ASTHMA

• ACRONYMS AND DEFINITIONS

• ATS - American Thoracic Society
• EIA - Exercise-induced asthma
• GERD - Gastroesophageal reflux disease
• GINA - Global Initiative for Asthma
• ICS - Inhaled corticosteroids
• LABA - Long-acting beta agonists
• LAMA - Long-acting antimuscarinic agents
• LTRAs - Leukotriene modifiers
• MDI - Metered-dose inhaler
• NHLBI - National Heart, Lung, and Blood Institute
• PFM - Peak flow meter
• RCT - Randomized controlled trial
• RTI - Respiratory tract infection
• SABA - Short-acting beta agonists
• VHC - Valved holding chambers

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• EPIDEMIOLOGY

• Asthma is a chronic inflammatory condition marked by restricted airflow in the lungs
• Asthma affects more than 22 million people in the U.S., and 5 - 16% of the worldwide population
• Children, African-Americans, and people with lower incomes have a higher incidence of asthma [1,2]

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• WHEEZING IN CHILDHOOD

• Wheezing is the characteristic lung sound heard when a patient is experiencing reactive airway disease. Wheezing may be triggered by a number of things (e.g. respiratory infections, allergens, etc.)
• Asthma is a chronic condition marked by episodes of recurrent wheezing
• It is very common for children to wheeze. The majority of children who wheeze will not go on to develop asthma
• Up to 50% of children have episodes of wheezing early in life, but only 7 - 9% of adults have active asthma. Based on these numbers, it can be estimated that around 20% of people who wheeze in childhood will go on to have asthma in adulthood. [3,4]
• In one study, 59% of children who wheezed before the age of three did not have any wheezing for a year by the age of six [3]
• Certain risk factors increase a person's chance of developing asthma

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• PHYSIOLOGY

• Asthma is a chronic condition marked by hyperresponsiveness of the smooth muscles in bronchial walls. When the smooth muscles contract, airways are narrowed and airflow is obstructed. Narrowed airways produce the characteristic "wheezing" sound heard in asthma
• Patients with asthma also exhibit chronic inflammatory changes in the bronchioles. These changes include: infiltration of neutrophils, lymphocytes, and eosinophils; mast cell activation; airway edema; and hypersecretion of mucus.
• In more severe cases, patients develop airway remodeling that includes thickening of membranes, smooth muscle hyperplasia, and fibrosis. These changes can be permanent. [2]

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• RISK FACTORS

• Known risk factors for asthma
• Family history (genetics)
• Sex - early in life, boys are more affected, from puberty on, girls are more affected
• Exposure to house dust mite allergens
• Viral respiratory infections (early exposure may be protective)
• Cat and dog dander (early exposure may be protective) [2]
• Cockroach allergen [2]


• Possible risk factors for asthma
• Tobacco smoke exposure
• Air pollution
• Occupational exposures
• Obesity [2]


• Possible protective factors
• Growing up in a rural environment (children who grow up on farms appear to have a lower risk of asthma) [5]
• Viral respiratory infections (early exposure may be protective)
• Cat and dog dander (early exposure may be protective) [2]
• Endotoxins and microbials (early exposure may be protective [14]

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• DIAGNOSIS OF ASTHMA

• NHLBI criteria (2007)
• STEP 1 - To make a diagnosis of asthma, the following should be true:
• Episodic symptoms of airflow obstruction or airway hyperresponsiveness are present (see symptoms below)
• Airflow obstruction is at least partially reversible
• Alternative diagnoses are excluded (see differential below)
• STEP 2 - If the above is established, then spirometry should be performed to confirm the diagnosis

• Symptoms
• Wheezing - high-pitched whistling sounds when breathing out, especially in children. Lack of wheezing and a normal chest examination do not exclude asthma.
• History of any of the following:
• Cough that may worse at night - in adults, isolated cough is seldom due to asthma
• Recurrent wheeze
• Recurrent difficulty in breathing
• Recurrent chest tightness
• Symptoms occur or worsen in the presence of triggers:
• Exercise
• Viral infection
• Animals with fur or hair
• House-dust mites (in mattresses, pillows, upholstered furniture, carpets)
• Mold
• Smoke (tobacco, wood)
• Pollen
• Changes in weather
• Strong emotional expression (laughing or crying hard)
• Airborne chemicals or dusts
• Menstrual cycles
• Aspirin and NSAIDs - see Aspirin-exacerbated respiratory disease for more
• Symptoms occur or worsen at night, awakening the patient

