsiveness: defined as the increase in airway resistance in response to the inhalation of physical or chemical irritants
  • Relationship Between Obstructive Airway Diseases

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Prevalence

  • 2006 Asthma Prevalence Data
    • Asthma affects 16.1 million adults (7.3% of the population) in the USA
    • Asthma affects 6.8 million children (9.4% of the population) in the USA
  • Increasing Asthma Prevalence
    • Asthma prevalence has increased (likely due to multiple factors) from 3% in 1980 to 7.7% in 2005
  • Age-Related Prevalence Data
    • Prevalence of asthma decreases with increasing age
  • 2005 Sex/Race-Related Prevalence Data
    • Puerto Ricans had asthma prevalence rates 12% higher than non-Hispanic whites and 80% higher than non-Hispanic blacks
    • Females had a 40% higher prevalence than males (except in <18 y/o group: where males had higher revalence than females)
  • International Study of Asthma and Allergies in Childhood (ISAAC): data from 1996-1997 in 6-7 y/o and 13-14 y/o children
    • Highly variable asthma rates worldwide: ranging from 2.1-4.4% in Albania/China/Greece/Indonesia to 29.1-32.2% in Australia/New Zealand/UK
    • Atopy/allergic rhinoconjunctivitis/atopic ezcema are highly correlated with the prevalence of asthma
  • International Study of Asthma and Allergies in Childhood (ISAAC)-Phase 2
    • Asthma prevalance rates are higher in more affluent countries: likely related to higher number of people living in urban (rather than rural) areas
  • International Study of Asthma and Allergies in Childhood (ISAAC)-Phase 3: examined temporal changes in asthma prevalence rates
    • Prevalence of asthma increased in Africa/Latin America/parts of Asia
    • Prevalence of astham decreased in English-speaking countries and Western Europe
  • European Community Respiratory Health Survey (ECRHS): 1996 data
    • Lowest asthma prevalance rates in India/Algeria and highest rates in UK/New Zealand/Australia/US
  • Worldwide Deaths from Asthma: approximately 180k deaths occur annually due to asthma wordlwide (although death rates vary geographically)
    • Increasing in US and worldwide between 1980 and the mid-1990’s
      • Increased death rates in New Zealand/Australia in early 1980’s has been attributed to the use of the beta agonist, fenoterol
    • More recent asthma-related death rates have been declining (likely due to increased use of inhaled steroids, improved access to care, and improved asthma diagnosis)
  • US Death Rates from Asthma: appoximately 4k deaths occur annually due to asthm ain US
    • Deaths from asthma are rare in <18 y/o age group
    • Death rates from asthma plateaued in the US between 2001-2003
    • In 2003, 4055 asthma deaths occurred in US (rate: 1.4 deaths/10k persons)
      • Death rates were higher in >65 y/o age group
      • Death rates were higher in females: females had 45% higher risk of death from asthma than males
      • Puerto Ricans had the highest risk of death from asthma -> 3.6x higher than that of non-Hispanic whites
      • Non-Hispanic blacks had a death rate that was 2x higher than non-Hispanic whites
    • Disparities in death rates are due to variations in asthma severity, lack of access to health care, increased exposure to exacerbants (in urban areas), lack of access to medications, and differences in asthma medications prescribed by providers

Risk Factors for Asthma

Hygiene Hypothesis

  • History: theory was first proposed by Strachan in 1989
  • Hypothesis: exposure to infections early in life results in development of a predominantly T-helper (Th)1-mediated immune response and downregulation of the (Th)2-mediated immune response
    • Epidemiologic studies support this hypothesis in European countries more strongly than in other countries
    • However, this hypothesis does not explain the higher prevalance of asthma in inner cities
  • Factors Associated with (Th)1-Predominant Immune Response: leads to protective immunity
    • Early Exposure to Daycare
    • Farm Environment
    • Presence of Older Siblings
    • Tuberculosis
    • Viral Infection
  • Factors Associated with (Th)2-Predominant Immune Response: predisposes allergic diseases (including asthma and allergic rhinitis)
    • Aeroallergens
    • Diet
    • *Urban Envronment
    • Westernized Lifestyle
    • Widespread Use of Antibiotics

Infections

  • Respiratory Infections (Especially Viral) are Common in Childhood
    • Viral illnesses are responsible for >90% of wheezing illnesess in early childhood
    • However, exposure to infections has a variable impact on the development of asthma, depending on host factors, timing, location, and the type of organism
    • Diagnosis of croup or having two or more ear infections in the first year of life is inversely related to atopy at school age
    • Bronchiolitis in first year of life was associated with increased odds of developing asthma at age 7
  • Role of Respiratory Syncytial Virus (RSV) (see Respiratory Syncytial Virus, [[Respiratory Syncytial Virus]])
    • Respiratory Syncytial Virus is the Most Common Cause of Bronchiolitis
    • Early Life Respiratory Syncytial Virus Infection is Associated with an Increased Risk of Asthma/Wheezing
      • Wheezing from RSV infection from birth-3 y/o increased odds ratio to 2.6 of developing asthma by age 6 [MEDLINE]
  • Role of Rhinovirus (see Rhinovirus, [[Rhinovirus]])

    • Rhinovirus Infection are Common in Childhood: occur most commonly in the spring and fall
    • Early Life Rhinovirus Infection is Associated with an Increased Risk of Asthma
      • Wheezing from Rhinovirus infection from birth-3 y/o increased odds ratio to 9.8 of developing asthma by age 6 (the odds ratio increased to 10.0 in presence of both RSV and rhinovirus-related wheezing illnesses from birth-3 y/o) [MEDLINE]
  • Role of Atypical Bacterial Pathogens: poorly-defined triggers of future asthma (most are associated with chronic stable asthma)

    • Chlamydophila Pneumoniae (see Chlamydophila Pneumoniae, [[Chlamydophila Pneumoniae]]): has been found in airways of chronic asthma are associated with increased airway inflammation and more severe asthma phenotype
    • Mycoplasma Pneumoniae (see Mycoplasma Pneumoniae, [[Mycoplasma Pneumoniae]]): has been found in airways of chronic asthma are associated with increased airway inflammation and more severe asthma phenotype

Atopy

  • Incidence of Asthma in Childhood is Strongly Associated with Hay Fever and Eczema
  • Positive Family History of Atopy is an Important Risk Factor for Atopy in Children
  • Relationship Between Atopy and Asthma in Adults
    • Approximately 40% of adults are atopic (by skin tests), but only 7% have asthma (those with worst asthma are the most atopic)
    • 85-90% of adults and children with documented asthma are atopic
      • After age adjustment, the prevalence of asthma increases with increasing IgE: patients with low IgE generally do not have asthma
  • Occupational Asthma: not all of those people exposed become sensitized (of those sensitized, some develop airway reactivity)
  • Development of Atopy Later in Life: seen in some non-affluent societies

Diet

  • Breast Feeding May be Protective Against the Development of Asthma
  • There is Some Association Between Sodium Intake and Asthma
  • Regular Fish Diet Decreased the Risk of Airway Hyperreactivity in Australian Children: possibly explains low prevalence of asthma in Mediterranean/Arctic countries

Obesity

  • Incidence of Obesity 30% of adults >18 y/o are obese
    • Approximately 68% of the US adult population is either overweight or obese
  • Asthma Risk is Associated with Obesity (BMI >30): demonstrated in multiple studies
    • May be related to adipokines and their role in airway inflammation

Genetics

  • Genetics Play a Major Role in the Development of Asthma
  • There is a Higher Concordance Rate for Asthma in Monozygotic than Dizygotic Twins
  • There is an Increased Prevalence of Asthma in First-Degree Relatives of Asthmatics

Environmental Exposures

  • Role of Tobacco (see Tobacco, [[Tobacco]]): role in the development of asthma is controversial
    • In utero/early childhood tobacco exposure increases risk for wheezing in childhood, persisting into adulthood
    • Environmental tobacco exposure in childhood increases the risk of asthma
  • Role of House Dust Mites: house dust mites are probably most potent allergen associated with sensitization and asthma
    • House dust mites are found where humidity is >55% for majority of the year and skin scales exist as food source
    • Correlation between degree of infestation and symptoms: threshold exists for sensitization and acute exacerbation
    • Early exposure to high quantity of mite allergen may be involved in infantile asthma
    • Most children with persistent asthma are allergic to mites
    • Dust mite feces enter the lungs: unclear if allergen binds to IgE or penetrates (due to proteases) mucosa to cause late allergic response

Asthma Triggers

Allergens

Food/Food-Related Allergens

  • General Comments: rarely cause isolated asthma without other symptoms
  • Aerosolized Food Allergens
    • Inhalation of Flour Dust in Wheat-Allergic Patients
    • Inhalation of Steam/Vapor from the Cooking Process in Seafood/Egg/Cow’s Milk-Allergic Patients
  • Food-Induced Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]]): may present with asthmatic symptoms as part of the presentation
  • Sulfites (Non-IgE-Mediated): used to preserve foods
    • High Sulfite Content: Dried Fruit (Excluding Dark Raisin/Prunes), Grape Juice, Lemon, Lime Juice, Wine
    • Moderate Sulfite Content: Dried Potatoes, Fruit Topping, Gravies/Sauces, Maraschino Cherries, Pectin, Pickled Vegetables, Sauerkraut, Shrimp (Fresh), Wine Vinegar
    • Low Sulfite Content: Beer, Canned Potatoes, Coconut, Cookies, Corn Starch, Crackers, Dried Cod, Dry Soup Mix, Fresh Fruit Salad, Fresh Mushrooms, Frozen Potatoes/Pizza Dough, Gelatin, Grapes, High Fructose Corn Syrup, Hominy, Jams/Jellies, Instant Tea, Malt Vinegar, Maple Syrup, Pie Dough, Soft Drinks, Sugar