• Reference [2,15]

Differential diagnosis for asthma symptoms
0 - 11 years old
Allergic rhinitis and sinusitis Aspiration from swallowing mechanism dysfunction or gastroesophageal reflux Bronchiectasis - recurrent infections, productive cough Bronchopulmonary dysplasia - preterm delivery, symptoms since birth Congenital heart disease - cardiac murmurs Cystic fibrosis - excessive cough and mucus production, gastrointestinal symptoms Enlarged lymph nodes or tumor Inhaled foreign body - sudden onset of symptoms, unilateral wheeze Laryngotracheomalacia, tracheal stenosis, or bronchostenosis Primary ciliary dyskinesia - recurrent infections, productive cough, sinusitis Tuberculosis - chronic cough, hemoptysis, dyspnea, fatigue, fever, (night) sweats, anorexia, weight loss Vascular rings or laryngeal webs Viral bronchiolitis or obliterative bronchiolitis Vocal cord dysfunction
≥ 12 years old
Allergic rhinitis and sinusitis Alpha 1-antitrypsin deficiency - shortness of breath, family history of early emphysema Bronchiectasis - productive cough, recurrent infections Chronic upper airway cough syndrome - sneezing, itching, blocked nose, throat-clearing Congenital heart disease - cardiac murmurs Congestive heart failure COPD - cough, sputum, dyspnea on exertion, smoking or noxious exposure Cystic fibrosis - excessive cough and mucus production Hyperventilation, dysfunctional breathing - dizziness, paresthesia, sighing Inducible laryngeal obstruction - dyspnea, inspiratory wheezing (stridor) Mechanical obstruction of the airways (benign and malignant tumors) Medications (e.g., angiotensin-converting enzyme (ACE) inhibitors) Parenchymal lung disease - dyspnea with exertion, non-productive cough, finger clubbing Pulmonary embolism - sudden onset of dyspnea, chest pain Pulmonary infiltration with eosinophilia Tuberculosis - chronic cough, hemoptysis, dyspnea, fatigue, fever, (night) sweats, anorexia, weight loss Vocal cord dysfunction

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• SPIROMETRY

• Definitions
• Spirometry - tests used to measure respiratory (lung) function. Children ≥ 5 years old are typically able to perform spirometry.
• FEV1 - forced expiratory volume in 1 second - volume of air exhaled during the first second of forced exhalation (after full inspiration)
• FEV6 - forced expiratory volume in 6 seconds - volume of air exhaled during the first six seconds of forced exhalation (after full inspiration)
• FEF 25-75% - forced expiratory flow - speed of air (in L/s) coming out of lungs over 25 - 75% of the FVC
• FVC - forced vital capacity - volume of air that can be forcibly blown out after full inspiration

• Reference [2,15]

Spirometry measures
Normal spirometry FEV1 / FVC ratio 8 - 19 years: 85% 20 - 39 years: 80% 40 - 59 years: 75% 60 - 80 years: 70% Predicted FEV1 Predicted FEV1 is based on a person's age, sex, height, weight, and ethnicity An online calculator is available here - online FEV1 calculator
Asthma (reactive airway disease) 1. Confirm that FEV1 and FEV1 / FVC ratio is reduced 2. 10 - 15 minutes after the inhalation of a short-acting bronchodilator (e.g. albuterol, 2-4 puffs), there should be an increase in FEV1 of > 200 ml and ≥ 12% from baseline
Exercise-induced asthma (EIA) For patients suspected of having exercise-induced asthma, a protocol that involves exercise before spirometry should be performed These protocols typically involve around 6 - 10 minutes of exercise on a stationary bike or treadmill before testing Spirometry is considered positive for EIA if the following is seen: Adults: Fall in FEV1 of > 10% and > 200 ml from baseline Children: Fall in FEV1 of > 12% of predicted
Bronchoprovocation test Bronchoprovocation testing involves administering an agent that is known to provoke asthma symptoms before performing spirometry Common provoking agents that are used include methacholine, histamine, hypertonic saline, mannitol, and cold air. Hyperventilation may also be used to provoke symptoms. Spirometry is considered positive for bronchoprovocation if the following is seen: Adults: Fall in FEV1 from baseline of ≥ 20% with standard doses of methacholine or histamine, or ≥ 15% with standardized hyperventilation, hypertonic saline or mannitol challenge
Patients using inhalers For patients who are already using inhalers, SABA should be held for at least 4 hours before spirometry testing and LABA should be held for 12 - 24 hours depending on the duration of action