Inhalant Allergens

  • Animal Allergens
  • Cockroaches
  • Fungi
    • Mildew
    • Mold
  • House Dust Mites
  • Outdoor Plant Allergens
    • Grass
    • Ragweed Pollen
    • Trees

Occupational Allergens (see Asthma-Occupational, [[Asthma-Occupational]])

  • Low Molecular Weight Chemicals (MW <5000 D)
  • High Molecular Weight Chemicals (MW >5000 D)

Emotional Factors

  • Chronic Stress
  • Depression (see Depression, [[Depression]])
  • Exposure to Community Violence

Hormonal Fluctuations

  • Menstrual Period
  • Pregnancy (see Pregnancy, [[Pregnancy]])
    • 33% of Cases: pregnancy has no impact on asthma
    • 33% of Cases: pregnancy exacerbates asthma
    • 33% of Cases: pregnancy improves asthma
    • Predictors of Asthma Severity in Pregnancy
      • Level of Asthma Severity Prior to Onset of Pregnancy
      • Level of Asthma Severity in Prior Pregnancies

Irritants

  • Air Pollution: contains sulfur dioxide, nitrogen dioxide, ozone, and particulate matter
    • Ambient Particulate Matter
    • Desert Dust: contains quartz particles (crystalline silica)
    • Elemental Carbon/Soot
    • Nitrogen Dioxide (see Nitrogen Dioxide, [[Nitrogen Dioxide]])
    • Ozone (see Ozone, [[Ozone]])
  • Chlorine (see Chlorine, [[Chlorine]]): in many cleaning products
  • Fumes from Unvented Gas Stoves
  • Glacial Acetic Acid (see Acetic Acid, [[Acetic Acid]]): in factory workers and professional cleaners
  • Odors
  • Sodium Azide Inhalation (see Sodium Azide, [[Sodium Azide]]): following automobile airbag deployment
  • Tobacco Smoke (see Tobacco, [[Tobacco]])
  • Volatile Organic Compounds and Formaldehyde: from newly-installed carpeting, paint, furniture

Medications

  • Beta Blockers (see β-Adrenergic Receptor Antagonists, [[β-Adrenergic Receptor Antagonists]])
    • However, studies indicate that propanolol does not worsen methacholine or histamine airway hyperresponsiveness or mini-asthma quality of life questionnaire (mini-AQLQ)/asthma control questionnaire (ACQ) scores [MEDLINE]
  • Non-Steroidal Anti-Inflammatory Drugs (NSAID) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal Anti-Inflammatory Drug]])
  • Prostaglandin F2: used in pregnancy

Respiratory Infections

Temperature/Weather

  • Cold, Dry Air
  • Hot, Humid Air
  • Wet Conditions/Thunderstorms

Other

  • Exercise

Agents that Provoke Airway Narrowing

  • Aeroallergens

    • IgE-mediated, cysteinyl leukotriene-mediated, may cause late asthmatic responses): animal (hair/ scales/ urine/ serum/ arthropod remains), vegetable (wood/ roots/leaves/flowers/cereal/grains/rye grass pollen/ soya beans/ green coffee and castor beans/ arabic, adragante, karaya gums), textiles (cotton/ jute/ flax/ hemp), chemical allergens (PCN/ ampicillin/ cephalosporin powder/ macrolides/ tetracyclines), metals (chromium/ nickel/ platinum/ vanadium/ mercury/ cobalt), plastics (isocyanates/ pthalic and trimellitic anhydrides/ formaldehyde/ latex)
  • Exercise: induces airway narrowing in 70-80% of childhood, adult asthmatics (due to changes in lining fluid osmolarity due to drying, rewarming with vasodilation/ cysteinyl leukotriene-mediated)
    -Exercise does not cause asthma, but is an indirect stimulus (mediated by cysteinyl leukotrienes) for bronchoconstriction in asthmatics
    -Exercise typically causes early bronchodilation in asthmatics (for 1-3 min) -> exercise-induced bronchoconstriction (peaks at 10-15 min) -> resolution within 60 min

  • Osmotic stimuli: hyperventilation with cold or dry air/inhalation of nonisotonic aerosols cause prompt airway narrowing in asthma (probably due to changes in osmolarity of lining fluid/ cysteinyl leukotriene-mediated) and also in COPD (to a lesser extent)
    -Blocked by cholinergic antagonists, inhibited by cromones (suggests neural mechanism)
    -Poorly controlled case reports of late asthmatic response after exercise (possibly due to release of different mediators, etc.)

  • Infection (probably neurally-mediated): viral respiratory infections are believed to be most common cause of exacerbation in asthma (although evidence is scanty)/ extracts of H. Flu cause induce early and late asthmatic responses (may cause exacerbations in adults but probably not children)

  • Sulfur Dioxide (see Sulfur Dioxide, [[Sulfur Dioxide]]): concentrations as low as 1 ppm (even after only 3 min exposures) cause severe bronchoconstriction in asthmatics (>5 ppm usually required in normals)/ patients with persistent asthma respond in a dose-dependent manner/exercise potentiates sulfur dioxide-induced bronchoconstriction (increases delivery to lower airways)/ dry air potentiates the effect of sulfur dioxide/ some wines and beers contain metabisulfite (which produces sulfur dioxide)/ probably acts via sensory nerve endings (cromones protect against it)

  • Air Pollution (contains sulfur dioxide, nitrogen dioxide, ozone, particulates): ozone in air pollution is an acute bronchoconstrictor/ exposure to pollutants can increase allergic responses/low level chronic nitrogen dioxide can increase airway reactivity/ particulate pollution may cause acute asthmatic attacks/ inhalation of sulfuric acid aerosols decreases particle clearance from normal airways

  • Odors: strong smells can induce bronchoconstriction

  • Weather: increased symptoms during high humidity (increased osmotic or allergen load)/ thunderstorms during high pollen counts cause particle disruption and can induce attacks

  • Emotion: stress and hypnotic suggestion induce bronchoconstriction in asthmatics (but usually do not produce attacks)/ hyperventilation (associated with panic attacks) can induce attacks (as described above)

  • Reflex Bronchoconstriction: gastroesophageal reflux disease (GERD) may induce attacks (especially in children)/ nasobronchial reflex may induce bronchoconstriction in some patients with initial rhinitis/ menstrual, premenstrual exacerbation can occur

  • Foods: allergic reactions to nuts may induce asthma/ attacks due to food preservatives (benzoates or tartrazine in ASA-sensitive asthmatics), MSG, coloring agents can be induced in some asthmatic patients with ASA sensitivity

  • Drugs

    • Propanolol (see Propanolol, [[Propanolol]]): neural mechanism involving blockade of ß2-receptor, not cysteinyl leukotriene-mediated
    • Isoproterenol (see Isoproterenol, [[Isoproterenol]])
    • Aspirin (ASA) (see xxxx, [[xxxx]]): acetylated >> non-acetylated salicylates/cysteinyl leukotriene-mediated) and NSAID’s
    • Crack Cocaine (see Cocaine, [[Cocaine]])
    • Radiographic Contrast (see xxxx, [[xxxx]])
    • Dipyridamole (see xxxx, [[xxxx]])
    • Hydrocortisone (see xxxx, [[xxxx]])
    • Interleukin-2 (IL-2) (see xxxx, [[xxxx]])
    • Nebulized Pentamidine (see xxxx, [[xxxx]])
    • Beclomethasone (see xxxx, [[xxxx]])
    • Propellants
    • Nitrofurantoin (see xxxx, [[xxxx]])
    • Propafenone (see xxxx, [[xxxx]])
    • Protamine (see xxxx, [[xxxx]])
    • Vinblastine with Mitomycin (see xxxx, [[xxxx]])
    • Amiodarone (see xxxx, [[xxxx]])
  • Hyperthyroidism (see xxxx, [[xxxx]]): most studies suggest that mild thyrotoxicosis is unlikely to make asthma difficult to control

Etiologic Classification

1) Persistent Asthma: continuing symptoms + chronic airway abnormality (abnormal dose response to histamine/methacholine or increased variation of daily PEFR)
-Generally incurable (some cases remit during adolescence)
2) Obstructed Asthma: symptoms + airflow limitation that persist after maximal treatment with bronchodilators and PO steroids/pathologic changes unknown
3) Episodic Asthma: periodic episodes of symptoms (usually requiring treatment) + no detectable abnormality of airway function between episodes
-Common type during the pollen season/ sometimes seen early in occupational asthma/ described in non-allergic patients/ pathologic changes are unknown
4) Asthma in Remission: past history of asthma without symptoms or therapy for >12 months (usually have some residual airway hyper reactivity)
5) Potential asthma: typically moderate airway hyperreactivity without symptoms or history of asthma
-Particularly occurs in atopic patients
6) Trivial Wheeze: mild or transient wheezing that do not require treatment + normal airway function (absence of airway hyper reactivity)
7) Extrinsic (Atopic) Asthma: asthma in atopic patient (may have attacks in response to non-allergen provoking agents)/ usually positive family history of atopy or asthma/evidence if IgE-mediated mechanisms
8) Occupational Asthma: episodic or persistent asthma due to workplace sensitizer (symptoms and airway narrowing are demonstrated by specific provocation with substance)
9) Intrinsic Asthma: asthma in non-atopic patient (often adult onset)/ usually negative family history of atopy or asthma/ usually no evidence of IgE-mediated mechanisms
-May follow severe respiratory illness/ may be refractory


Physiology

  • CD4 Lymphocytes: Th2 cells have a predominant role in asthma pathogenesis
  • Eosinophils: prominent cells in the airways of many patients with asthma
    • Most asthma phenotypes are associated with blood, bone marrow, and lung eosinophilia: eosinophil is a central effector cell in asthma that contributes to ongoing airway inflammation
  • Inflammatory Cytokines: Th2 cells regulate allergic inflammation via the production of IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13
    • IL-13: likely plays a role in inducing allergic asthma
      -IL-13 has a similar structure to IL-4 and shares the functional receptor, IL-4Rα
  • Reactive Oxygen Species: asthma is characterized by altered airway redox chemistry and increased oxidative stress in the airways
  • Reactive Nitrogen Species: play a role in asthma pathogenesis
  • Arginase: increased arginase activity is observed in allergic asthma
  • Arachidonic Acid Metabolites: play a major role in asthma
    • Cysteinyl Leukotrienes
    • Other 5-Lipoxygenase Pathway Metabolites
  • Histamine: causes bronchoconstriction (in both early and late allergic response), vasodilation, leakage of fluid and albumin from postcapillary venules (increased permeability of epithelium to proteins and fluid occurs only during attacks), smooth muscle proliferation
    • Histamine is increased in the serum of asthmatics

Airway Remodeling

  • Airway Remodeling: cardinal feature of chronic asthma
    • Degree of Airway Remodeling is a Function of Disease Severity Over Time
    • Asthma Treatments May Have Effects on Airway Remodeling
      • Leukotriene Modified Agents Can Decrease Airway Smooth Muscle Mass and Subepithelial Collagen in Animal Models
      • Bronchial Thermoplasty Can Decrease Airway Smooth Muscle Mass
  • Airway Epithelium: altered in asthma
  • Epithelial Basal Lamina: hyalinization and thickening of basal lamina (beneath a normal-appearing epithelial basement membrane) is seen in asthma
  • Extracellular Matrix: increased in airway walls in asthma
  • Airway Smooth Muscle: increased in asthma
  • Goblet Cell Hyperplasia and Mucus Hypersecretion: hallmark of asthma
  • Microvascular Changes: bronchial neovascularization is associated with airway remodeling

Physiologic Manifestations

  • Airway Hyperresponsiveness
    • Diurnal Variation in Airway Responsiveness: normals and asthmatics show increased early morning increases in smooth muscle tone (asthmatics show early morning decreases in PEFR, but normals do not)
  • Increased Airway Epithelial Permeability
  • Smooth Muscle Hypercontractility

Airflow Limitation

  • During Asthma Exacerbation
    • Narrowing Occurs in Large Airways, Medium Airways, and Small Bronchi
  • Increased Airway Resistance with Decreased Maximal Expiratory Flow
  • Airway Narrowing Prevents the Lungs from Completely Emptying Resulting in Gas Trapping: due to resistance to expiratory flow and to bronchial closure at higher than normal lung volumes
    • Dynamic Hyperinflation: results in higher total lung volume with increased residual volume (RV)
    • Increased Work of Breathing: due to decreased lung/chest wall compliance at higher thoracic volumes and the greater effort required to overcome the resistance of narrowed airways

Pathology

  • Pathology (clinical types correlate poorly with pathology):
  • Macroscopic (from autopsy cases): hyperinflation/airway plugging with thick secretions (containing eos possibly recruited by IgA, epithelial cells, macrophages, and mast cells/lymphocytes/epithelial cells/ serum)/normal lung parenchyma/thickened airway walls/bronchiectasis (sometimes)
  • Microscopic: epithelium infiltration and inflammation (persists between exacerbations and in some cases who are never symptomatic)/desquamated epithelium (due to cationic proteins or elastase from eos/ responds to inhaled steroids after weeks, airway hyperreactivity persists longer)/thickened BM (increased type 3 and 5 collagen, posssibly due to release of the fibroblast mitogen tryptase from mast cells/ may persist even after other features have improved with therapy/ may improve after withdrawal in cases of toluene diisocyanate exposure)/increased cells in lamina propria (especially, eos and mast cells but also lymphocytes, monocytes, basophils, plasma cells)/increased thickness of lamina propria (increased collagen and blood vessels)/increased smooth muscle (hyperplastic and hypertrophic/normal ex vivo contraction properties but abnormal in vivo contraction and relaxation, probably due to esoinophil and lymphocyte products/ possibly due to increased work, histamine, tryptase)/ mucous gland hyperplasia (hyperse-cretion due to chymase and elastase/ adrenergic and cholinergic stimulation)/increased goblet cells/ thickened adventitia (inflammatory cells, few mast cells, increased vessels/ uncouples local parenchymal recoil from smooth muscle)
  • Nasal Polyps: smooth, gelatinous, semtranslucent mass of edema tissue with abundant eosinophils, as well as lymphocytes, neutrophils, and mast cells
    • Usually arise from ethmoid sinus
    • Mechanism: not IgE-mediated (atopy is not more common in nasal polyposis than it is in normals)

Diagnosis

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

  • Hypoxemia (see Hypoxemia, [[Hypoxemia]]): due to V/Q mismatch
  • Hypocapnia (see Hypocapnia, [[Hypocapnia]]): presence of relative or absolute hypercapnia suggests impending respiratory failure

Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])

  • Friable mucosa
  • Bronchoalveolar Lavage (BAL): similar to airway washings/findings seen even in mild disease): increased epithelial cells, eos, mast cells or basophils/ prostaglandins, tryptase (in BAL of moder-ately symptomatic asthmatics, suggests ongoing mediator release/in BAL in early allergic res-ponse), chymase (in BAL in early allergic res-ponse), histamine (in BAL between attacks, probably released from basophils), eosinophil products, IgE, albumin (epithelium allows large molecules into lumen)
  • Transbronchial Biopsy (TBB): eosinophils present

Chest X-Ray (see Chest X-Ray, [[Chest X-Ray]])

  • Hyperinflation

Chest CT (see Chest Computed Tomography, [[Chest Computed Tomography]])

  • Hyperinflation

Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

  • Mild-Moderate Eosinophilia (see Peripheral Eosinophilia, [[Peripheral Eosinophilia]]): <1500 eosinophils per uL)
    • Absent if patient on corticosteroids
    • Higher degree of eosinophilia suggests ABPA as an alternate diagnosis

Electrocardiogram (EKG) (see Electrocardiogram, [[Electrocardiogram]])

  • Sinus Tachycardia: may be observed during asthma exacerbation
  • Right Axis Deviation (RAD)
  • Right Bundle Branch Block (RBBB)
  • RV Strain: some cases
  • Ectopy

Fraction of Exhaled Nitric Oxide (FeNO)

  • xxx

Serum Immunoglobulin E (IgE) (see Serum Immunoglobulin E, [[Serum Immunoglobulin E]])

  • xxx

Peak Expiratory Flow Rate (PEFR) (see Peak Expiratory Flow Rate, [[Peak Expiratory Flow Rate]])

  • Not useful in ER unless patient has been using as outpatient (PEFR does not predict admission, relapse, or successful discharge due to overlap of values across patients/NEJM, 1981)
  • PEFR is lower in early AM (due to diurnal variation in airway smooth muscle tone)

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • FEV1: there is a more rapid rate of annual FEV1 decline in asthmatics than there is in normals (this is compounded by smoking)
  • VC: decreased
  • FRC: increased (due to inspiratory muscle activity during expiration, air trapping)
  • RV, TLC: both increased (with increased RV/TLC ratio)
  • Raw: increased
  • DLCO: normal-increased
  • Methacholine Challenge (measures airway reactivity: inhalation of discrete dose or tidal breathing of known concentration): dose required to induce change from baseline (>20% decrease in FEV1, reflected as PD20FEV1 or >35-50% decrease in airway conductance)
    • Correlation between position of curve and plateau height
    • Affected by: smoking/resting lung function/recent exacerbation/use of ß-agonists/time of day/posture/atopy
    • False-Positives: in some normals (if asymptomatic, PD20FEV1 is usually >1.0 µmol and not persistent), chronic airway inflammation, COPD, BPD, allergic rhinitis, IBS
    • False-Negatives: in some asthmatics
    • PD20FEV1 correlates inconsistently with symptom severity or diurnal variation of PEFR, especially in longitudinal studies (however, in population studies, decreased PD20FEV1 is correlated with asthmatic symptoms)
    • Persistent asthma: methacholine curve normalizes (to right) with inhaled steroids, allergen avoidance
    • Low PD20FEV1 values: associated with increased risk of life-threatening asthma
  • Metabisulfite challenge (for SO2)

Skin Testing

  • To aeroallergens from 4 groups: mites and cockroaches/animals/pollens/molds): many allergens within each group cross-react (severe reaction to one untested allergen is unusual)

Sputum Gram Stain/Culture

  • Disease activity may correlate with number of eosinophils (Charcot-Leyden crystals, from degeneration of eos may be seen) and epithelial cells (Curschmann’s spirals or Creola bodies: epithelial cells in sputum, suggests severe attack)

Clinical Manifestations

Otolayngologic Manifestations

Paradoxical Vocal Fold Motion (Vocal Cord Dysfunction) (see Paradoxical Vocal Fold Motion, [[Paradoxical Vocal Fold Motion]]): if present

  • Epidemiology: up to 75% of asthmatics have co-existent vocal cord dysfunction
  • Diagnosis

Pulmonary Manifestations

Allergic Bronchopulmonary Aspergillosis (ABPA)

  • Epidemiology: present in 2-32% of asthmatics [MEDLINE]
  • Diagnostic Features
    • Aspergillus Fumigatus-Specific Antibodies
    • Asthma-Like Presentation
    • Central Bronchiectasis (see Bronchiectasis, [[Bronchiectasis]])
    • Elevated Serum IgA (see see Serum Immunoglobulin A, [[Serum Immunoglobulin A]])
    • Elevated Serum IgE (see Serum Immunoglobulin E, [[Serum Immunoglobulin E]])
    • Peripheral Eosinophilia (see Peripheral Eosinophilia, [[Peripheral Eosinophilia]])
    • Positive Skin Test to *Aspergillus Fumigatus
    • Precipitating Antibodies Against Aspergillus Fumigatus Antigen