• NOTE: Values are for persistent asthma
• Intermittent asthma should have normal values in between exacerbations
• Reference [2]

Asthma severity based on spirometry findings
Ages 5 - 11 years
	Mild	Moderate	Severe
FEV1	≥ 80% of predicted	61 - 79% of predicted	≤ 60% of predicted
FEV1 / FVC	> 80%	75 - 80%	< 75%
Age ≥ 12 years
	Mild	Moderate	Severe
FEV1	≥ 80% of predicted	61 - 79% of predicted	≤ 60% of predicted
FEV1 / FVC	normal	reduced ≤ 5%	reduced > 5%

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• NITRIC OXIDE (FeNO)

• Overview
• Nitric oxide is a gas produced by inflammatory cells in the airways, particularly eosinophils. The fractional concentration of nitric oxide (FeNO) can be measured in exhaled air with special equipment. FeNO is measured in parts per billion (ppb).
• High FeNO values may be an indication of allergic or eosinophilic asthma. This type of asthma typically responds well to inhaled corticosteroids. In severe cases, it may also be treated with immunomodulators.
• FeNO is a nonspecific measure in that it may also be elevated in other conditions such as eosinophilic bronchitis, atopy, allergic rhinitis, and eczema. Smoking and ongoing bronchoconstriction lower FeNO, and viral respiratory infections can both increase and decrease levels. FeNO values also change with age.
• Recommendations from the NHLBI for the use of FeNO are presented below [15,16]


• NHLBI 2020 FeNO recommendations
• In individuals aged 5 years or older for whom the diagnosis of asthma is uncertain using history, clinical findings, clinical course, and spirometry, including bronchodilator responsiveness testing, or in whom spirometry cannot be performed, the expert panel conditionally recommends addition of FeNO measurement as an adjunct to the evaluation process (conditional recommendation, moderate certainty of evidence).
• In individuals aged 5 years or older with persistent allergic asthma, for whom there is uncertainty in choosing, monitoring, or adjusting anti-inflammatory therapies based on history, clinical findings, and spirometry, the expert panel conditionally recommends addition of FeNO measurement as part of an ongoing asthma monitoring and management strategy that includes frequent assessments (conditional recommendation, low certainty of evidence).
• In individuals aged 5 years or older with asthma, the expert panel recommends against the use of FeNO measurement in isolation to assess asthma control, predict future exacerbations, or assess exacerbation severity. If used, it should be as part of an ongoing monitoring and management strategy (strong recommendation against, low certainty of evidence). [18]

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• ASTHMA CLASSIFICATION

• Overview
• Asthma may be classified according to its clinical manifestations (phenotype) and severity

• Clinical manifestations (phenotype)
• Allergic asthma - typically starts in childhood and is associated with a personal or family history of eczema, allergic rhinitis, and/or food and drug allergies. Allergen triggers exacerbate symptoms. Pathologically, it is marked by eosinophilic airway inflammation. Allergic asthma typically responds well to ICS.
• Non-allergic asthma - asthma that is not associated with allergies or allergen-exposure. Pathologically, airway inflammation may contain neutrophils, eosinophils, or few inflammatory cells. Non-allergic asthma does not respond as well to ICS.
• Adult-onset asthma - asthma symptoms that present for the first time in adult life. Adult-onset asthma is more common in women. Asthma tends to be non-allergic and does not respond as well to ICS. Occupational exposures should also be evaluated in adult-onset asthma.
• Asthma with persistent airflow obstruction - patients with chronic asthma may develop a degree of airflow obstruction that is nonreversible. This is thought to occur secondary to airway remodeling.
• Asthma with obesity - obesity is a risk factor for asthma and weight loss can improve symptoms in these patients [15]