Cough (see Cough, [[Cough]])

  • xxx

Dyspnea (see Dyspnea, [[Dyspnea]])

  • xxx

Other Manifestations

  • xxxx

Classification:
– Mild: 4.0 PD20FEV1/inhaled steroid need <0.5 mg per day
– Moderate: symptoms most days/25% variation in PEFR/ <1.0 PD20FEV1/inhaled steroid need 2.0 mg per day
– Very Severe: recent hospitalization/nocturnal BD need/>35% variation in PEFR/ <0.1 PD20FEV1/inhaled steroid need 2.0 mg per day

Persistent Asthma (insidious onset or episodic/symptoms lasting for months-years):

-Symptoms/Signs: H+P does not usually fully elucidate the severity of disease/usually responsive to ß-agonists (typically regular use)
1) Wheezing:
2) Dyspnea: dyspnea correlates poorly with FEV1 (patients who are poor perceivers of airflow obsruction are at increased risk of bad outcomes)
3) Chest Tightness:
4) Prolonged Expiratiory Phase:
5) Cough: this is the only presenting symptom in 57% of cases and is often the prominent symptom
-Cough may be the first sign of worsening control (particularly occurring at night)
6) Pulsus Paradoxus (due to high negative intrathoracic pressure):

Nocturnal Asthma

-This is associated with asthma severity (and is an indicator of overall control)
-Usually early AM (circadian variation in airway muscle tone, inflammation, catecholamine and cortisol secretion, supine posture, snoring, GERD, or waning medication levels)
-In dogs, REM autonomic hyperactivity with fluctuation in airway smooth muscle tone occurs but REM is not clearly associated with nocturnal asthma in humans

Episodic (Seasonal) Asthma (episodic exacerbations lasting days-weeks, symptom-free intervals without therapy):

-Seasons: Spring (grass or tree pollen)/ Fall (ragweed pollen)
-Allergic rhinitis may also be present

Occupational Asthma: See Occupational Asthma

-Known asthmatics that develop symptoms at work (due to dust, etc.) are classified as having Work-Aggravated Asthma (not Occupational Asthma)

Cough-Variant Asthma

-Common type in children and elderly

Exercise-Induced Asthma (aka Exercise-Induced Bronchoconstriction): this is typically viewed as an indicator of the adequacy of asthma control

-Exercise-induced bronchoconstriction occurs in 70-80% of patients with actively symptomatic asthma (it is more likely to occur in patients with moderately-severely increased airway responsiveness)
-Nasal breathing decreases exercise-induced bronchoconstriction
-Repeated exercise usually decreases exercise-induced bronchoconstriction (exercise refractoriness usually lasts around 4 hrs)

Aspirin-Sensitive Asthma: ASA produces airway narrowing in 2-10% of adult (most have severe chronic asthma) and childhood asthmatics

-Associated with (nasal symptoms are less prominent in children): hyperplastic rhinitis/nasal polyps/sinusitis
-Epidemiology: having both nasal polyps + asthma = 40% risk of having ASA-sensitivity
–Most patients have history of perennial rhinitis dating back to 20 s, often after a viral illness
-Pathogenesis: due to decreased PG production
-Clinical: some asthmatics patients actually improve with ASA (unclear why)
–Samter’s Syndrome (most patients are adults): asthma + vasomotor rhinitis/nasal polyposis + ASA sensitivity
–Diagnosis is usually made by history + ASA challenge: ASA ingestion results in asthma exacerbation, rhinitis, facial flushing, periorbital edema, and conjunctival injection
-Treatment:
1) ASA Avoidance: best treatment
-NSAIDs with minimal COX-inhibition may be safely used: sodium salicylate, salicylamide, choline magnesium trisalicylate
-Although lower doses of acetaminophen are safe in these patients, higher doses (>1000 mg) may manifest cross-reactivity with ASA
-Selective COX-2 inhibitors have not been studied in this setting
2) ASA Desensitization: improves both asthma and nasal polyps
-Ideal after polypectomy, as it delays recurrence of polyps up to 6 yrs
3) Cromones: somewhat protective
4) Leukotriene antagonists: protective
5) Diet Screening: ASA sensitivity may predispose sensitivity to tartrazine/benzoates (diet may need to be screened for salicylates, etc.)

Asthma in Pregnancy: asthma during pregnancy increases preterm births, low birth weight (low FEV1 during pregnancy increases risk of IUGR), and neonatal mortality

-Pathophysiology of Pregnancy:
1) ABG: pCO2 is usually <35 with slight metabolic acidosis (pH ranges from 7.4-7.45) and normal pO2
a) Increased VE (begins during first trimester, up to 48% increase by term) with Normal-Mildly Elevated RR: due to progesterone
b) Increased VT (30-35% above normal, to around 450-600 ml) with Increased A-P Diameter of Chest
2) Swan:
a) PVR decreased (up to 35% by late pregnancy):
b) Increased CO and blood volume with normal PCWP and CVP
3) PFT s/Exercise Testing:
a) FRC and RV are decreased (with preserved FEV1 and VC)
b) Increased oxygen consumption (rises to 40-100% above normal) + Increased CO2 Production (rises to 30-50% above normal by third trimester)
4) Symptoms:
a) Dyspnea is common in all pregnancies (due to progesterone secreted by placenta)
b) Pregnancy may improve asthma (due to progesterone-induced bronchodilation and increased circulating histaminase)
-Treatment:
–Asthma Drugs: safe in pregnancy (steroids increase cleft palate in animals/ only effect in humans is a decrease birth weight by 300-400 g)
–Uterine Contractions: common during exacerbation
–Preterm Labor: treat with Magnesium Sulfate (it avoids excessive use of ß2-agonists and it produces bronchodilation)

Reversible Airway Restriction

-Rare presentation with low lung volumes, normal or near normal expiratory airflow, increased lung elastance, and decreased lung compliance that may reverse with bronchodilators or steroids
-The mechanism of reversible restriction in humans is not known, it likely involves closure of terminal lung units due to alveolar duct constriction (ie, pneumoconstriction ) similar to what has been observed in cats
[Kaminsky DA, Irvin CG. Anatomic correlates of reversible restrictive lung disease. Chest. 1993;103:928-931
Hudgel DW, Cooper D, Souhrada J. Reversible restrictive lung disease simulating asthma. Ann Intern Med. 1976;85:328-332]

Acute Asthma Exacerbation

-Symptoms/Signs: wheezing (may be absent in severe disease)/dyspnea/cough (may be only symptom)/pulsus paradoxus (>15 suggests severe attack)
-Difficult to distinguish from acute bronchiolitis in children without asthma history
-Previous life-threatening episode portends poorer prognosis
-Patient is usually better judge of attack severity than physician
-Patients who are poor perceivers of airflow obsruction are at increased risk of bad outcomes (including death)

Complications of Asthma

  • Pneumothorax/Pneumomediastinum:
  • Respiratory Failure/Death: most asthma deaths are preventable (most asthma deaths occur before they get to the hospital)
  • Status Asthmaticus:
  • Hypercapnia during status asthmaticus occurs when FEV1 falls <20% predicted and often signals the need for ventilatory support
  • Mucous Impaction: usually seen in ABPA cases though
  • Pneumonia:
  • Bronchiectasis: occurs in a few cases (especially those with mucoid impaction)
  • SIADH: occurs during severe prolonged attacks
  • Irreversible Airflow Limitation (development is related to severity and duration of disease/asthma does not appear to lead to emphysema): PFT’s are often abnormal during symptom-free intervals

Treatment

Address Underlying Factors Contributing to Asthma Pathogenesis

  • Allergen Avoidance: decreases asthma severity
    • Decrease Home Allergens: with ventilation, removal of pets, etc
    • Lifelong Occupational Exposure Avoidance: in cases of occupational asthma
  • Assure Medication Compliance: ascertain compliance with regimen
    • Compliance is poorly judged by health care providers
    • Compliance is related to simpler dosing regimens, but is not related to educational level, drug route (PO vs. MDI), or disease chronicity
  • Avoid Dietary Sulfites
  • Prevention of Infection
  • Tobacco Cessation (see Tobacco, [[Tobacco]])
  • Treat Atopy and Allergic Rhinitis (see Allergic Rhinitis, [[Allergic Rhinitis]]): treatment of concomitant allergic rhinitis with nasal steroids improves both airway reactivity AND asthma symptoms
  • Treat Chronic Rhinosinusitis (see Chronic Rhinosinusitis, [[Chronic Rhinosinusitis]])
  • Treat Gastroesophageal Reflux Disease (GERD) (see Gastroesophageal Reflux Disease, [[Gastroesophageal Reflux Disease]]): when GERD is diagnosed by pH monitoring, randomized studies suggest that omeprazole improves nocturnal (but not daytime) control [Chest 1999: 116: 5: 1257-1264]
    • GERD is often clinically silent
  • Treat Nasal Polyps (see Nasal Polyps, [[Nasal Polyps]]): inhaled steroids are mainstay of therapy (leukotriene antagonists are not effective)
    • Anosmia and/or Obstruction: systemic steroids (for 3 wks) are indicated (as inhaled steroids alone are ineffective) -> if steroid burst is ineffective, surgery
    • Post-Polypectomy: post-op ASA desensitization delays polyp recurrence for up to 6 yrs
  • Treat Obesity (see Obesity, [[Obesity]]): if present
  • Treat Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]]): if present
  • Treat Paradoxical Vocal Fold Motion (Vocal Cord Dysfunction) (see Paradoxical Vocal Fold Motion, [[Paradoxical Vocal Fold Motion]]): if present
  • Treat Psychological Factors (Anxiety/Depression) (see Depression, [[Depression]])

Management of Specific Asthma Situations

Management of Exercise-Induced Asthma

  • xxx

Management of Asthma in Pregnancy

  • General Information
    • Uncontrolled Asthma Increases the Risk of Perinatal Mortality, Pre-Eclampsia, Preterm Birth, and Low Birthweight Infant
    • Asthma Improves in 33% of Women, Worsens in 33% of Women, and Stays the Same in 33% of Women
  • Management
    • Albuterol is the Preferred SABA (see Albuterol, [[Albuterol]]): due to safety considerations
    • Inhaled Corticosteroids are the Preferred Long-Term Controller Medication (see Corticosteroids, [[Corticosteroids]])
      • Budesonide (see Budesonide, [[Budesonide]]): preferred inhaled corticosteroid, due to the amount of safety data

Management of Asthma in the Peri-Operative Period

  • General Information
    • Asthma Increases the Risk of Peri-Operative Complications
      • Bronchospasm Triggered by Intubation
      • Hypoxemia/Hypercapnia
      • Impairment of Cough and Secretion Clearance
      • Reaction to Latex and Anesthetics: in cases where sensitivity to these has been previously documented
      • Respiratory Infection
  • Management
    • Optimize Asthma Control Prior to Surgery: may require short course of systemic corticosteroids
    • In Asthmatic Patients Who Have Received Oral Systemic Corticosteroids Within 6 Months Prior to Surgery, Stress-Dose Corticosteroids (Hydrocortisone 100 mg q8hrs) Should Be Considered Peri-Operatively: subsequently, corticosteroids should be tapered within 24 hrs after surgery

Management of Asthma Risks with Scuba Diving

  • Asthma may increase the risk of diving-related complications
  • Spirometry does not predict risk
  • Wheezing induced by cold, emotion, or exercise are probable contraindications to diving
  • Clearance for Diving: normal PFT s + normal exercise test (to 80% maximal HR)
    • Prior to testing, no short-acting ß2-agonists x 8 hrs, no long-acting ß2 agonists x 48 hrs, and no ipratropium x 24 hrs
    • Normal Test: <15% decrease in FEV1 with exercise)

Asthma Biomarkers, Associated Phenotypes, and Predictors of Response to Asthma Therapies

  • Elevated Exhaled Nitric Oxide (FeNO): >50 ppb in adults, >35 ppb in children
    • Asthma Phenotype: Th2 High
    • Predicts Clinical Response to Inhaled Corticosteroids (see Corticosteroids, [[Corticosteroids]])
  • Elevated Total IgE: >30 IU
    • Asthma Phenotype: Allergic
    • Predicts Clinical Response to Anti-IgE Therapy
  • Lack of Peripheral/Sputum Eosinophilia and Low FeNO
    • Asthma Phenotype: Th2 Low
    • Predicts Clinical Response to Tiotropium (Spiriva) (see Tiotropium, [[Tiotropium]])
    • Predicts Clinical Response to Macrolides (see Macrolides, [[Macrolides]])
    • Predicts Poor Clinical Response to Inhaled Corticosteroids (see Corticosteroids, [[Corticosteroids]])
  • Periostin
    • Asthma Phenotype: Th2 High
    • Predicts Clinical Response to Anti-IL-4 Receptor Therapy
      • Dupilumab (see Dupilumab, [[Dupilumab]]): fully human monoclonal antibody that binds to the alpha subunit of the IL-4 receptor -> inhibits downstream signaling of both IL-4 and IL-13
    • Predicts Clinical Response to Anti-IL-13 Therapy
      • Lebrikizumab (TNX-650) (see Lebrikizumab, [[Lebrikizumab]])
  • Peripheral Eosinophilia (see Peripheral Eosinophilia, [[Peripheral Eosinophilia]]): 0.3 x 10 to the 9th/L or 300/µL
    • Asthma Phenotype: Th2 High
    • Predicts Clinical Response to Anti-IL-5 Therapy
      • Mepolizumab (Nucala) (see Mepolizumab, [[Mepolizumab]])
      • Reslizumab (Cinqair) (see Reslizumab, [[Reslizumab]])
  • Positive Allergy Skin Tests and Elevated Specific IgE
    • Asthma Phenotype: Allergic Asthma with Atopy
    • Predicts Clinical Response to Allergen Immunotherapy (see Allergen Immunotherapy, [[Allergen Immunotherapy]])
    • Predicts Clinical Response to Anti-IgE Therapy
  • Sputum Eosinophilia: >3%
    • Asthma Phenotype: Th2 High
    • Predicts Clinical Response to Inhaled Corticosteroids (see Corticosteroids, [[Corticosteroids]])

Allergen Immunotherapy (see Allergen Immunotherapy, [[Allergen Immunotherapy]])

  • Indications
    • Asthma Associated with Atopy
  • Techniques
    • Oral
    • Subcutaneous
  • Clinical Efficacy
    • Systematic Review (88 Trials) of Injection Allergen Immunotherapy in Asthma (Cochrane Database Syst Rev, 2010) [MEDLINE]
      • Trials Used Multiple Allergens: House Dust Mites, Pollen, Animal Dander, Cladosporium Mold, and Latex
      • Allergen Immunotherapy Decreased Asthma Symptoms, Medication Use, and Airway Reactivity
      • Allergen Immunotherapy Had No Consistent Effect on Lung Function
      • Local or Systemic Adverse Effects (Anaphylaxis) Were Observed in Trials

Antihistamines (see H1-Histamine Receptor Antagonists, [[H1-Histamine Receptor Antagonists]])

  • Indications
    • Asthma Associated with Allergic Rhinitis (see Allergic Rhinitis, [[Allergic Rhinitis]])
    • Asthma Associated with Grass Pollen
  • Agents
    • Cetirizine (Zyrtec) (see Cetirizine, [[Cetirizine]])
    • Desloratadine (Clarinex) (see Desloratadine, [[Desloratadine]])
    • Fexofenadine (Allegra, Axodin) (see Fexofenadine, [[Fexofenadine]])
    • Levocetirizine (Xyzal) (see Levocetirizine, [[Levocetirizine]])
    • Loratidine (Claritin) (see Loratidine, [[Loratidine]])
  • Clinical Efficacy
    • xxx

Asthma Action Plans

  • xxx

Cromones (Cromoglycates)

  • Indications
    • xxx
  • Agents
  • Pharmacology: xxx
  • Adverse Effects: no long-term adverse effects
    • Nedocromil: bad taste
  • Clinical Efficacy

    • xxx
  • Protect sensory nerve endings/minimal inhibition of mast cell degranulation/decrease B-cell IgE production/ inhibit early, late allergic responses (late response may play role in disease severity)

  • Nedocromil also inhibits eosinophils
  • Protect against: nebulized water, exercise, allergens, cold air hyperventilation, SO2, bradykinin
  • Clinical Uses: require regular 3-4x per day use for weeks before effect is seen
    • Exercise-induced asthma
    • Mild, episodic, or seasonal asthma (especially birch pollen asthma)
    • Little effect on severity of persistent asthma (despite effect on late allergic response)
    • May provide some protection against ASA-induced asthma
  • Nedocromil more effective than Cromolyn in adults (may produce some reduction in steroid dose)
  • No evidence that cromolyn provides additional benefit in patients already on high-dose inhaled steroids

Short-Acting β2-Adrenergic Receptor Agonists (SABA) (see β2-Adrenergic Receptor Agonists, [[β2-Adrenergic Receptor Agonists]])

  • Agents

    • Albuterol (Proventil) (see Albuterol, [[Albuterol]])
    • Levalbuterol (Xopenex) (see Levalbuterol, [[Levalbuterol]]): R-albuterol
    • Pirbuterol (Maxair) (see Pirbuterol, [[Pirbuterol]])
  • Pharmacology: ß2 adrenergic receptor agonism -> inhibit mast cell mediator release, relax airway smooth muscle (dose-related protection against osmotics, allergens, exercise, histamine, methacholine, SO2), increase mucus clearance, protect venular endothelial cells/ long-term use may impair healing after acute allergic reaction (possibly due to less mast cell heparin release)

  • PO dosing of short-acting ß2-agonists: more systemic SE, less protection/may be useful in some cases though for nocturnal symptoms
  • Regular use of short-acting ß2-agonists: may worsen asthma (therefore, should use these intermittently, as rescue medications)
    • Normals but not asthmatics become tolerant to bronchodilation with regular use
    • Regular use of salbutamol/fenoterol shown to decrease lung function, worsen hyperreactivity, and worsen disease control
  • Clinical Efficacy
    • xxx
    • xxx

Long-Acting β2-Adrenergic Receptor Agonists (LABA) (see β2-Adrenergic Receptor Agonists, [[β2-Adrenergic Receptor Agonists]])

  • Agents
  • Pharmacology: ß2-adrenergic receptor agonism -> inhibit mast cell mediator release, relax airway smooth muscle (dose-related protection against osmotics, allergens, exercise, histamine, methacholine, SO2), increase mucus clearance, protect venular endothelial cells/ long-term use may impair healing after acute allergic reaction (possibly due to less mast cell heparin release)

    • No evidence that regular use of long-acting ß2-agonists decreases responsiveness to short-acting ß2-agonists
  • Clinical Efficacy

    • ß2-Adrenergic Receptor Gene (ADRB2) Variants as Predictors of Risk with Use of LABA’s in Multiethnic Asthma Population (Lancet Resp Med, 2014) [MEDLINE]: the rare ADRB2 alleles, Ile164 and -376ins, are associated with adverse events during LABA therapy