• Severity
• The NHLBI guidelines recommend that each patient have their asthma classified based on severity and risk
• A table is presented in the guidelines to help establish a classification. The table is available on page 5 in this publication from the NHLBI - NHLBI asthma quick reference guide
• In practice, many healthcare providers will not have the time to sit down with patients and clearly delineate which classification they meet
• A simple, pragmatic way to approach asthma treatment is to treat patients in a stepwise fashion in hopes of achieving a set of goals - see treatment below

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• ASTHMA TREATMENT

• Drug classes
• Short-acting beta agonist (SABA) - albuterol, levalbuterol
• Long-acting beta agonist (LABA) - salmeterol and formoterol
• Leukotriene modifiers (LTRAs) - montelukast, zafirlukast, zileuton
• Inhaled corticosteroids (ICS) - fluticasone, beclomethasone, mometasone, budesonide, ciclesonide, flunisolide
• Biologics - omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, tezepelumab
• Mast cell stabilizers - cromolyn sodium
• Methylxanthines - theophylline
• Anticholinergics (also called antimuscarinics) - ipratropium, tiotropium
• Corticosteroids - prednisone, prednisolone, methylprednisolone

• Treatment goals
• Infrequent need (≤ 2 days a week) of rescue inhaler (albuterol or levalbuterol)
• Maintain normal activity (exercise, work, etc.) levels without symptoms (cough, shortness of breath)
• Reduce or eliminate emergency room visits and hospitalizations
• Prevent loss of pulmonary function [2]

• Reference [16]

NHLBI 2020 Asthma Treatment Recommendations (0 - 4 years of age)
Proceed to next step if no clear benefit after 4 - 6 weeks Inadequate control generally defined as increasing use of SABA or use of SABA > 2 times per week (excluding EIA) See ICS dosing for low, medium, high dosing
Step	Treatment
Step 1	SABA as needed At start of RTI: short course of ICS and SABA as needed
Step 2	Preferred Daily low-dose ICS and SABA as needed Alternative Daily LTRA and SABA as needed
Step 3	Preferred (one of the following) Daily low-dose ICS + either LABA or LTRA and SABA as needed Daily medium-dose ICS and SABA as needed
Step 4	Preferred Daily medium-dose ICS + LABA and SABA as needed Alternative Daily medium-dose ICS + LTRA and SABA as needed
Step 5	Preferred Daily high-dose ICS + LABA and SABA as needed Alternative Daily high-dose ICS + LTRA and SABA as needed
Step 6	Preferred Daily high-dose ICS + LABA + oral systemic corticosteroid and SABA as needed Alternative Daily high-dose ICS + LTRA + oral systemic corticosteroid and SABA as needed

• Reference [16]

NHLBI 2020 Asthma Treatment Recommendations (5 - 11 years of age)
Proceed to next step if no clear benefit after 4 - 6 weeks Inadequate control generally defined as increasing use of SABA or use of SABA > 2 times per week (excluding EIA) See ICS dosing for low, medium, high dosing
Step	Treatment
Step 1	SABA as needed
Step 2	Preferred Daily low-dose ICS and SABA as needed Alternative Daily LTRA and SABA as needed
Step 3	Preferred Daily and as needed combination low-dose ICS/formoterol As needed ICS/formoterol is defined as 2 puffs every 4 hours as needed up to a maximum of 8 puffs per day Alternative (one of the following) Daily medium-dose ICS and SABA as needed Daily low-dose ICS + LABA or LTRA and SABA as needed
Step 4	Preferred Daily and as needed combination medium-dose ICS/formoterol As needed ICS/formoterol is defined as 2 puffs every 4 hours as needed up to a maximum of 8 puffs per day Alternative (one of the following) Daily medium-dose ICS + LABA and SABA as needed Daily medium-dose ICS + LTRA and SABA as needed
Step 5	Preferred Daily high-dose ICS + LABA and SABA as needed Alternative Daily high-dose ICS + LTRA and SABA as needed
Step 6	Preferred Daily high-dose ICS + LABA + oral systemic corticosteroid and SABA as needed Alternative Daily high-dose ICS + LTRA + oral systemic corticosteroid and SABA as needed