Short-Acting Anti-Muscarinic/Anti-Cholinergic (SAMA) Agents (see Muscarinic Antagonists, [[Muscarinic Antagonists]])

  • Agents
  • Pharmacology: short-acting muscarinic antagonist

  • Clinical Efficacy

    • xxxx

Long-Acting Anti-Muscarinic/Anti-Cholinergic (LAMA) Agents (see Muscarinic Antagonists, [[Muscarinic Antagonists]])

  • Agents
    • Aclidinium (Tudorza Pressair) (see Aclidinium, [[Aclidinium]])
    • Tiotropium (Spiriva) (see Tiotropium, [[Tiotropium]])
  • Pharmacology: anti-muscarinic
  • Clinical Efficacy
    • Tiotropium Add-On Therapy to Corticosteroids and LABA in Asthma (NEJM, 2012) [MEDLINE]
      • Tiotropium Increased Time to First Severe Exacerbation (282 Days, As Compared to 226 Days) and Resulted in a 21% Decreased Risk of Severe Exacerbations (Hazard Ratio: 0.79)
      • Tiotropium Provided Modest Sustained Bronchodilation (Increased FEV1)
    • Systematic Review of LAMA in Asthma (Cochrane Database Syst Rev, 2016) [MEDLINE]
      • Tiotropium Add-On Therapy May Have Additional Benefits Over Inhaled Corticosteroids/LABA Alone in Decreasing the Need for Rescue Oral Corticosteroids in Severe Asthma: no evidence is available for other LAMA’s
      • Possible Benefits of Tiotropium on Quality of Life Were Negligible and Evidence for the Effect on Serious Adverse Events was Inconsistent
      • Benefits of Tiotropium Add-On Therapy on the Frequency of Hospital Admissions are Unknown

Leukotriene Modifier Agents

  • Indications
    • Excercise-Induced Asthma: however, these are less effective than inhaled corticosteroids
  • Agents
    • Montelukast (Singulair) (see Montelukast, [[Montelukast]])
    • Zafirlukast (Accolate) (see Zafirlukast, [[Zafirlukast]])
    • Zileuton (Zyflo) (see Zileuton, [[Zileuton]])
  • Pharmacology: xxx
  • Adverse Effects: generally well-tolerated
    • Rare Cases of Churg-Strauss Syndrome Have Been Reported with Montelukast and Corticosteroid Withdrawal (see Churg-Strauss Syndrome, [[Churg-Strauss Syndrome]]): unclear association
  • Clinical Efficacy

    • xxx
  • Improve airway function/protect against exercise (block 60-80% of bronchoconstriction), hyperventilation, (block 60-80% of bronchoconstriction), allergen (block 80-90% of bronchoconstriction), ASA (completely block bronchoconstriction), and cold-induced asthma

  • More effective when given systemically (suggests major effect occurs below epithelium)
  • Decreases need for rescue ß2-agonists, improves FEV1, decreases symptoms, decreases asthma exacerbations requiring PO steroids, and decreases inhaled steroid requirements
  • Leukotriene antagonists have no effect on nasal polyps
  • Particularly useful: exercise-associated asthma and ASA-sensitve asthma

Theophylline (Theo-Dur) (see Theophylline, [[Theophylline]])

  • Epidemiology: theophylline is the most widely-used asthma drug worldwide
  • Pharmacology: methylxanthine
    • Anti-Inflammatory Effects
    • Decreased Mast Cell Mediator Release
    • Diuretic
    • Immunomodulatory Effects
    • Increased Diaphragmatic Contractility
    • Weak Bronchodilator
  • Administration
    • Need to Monitor Theophylline Levels: target steady-state level: 5-15 ug/mL
    • Serum Theophylline Levels May Be Altered by Various Factors: fever, diet/food, age, smoking, other medications
  • Adverse Effects: generally dose-related
  • Potential Clinical Scenarios in Asthma Where Theophylline May Have Utility
    • Acute Asthma Exacerbation in the Intensive Care Unit: data for clinical benefit in this situation are lacking
    • Add-On Therapy for Disease Uncontrolled on Inhaled Corticosteroids or When LABA is Not Beneficial or Desired
      • Theophylline is Probably More Efficacious Than Cromolyn/Nedocromil When Added to Inhaled Corticosteroids
    • Primary Maintenance Therapy Where Compliance to an Oral Agent is More Likely, But Montelukast is Ineffective
    • Primary Maintenance Therapy Where Inhaled Corticosteroid Use is Difficult (Small Children, etc), But Montelukast is Ineffective
  • Clinical Efficacy
    • Theophylline is Less Efficacious Than Long-Acting Beta Agonists (LABA) [MEDLINE]
    • Theophylline Withdrawal in Severe Asthma is Associated with an Increased Rate of Asthma Exacerbations [MEDLINE]

Inhaled Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • xxxx
  • Decrease severity of persistent asthma/increase dosing with more severe disease (quicker response with higher doses: symptoms respond within days, airway reactivity and PEFR respond within weeks)/use high dose x3-6 months to control, then decrease to level that prevents exacerbations (improvement continues over months)
  • Target: <15% PEFR variability, decreased symptoms, etc.
  • Timing of Inhaled Steroid Introduction: the FEV1 is less likely to normalize the later inhaled steroids are initiated
  • Effect on Asthma Mortality: in study of 5-44 y/o patients, inhaled steroids (>6 canisters during 12-month period) result in 50% decrease in asthma mortality (effect is dose-dependent)
  • SE: thrush/dysphonia (due to vocal cord myopathy)/systemic effects (potential for systemic absorption increases with dose)
    • No cases of adrenal insufficiency occur at <2000 µg/day
  • Steroid-resistance (failure after >6 months of inhaled steroids/possibly due to Ab against lipocortin-1, decreased monocyte receptor response): actual resistance is rare (must rule out poor drug delivery, GERD, OSA, non-compliance, etc.)

  • Agents

  • Clinical Efficacy

    • Inadequate Response to Low-Dose Inhaled Steroids: data suggest that adding long-acting ß2-agonist is superior to increasing the steroid dose
      • FACET trial (1997): adding long-acting ß2-agonist (instead of increasing steroids alone) decreases asthma exacerbations and improves PEFR in moderate asthma
  • Variability in Individual Responsiveness to Inhaled Corticosteroids

    • Variability in Individual Responsiveness to Inhaled Corticosteroids Can Be Predicted by Single Nucleotide Polymorphisms (SNP) in the T Gene (Am J Respir Crit Care Med, 2012) [MEDLINE]: 2-3x differences in FEV1 response were observed for subjects homozygous for wild-type vs mutant alleles for each T gene SNP
  • Use of Inhaled Corticosteroids in Asthma and Risk of Pneumonia
    • Retrospective Analysis of Risk of Pneumonia in Asthma Patients on Budesonide (2011) [MEDLINE]: budesonide use in asthma does not increase the risk of pneumonia
    • Case-Control Study from Health Improvement Network (Chest, 2013) [MEDLINE]: inhaled corticosteroids dose-dependently increase the risk of pneumonia
  • Inhaled Corticosteroid Use in Children and Effects on Growth
    • Cochrane Database Systematic Reviews (Cochrane Database Syst Rev, 2014) [MEDLINE] [MEDLINE]: inhaled corticosteroids inhibit growth in children

Systemic Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • Indications
    • Acute Asthma Exacerbation/Status Asthmaticus
  • Administration
    • *PO *(Usually Prednisone)
    • IV (Usually Methylprednisolone as Solumedrol)
    • IM (Usually Methylprednisolone as Medrol):
  • Pharmacology
    • Anti-Inflammatory
  • Adverse Effects
    • Cataracts
    • Hyperglycemia
    • Immunosuppression
    • Myopathy
    • Other
  • Drug Interactions
    • Antacids: decrease gastrointestinal corticosteroid absorption
    • Rifampin/Phenobarbital/Phenytoin/Ephedrine: via effects on hepatic P-450 metabolism, these drugs increase corticosteroid clearance
  • Clinical Efficacy

    • xxx

    • IV onset probably faster than PO onset

    • Post-steroid course PEFR provides “best” PEFR for future reference
    • Probably do not need to stop inhaled steroids during exacerbation

Omalizumab (Xolair) (see Omalizumab, [[Omalizumab]])

General Information

  • Indications
    • Asthma with Positive Allergy Skin Tests and Elevated Specific IgE: indicates allergic asthma with atopy phenotype
    • Asthma with Elevated IgE (>30 IU): indicates allergic asthma phenotype
  • Pharmacology: xxx
  • Administration: xxx
  • Adverse Effects
    • Injection Site Reaction
  • Clinical Efficacy
    • Trial of Omalizumab for Asthma in Inner-City Children (NEJM, 2011) [MEDLINE]: omalizumab added to standard asthma therapy in inner-city children/adolescents/young adults
      • Omalizumab Decreased the Number of Days with Asthma Symptoms
      • Omalizumab Decreased Asthma Exacerbations: nearly eliminated seasonal peaks in exacerbations
      • Omalizumab Decreased the Need for Other Medications to Control Asthma
    • Cochrane Database Systematic Review Examining Omalizumab in Adults/Children with Asthma (2014) [MEDLINE]
      • As Adjunct to Inhaled Corticosteroids (and During Corticosteroid Tapering), Omalizumab Decreased Asthma Exacerbations/Hospitalizations
      • Omalizumab was Effective in Allowing Corticosteroid Taper/Withdrwal
      • Unclear Whether There is a Threshold Level of Serum IgE Which Predicts Optimal Efficacy of Omalizumab

Anti-Interleukin-4 (IL-4) Therapy

Dupilumab (see Dupilumab, [[Dupilumab]])