• Reference [18]

NHLBI 2020 Asthma Treatment Recommendations (≥ 12 years of age)
Proceed to next step if no clear benefit after 2 - 6 weeks Inadequate control generally defined as increasing use of SABA or use of SABA > 2 times per week (excluding EIA) See ICS dosing for low, medium, high dosing
Step	Treatment
Step 1	SABA as needed
Step 2	Preferred (one of the following) Daily low-dose ICS and SABA as needed As needed concomitant ICS and SABA Alternative Daily LTRA and SABA as needed
Step 3	Preferred Daily and as needed combination low-dose ICS/formoterol (as needed ICS/formoterol is defined as 2 puffs every 4 hours as needed up to a maximum of 10 puffs per day) Alternative (one of the following) Daily medium-dose ICS and SABA as needed Daily low-dose ICS + LABA and SABA as needed Daily low-dose ICS + LAMA and SABA as needed Daily low-dose ICS + LTRA and SABA as needed
Step 4	Preferred Daily and as needed combination medium-dose ICS/formoterol (as needed ICS/formoterol is defined as 2 puffs every 4 hours as needed up to a maximum of 10 puffs per day) Alternative (one of the following) Daily medium-dose ICS + LABA and SABA as needed Daily medium-dose ICS + LAMA and SABA as needed
Step 5	Preferred Daily medium-to-high dose ICS + LABA + LAMA and SABA as needed Alternative (one of the following) Daily medium-to-high-dose ICS + LABA and SABA as needed Daily high-dose ICS + LTRA and SABA as needed Consider adding biologic. See severe asthma below.
Step 6	Daily high-dose ICS + LABA + oral corticosteroids and SABA as needed Consider adding biologic. See severe asthma below.

• Reference [2,6]

Treatment recommendations for exercise-induced asthma
Step 1 SABA 5 - 20 minutes before exercise (effective in up to 80% of patients) If symptoms not controlled during exercise, then proceed to Step 2
Step 2 Add one of the following: Cromolyn sodium before exercise Anticholinergic before exercise LABAs can be protective for up to 12 hours (NOTE: LABAs will have shortened duration of effectiveness if used daily) If symptoms occur daily, then proceed to Step 3
Step 3 Add one of the following: Daily ICS +/- LABA Daily LTRA (effective in up to 50% of patients)
Nonpharmacological treatment A warm-up period before exercise may reduce the degree of symptoms A mask or scarf over the mouth may attenuate cold-induced symptoms

• Vaccinations
• Flu vaccine - Annual flu vaccine is recommended by the CDC and the Global Initiative for Asthma
• Pneumococcal vaccine - The pneumonia vaccine (PPSV23 | Pneumovax) is recommended by the CDC for adults 19 - 64 years with asthma. The 2019 GINA recommendations state that there is insufficient evidence to recommend routine pneumococcal vaccination in people with asthma. [15,16]

• Allergen mitigation
• There are numerous environmental allergens (see triggers above) that can exacerbate asthma. A number of strategies and products exist to help mitigate exposure to these allergens (see table below).
• Because environmental allergens are ubiquitous, most mitigation strategies do not achieve meaningful reductions in allergen exposure; therefore, it's not surprising that mitigation strategies have had mixed results in clinical trials (see laminar airflow study and pest control/HEPA filter study below).
• Recommendations from GINA and the NHLBI 2020 guidelines are given below along with a table of allergens and their associated mitigation strategy [15,16]