  • Indications
    • Asthma with Elevated Periostin Level
  • Pharmacology: fully human monoclonal antibody that binds to the alpha subunit of the IL-4 receptor -> inhibits downstream signaling of both IL-4 and IL-13
  • Clinical Efficacy
    • Multi-Center Phase 2 Trial of Dupilumab in Adults with Moderate-Severe Asthma [MEDLINE]
      • Study Indications in Phase 2 Trial in Adults with Mild-Moderate Severe Asthma
        • Peripheral Eosinophilia: ≥300 cells/µL
        • Sputum Eosinophilia: ≥3%
        • Symptoms Not Well-Controlled on Medium-High Dose Inhaled Corticosteroids and Long-Acting Beta Agonist (LABA)
      • Dupilumab Decreased Asthma Exacerbations When Corticosteroids and LABA Were Withdrawn: improved lung function and decreased Th2-associated inflammatory markers

Anti-Interleukin-5 (IL-5) Therapy

Mepolizumab (Nucala) (see Mepolizumab, [[Mepolizumab]])

  • Indications
    • Asthma with Eosinophilic Inflammation (Peripheral Eosinophilia >300/µL)
      • FDA-Approved for Maintenance Therapy of Severe Asthma in Patients Age 12 and Older
  • Pharmacology: humanized monoclonal antibody against interleukin-5 (IL-5) -> decreases the production and survival of eosinophils
  • Administration: 100 mg SQ (approximate cost: $3000)
  • Adverse Effects
    • Headache (see Headache, [[Headache]]): occurs in 19% of cases
    • Herpes Zoster Infection (see Varicella-Zoster Virus, [[Varicella-Zoster Virus]])
    • Hypersensitivity Reaction: typically occur within hours of administration
    • Unknown Impact on Immune Response to Helminth Infections
  • Clinical Efficacy
    • DREAM Trial in Asthma with Eosinophilic Inflammation (Sputum Eosinophilia, Peripheral Eosinophilia, Increased Exhaled NO, or Decreased Control with Inhaled/Systemic Steroid Taper) (Severe Eosinophilic Asthma) (Lancet, 2012) [MEDLINE]
      • Mepolizumab Decreased Asthma Exacerbations in Severe Eosinophilic Asthma
    • MENSA Trial of Mepolizumab in Asthma with Eosinophilic Inflammation (Severe Eosinophilic Asthma) (Peripheral Eosinophilia) Without Control on High-Dose Inhaled Corticosteroids (NEJM, 2014) [MEDLINE]
      • Mepolizumab (IV, SQ) Decreased Asthma Exacerbations
      • Mepolizumab Improved FEV1
      • Mepolizumab Improved 5-Item Asthma Control Questionnaire Scores (ACQ-5): marker of asthma symptom control
      • Mepolizumab Improved St. George’s Respiratory Questionnaire (SGRQ) Scores
    • SIRIUS Trial in Asthma with Eosinophilic Inflammation (Peripheral Eosinophilia) Treated with Systemic Corticosteroids (NEJM, 2014) [MEDLINE]
      • Mepolizumab Decreased Asthma Exacerbations
      • Mepolizumab had a Significant Glucocorticoid-Sparing Effect
      • Mepolizumab Improved 5-Item Asthma Control Questionnaire Scores (ACQ-5): marker of asthma symptom control

Reslizumab (Cinqair) (see Reslizumab, [[Reslizumab]])

  • Indications
    • Asthma with Eosinophilic Inflammation (Peripheral Eosinophilia >300/µL)
  • Pharmacology: monoclonal antibody against interleukin-5 (IL-5)
  • Clinical Efficacy
    • Phase 2 Trials of Reslizumab in Asthma with Peripheral Eosinophilia (Lancet Resp Med, 2015) [MEDLINE]
      • Reslizumab Decreased Asthma Exacerbations
      • Adverse Effects*: similar to placebo (although 2 patients experienced anaphylaxis)
    • Phase 3 Trial of Reslizumab in Poorly-Controlled Asthma (Chest, 2016) [MEDLINE]
      • In Overall Population: Reslizumab Did Not Improve FEV1
        • In Subgroup of Patients with Baseline Peripheral Blood Eosinophils <400/μL: Reslizumab Did Not Improve FEV1
        • In Subgroup of Patients with Baseline Peripheral Blood Eosinophils ≥400/μL: Reslizumab Improved FEV1, ACQ-7, Rescue SABA Use

Anti-Interleukin-13 (IL-13) Therapy

Lebrikizumab (TNX-650) (see Lebrikizumab, [[Lebrikizumab]])

  • Indications: asthma with elevated periostin level
  • Pharmacology: IgG4 humanized monoclonal antibody that binds to IL-13 -> inhibits IL-13 function
    • IL-13 induces bronchial epithelial cells to secrete periostin (a matricellular protein that may induce airway remodeling in asthma)
  • Administration: SQ
  • Clinical Efficacy
    • Randomized, Double-Blinded, Placebo-Controlled Trial of Lebrikizumab in Adult Asthmatics Who Were Uncontrolled Despite Inhaled Corticosteroid Therapy (NEJM, 2011) [MEDLINE]
      • Lebrizumab Improved FEV1: lebrikizumab resulted in a larger increase in FEV1 in patients with high pre-treatment periostin levels (8.2% increase in FEV1) vs patients with low with pre-treatment periostin levels (1.6% increase in FEV1) -> therefore, high levels of IL-13 activity predicted lebrikizumab efficacy
      • Lebrikizumab Decreased the Fraction of Exhaled Nitric Oxide (FeNO) Indirectly

Bronchial Thermoplasty (see Bronchial Thermoplasty, [[Bronchial Thermoplasty]])

  • Technique: use of thermal energy to directly target the airway smooth muscle responsible for bronchoconstriction
    • Alair Bronchial Thermoplasty System (Boston Scientific; Marlborough, Massachusetts)
  • Adverse Effects
    • Bronchial Irritation
    • Cough (see Cough, [[Cough]])
    • Discolored Sputum
    • Upper Respiratory Infection
    • Wheezing
    • Worsening of Dyspnea (see Dyspnea, [[Dyspnea]])
  • Clinical Efficacy
    • Air Trial in Moderate-Severe Asthma (NEJM, 2007) [MEDLINE]
      • Bronchial Thermoplasty Decreased Asthma Exacerbations
      • At 12 mo, Bronchial Thermoplasty Improved Morning Peak Expiratory Flow, Scores on AQLQ, ACQ, Percentage of Symptom-Free Days, Symptom Scores, Need for Rescue Medication
      • Bronchial Thermoplasty Had No Impact on FEV1
    • AIR-2 Trial Studying the Long-Term Safety and Efficacy of Bronchial Thermoplasty in Patients with Severe Persistent Asthma (J Allergy Clin Immunol, 2013) [MEDLINE]
      • Bronchial Thermoplasty Has Durable 5-Year Benefits with Regard to Asthma Control (Maintained Decrease in Severe Exacerbations and ED Visits for Respiratory Symptoms) and Safety
    • Systematic Review of Bronchial Thermoplasty in Moderate-Severe Asthma (Cochrane Database Syst Rev, 2014) [MEDLINE]
      • Bronchial Thermoplasty Provides a Modest Clinical Benefit in Quality of Life and Lower Rates of Asthma Exacerbation
      • Bronchial Thermoplasty Provides No Significant Difference in Asthma Control Scores

Hypotherapy

  • Small benefits in some studies but duration is unknown

Acupuncture

  • Not supported by clinical trials

Step-Down Therapy

  • In the setting of improved control on an inhaled steroid and other agents, stepping down the dose of inhaled steroid is preferred to minimize the potential complications (including adrenal suppression, cataracts, osteoporosis, growth rate

Agents With Unclear Clinical Benefit in Asthma

  • Anti-Fungal Therapy
  • Anti-Interleukin-2 Receptor (IL-2R) Antibody
  • Anti-Interleukin-4 Receptor Alpha Subunit Antibody
  • Anti-Thymic Stromal Lymphopoietin
  • Anti-Tumor Necrosis Factor-α (Anti-TNFα) Therapy (see Anti-Tumor Necrosis Factor-α Therapy, [[Anti-Tumor Necrosis Factor-α Therapy]])
    • Etanercept (Enbrel) (see Etanercept, [[Etanercept]])
    • Golimumab (Simponi, Simponi Aria) (see Golimumab, [[Golimumab]])
  • Calcium Channel Blockers (see Calcium Channel Blockers, [[Calcium Channel Blockers]])
  • Chloroquine (see Chloroquine, [[Chloroquine]])
  • Colchicine (see Colchicine, [[Colchicine]])
  • Cyclosporine A (see Cyclosporine A, [[Cyclosporine A]])
  • Dapsone (see Dapsone, [[Dapsone]])
  • GATA3-Specific DNAzyme
  • Glucocorticoid Receptor Agonist AZD5423
  • Gold (see Gold, [[Gold]])
  • Hydroxychloroquine (Plaquenil) (see Hydroxychloroquine, [[Hydroxychloroquine]])
  • Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin, [[Intravenous Immunoglobulin]])
  • Ketotifen (xxx) (see Ketotifen, [[Ketotifen]]): no clinical benefit to alter airway reactivity in persistent asthma
  • Macrolides [MEDLINE]: no clinical benefit
    • Azithromycin (Zithromax) (see Azithromycin, [[Azithromycin]])
    • Clarithromycin (Biaxin) (see Clarithromycin, [[Clarithromycin]])
    • Roxithromycin (Biaxsig, Coroxin, Romac, Roxar, Roximycin, Roxl-150, Roxo, Roxomycin, Rulid, Rulide, Surlid, Tirabicin, Xthrocin) (see Roxithromycin, [[Roxithromycin]])
    • Troleandomycin (Triocetin, Tekmisin) (see Troleandomycin, [[Troleandomycin]])
  • Methotrexate (see Methotrexate, [[Methotrexate]])
  • Nebulized Heparin (see Heparin, [[Heparin]])
  • Neobulized Lidocaine (see Lidocaine, [[Lidocaine]])

Specific Treatment of Asthma Exacerbation

Magnesium Sulfate (see Magnesium Sulfate, [[Magnesium Sulfate]])

  • MAGNETIC Trial: Nebulized Isotonic Magnesium Sulfate in Children with Acute Asthma Exacerbation (Lancet Resp Med, 2013) [MEDLINE]: nebulized isotonic magnesium sulfate did not impact asthma severity score in children with acute asthma exacerbation
    • However, the greatest benefit was seen in children with more severe attacks (SaO2 <92% at presentation and with preceding symptoms lasting <6 hrs)
  • Systematic Review of Intravenous Magnesium Sulfate in Adults with Acute Asthma Exacerbation in the Emergency Department (Cochrane Database Syst Rev, 2014) [MEDLINE]: single infusion of intravenous magnesium sulfate (1.2-2g over 15-30 min) decreased hospital admissions and improves lung function in patients who have not responded to oxygen, nebulized beta-2 agonists, and intravenous corticosteroids
    • However, differences in the ways the trials were conducted made it difficult for the authors to assess whether severity of the exacerbation or additional co-medications altered the treatment effect of magnesium sulfate

Oxygen (see Oxygen, [[Oxygen]])

  • xxx

Short-Acting β2-Adrenergic Receptor Agonists (SABA) (see β2-Adrenergic Receptor Agonists, [[β2-Adrenergic Receptor Agonists]])

  • xxx

Short-Acting Anti-Muscarinic/Anti-Cholinergic Agents (SAMA) (see Muscarinic Antagonists, [[Muscarinic Antagonists]])

  • xxx

Systemic Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • xxxx

Pregnancy

  • Asthma Remission Rates:
  • Childhood Asthma: mild persistent disease may remit but mod-severe disease probably will continue into adulthood (about 50% achieve remission)
  • Adult Asthma: middle-aged and older adult asthmatics rarely achieve complete remission (only 10-15% achieve remission, as is defined by being asyptomatic with normal FEV1 and normal airway responsiveness)
    • Remission is associated with milder asthma, male gender, younger age at first diagnsosis, and less initial airway responsiveness
    • There is a more rapid rate of annual FEV1 decline in asthmatics than there is in normals (this is compunded by smoking)

Mortality Rates: lower mortality rate in USA compared to other countries (possibly due to different patterns of aerosol bronchodilator use)

  • Relatively stable mortality rate in USA in 5-34 y/o group since 1960 (but 25% increase in total number of deaths)
  • Countries with highest mortality rates usually have highest prevalence

Risk of Fatal Asthma: greatest in those asthmatics with highest degree of airway hyperresponsiveness and FEV1 lability (rather than in those with severe, fixed airway obstruction)

  • In patients with >50% FEV1 response to bronchodilator (as compared to those with <25% bronchodilator response): 7-fold higher risk of death from asthma
  • Persistent FEV1 lability is most common in smokers and those with persistent atopic asthma
  • Other risk factors for asthma mortality: age >40, smoking, and blood eosinophilia

References

General

  • Wheezing Rhinovirus Illnesses in Early Life Predict Asthma Development in High-Risk Children. Am J Respir Crit Care Med. 2008 October 1; 178(7): 667–672 [MEDLINE]
  • Aspergillus hypersensitivity and allergic bronchopulmonary aspergillosis in patients with bronchial asthma: systematic review and meta-analysis. Int J Tuberc Lung Dis. 2009 Aug;13(8):936-44 [MEDLINE]
  • Randomized Placebo-controlled Trial to Evaluate Chronic Dosing Effects of Propranolol in Asthma. Am J Respir Crit Care Med. 2013 Jun 15;187(12):1308-14 [MEDLINE]

Treatment

General

  • Effect of rare variants in ADRB2 on risk of severe exacerbations and symptom control during long-acting β agonist treatment in a multiethnic asthma population: a genetic study. Lancet Respir Med. 2014 Mar;2(3):204-13. doi: 10.1016/S2213-2600(13)70289-3 [MEDLINE]

Allergen Immunotherapy

  • Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010 Aug 4;(8):CD001186. doi: 10.1002/14651858.CD001186.pub2 [MEDLINE]

Long-Acting Muscaninic Antagonists (LAMA)

  • Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012 Sep 27;367(13):1198-207. Epub 2012 Sep 2 [MEDLINE]
  • Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. Cochrane Database Syst Rev. 2016 Jan 21;1:CD011721. doi: 10.1002/14651858.CD011721.pub2 [MEDLINE]

Theophylline

  • Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med. 1995;151(6):1907 [MEDLINE]
  • The efficacy and safety of salmeterol compared to theophylline: meta-analysis of nine controlled studies. Respir Med. 1998;92(2):256 [MEDLINE]
  • Effects of salmeterol in patients with persistent asthma receiving inhaled corticosteroid plus theophylline. Respiration. 2007;74(6):611 [MEDLINE]
  • Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med. 2007;175(3):235 [MEDLINE]

Inhaled Corticosteroids (see Corticosteroids, [[Corticosteroids]])

  • Risks of pneumonia in patients with asthma taking inhaled corticosteroids. Am J Respir Crit Care Med 2011;183:589-595 [MEDLINE]
  • Genome-wide association identifies the T gene as a novel asthma pharmacogenetic locus. Am J Respir Crit Care Med 2012;185:1286-1291 [MEDLINE]
  • Inhaled corticosteroids and the risk of pneumonia in people with asthma: a case-control study. Chest. 2013 Dec;144(6):1788-94. doi: 10.1378/chest.13-0871 [MEDLINE]
  • Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth. Cochrane Database Syst Rev. 2014 Jul 17;7:CD009878. doi: 10.1002/14651858.CD009878.pub2 [MEDLINE]
  • Inhaled corticosteroids in children with persistent asthma: effects on growth. Cochrane Database Syst Rev. 2014 Jul 17;7:CD009471. doi: 10.1002/14651858.CD009471.pub2 [MEDLINE]

Omalizumab (see Omalizumab, [[Omalizumab]])

  • Randomized trial of omalizumab (Anti-IgE) for asthma in inner-city children. N Engl J Med 2011;364:1005-1015 [MEDLINE]
  • Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy. Ann Intern Med 2011;154:573-582 [MEDLINE]
  • Omalizumab for the treatment of severe persistent allergic asthma: a systematic review and economic evaluation. Health Technol Assess. 2013 Nov;17(52):1-342. doi: 10.3310/hta17520 [MEDLINE]
  • Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014 Jan 13;1:CD003559. doi: 10.1002/14651858.CD003559.pub4 [MEDLINE]

Dupilumab (see Dupilumab, [[Dupilumab]])

  • Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455 [MEDLINE]

Mepolizumab (see Mepolizumab, [[Mepolizumab]])

  • Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984 [MEDLINE]
  • Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-659 [MEDLINE]
  • MENSA Trial. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371:1198-1207 [MEDLINE]
  • SIRIUS Trial. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371:1189 [MEDLINE]

Reslizumab

  • Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011 Nov 15;184(10):1125-32. doi: 10.1164/rccm.201103-0396OC. Epub 2011 Aug 18 [MEDLINE]
  • Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015 May;3(5):355-66. doi: 10.1016/S2213-2600(15)00042-9. Epub 2015 Feb 23 [MEDLINE]
  • Phase 3 Study of Reslizumab in Patients with Poorly Controlled Asthma: Effects Across a Broad Range of Eosinophil Counts. Chest. 2016 Mar 24. pii: S0012-3692(16)45715-6. doi: 10.1016/j.chest.2016.03.018 [MEDLINE]

Lebrikizumab (see Lebrikizumab, [[Lebrikizumab]])

  • Lebrikizumab treatment in adults with asthma. N Engl J Med 2011;365:1088-1098 [MEDLINE]
  • Role of periostin, FENO, IL-13, lebrikzumab, other IL-13 antagonist and dual IL-4/IL-13 antagonist in asthma. Expert Opin Biol Ther. 2014 Feb;14(2):165-81. doi: 10.1517/14712598.2014.859673. Epub 2013 Nov 28 [MEDLINE]

Bronchial Thermoplasty

  • AIR Trial. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;156:1327-1337 [MEDLINE]
  • AIR-2 Trial. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013 Dec;132(6):1295-302. doi: 10.1016/j.jaci.2013.08.009. Epub 2013 Aug 30 [MEDLINE]
  • Bronchial thermoplasty: a novel therapy for severe asthma. Clin Chest Med. 2013 Sep;34(3):437-44. doi: 10.1016/j.ccm.2013.03.003. Epub 2013 Aug 1 [MEDLINE]
  • Bronchial thermoplasty for moderate or severe persistent asthma in adults. Cochrane Database Syst Rev. 2014 Mar 3;3:CD009910. doi: 10.1002/14651858.CD009910.pub2 [MEDLINE]
  • Bronchial thermoplasty: a review of the evidence. Ann Allergy Asthma Immunol. 2016 Feb;116(2):92-8. doi: 10.1016/j.anai.2015.11.002. Epub 2015 Dec 2 [MEDLINE]

Magnesium (see Magnesium Sulfate, [[Magnesium Sulfate]])

  • Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial. Lancet Respir Med. 2013 Jun;1(4):301-8. doi: 10.1016/S2213-2600(13)70037-7. Epub 2013 Apr 22 [MEDLINE]
  • Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev. 2014 May 28;5:CD010909. doi: 10.1002/14651858.CD010909.pub2 [MEDLINE]

Macrolides

  • Macrolides for chronic asthma. Cochrane Database Syst Rev. 2015;9:CD002997 [MEDLINE]

Other Treatment

  • xxx