• GINA 2019 recommendations for allergen mitigation
• Allergen avoidance is not recommended as a general strategy for people with asthma
• For sensitized patients, although it would seem logical to attempt to avoid allergen exposure in the home, there is some evidence for clinical benefit with single avoidance strategies and only limited evidence for benefit with multi-component avoidance strategies (in children)
• Although allergen avoidance strategies may be beneficial for some sensitized patients, they are often complicated and expensive, and there are no validated methods for identifying those who are likely to benefit [15]
• NHLBI 2020 recommendations for allergen mitigation
• In individuals with asthma who do not have sensitization to specific indoor allergens or who do not have symptoms related to exposure to specific indoor allergens, the expert panel conditionally recommends against allergen mitigation interventions as part of routine asthma management (conditional recommendation against, low certainty of evidence)
• In individuals with asthma who have symptoms related to exposure to identified indoor allergens, confirmed by history taking or allergy testing, the expert panel conditionally recommends a multicomponent allergen-specific mitigation intervention (conditional recommendation, low certainty of evidence)
• In individuals with asthma who have sensitization or symptoms related to exposure to pests (cockroaches and rodents), the expert panel conditionally recommends the use of integrated pest management alone or as part of a multicomponent allergen-specific mitigation intervention (conditional recommendation, low certainty of evidence)
• In individuals with asthma who have sensitization or symptoms related to exposure to dust mites, the expert panel conditionally recommends impermeable pillow/mattress covers only as part of a multicomponent allergen mitigation intervention, not as a single-component intervention (conditional recommendation, moderate certainty of evidence) [18]

• Reference [15,16]

Allergen Mitigation Strategies
House dust mites Encase bedding in impermeable covers Wash bedding on hot cycle (55–60°C) Replace carpets with hard flooring Acaricides and/or tannic acid Minimize objects that accumulate dust Vacuum cleaners with integral HEPA filter and double-thickness bags Remove, hot wash, or freeze soft toys
Pets Remove cat/dog from the home Keep pet from the main living areas/bedrooms HEPA-filter air cleaners Wash pet Replace carpets with hard flooring Vacuum cleaners with integral HEPA filter and double-thickness bags
Cockroaches Bait plus professional extermination of cockroaches Baits placed in households
Fungi Remediation of dampness or mold in homes Air filters, air conditioning

• Allergen immunotherapy (allergy shots/drops/tablets)
• Allergen immunotherapy (a.k.a. allergy shots/drops/tablets) is a process where patients are tested for allergic reactivity to specific allergens. The offending allergens are then administered to the patient in small doses through subcutaneous injections or sublingual drops/tablets over a period of time (typically years) with the hope that desensitization or tolerance to the allergen will develop.
• Allergen immunotherapy is expensive and time consuming, and there is limited evidence from clinical trials supporting its benefits in asthma. A trial that compared sublingual dust mite tablets to placebo is detailed below (see dust mite tablet study)
• Recommendations from GINA and the NHLBI 2020 guidelines are given below [15,16]

• GINA 2019 recommendations for allergen immunotherapy
• Compared to pharmacological and avoidance options, potential benefits of subcutaneous immunotherapy must be weighed against the risk of adverse effects and the inconvenience and cost of the prolonged course of therapy, including the minimum half-hour wait required after each injection
• For adult patients with allergic rhinitis and sensitized to house dust mite, with persisting asthma symptoms despite low-moderate dose ICS-containing therapy, consider adding sublingual allergen immunotherapy (SLIT), provided FEV1 is > 70% predicted
• As for any treatment, potential benefits of SLIT for individual patients should be weighed against the risk of adverse effects, and the cost to the patient and health system [15]
• NHLBI 2020 recommendations for allergen immunotherapy
• In individuals aged 5 years or older with mild to moderate allergic asthma, the expert panel conditionally recommends the use of subcutaneous immunotherapy as an adjunct treatment to standard pharmacotherapy in individuals whose asthma is controlled at the initiation, buildup, and maintenance phases of immunotherapy (conditional recommendation, moderate certainty of evidence)
• In individuals with persistent allergic asthma, the expert panel conditionally recommends against the use of sublingual immunotherapy in asthma treatment (conditional recommendation, moderate certainty of evidence) [18]

• Bronchial thermoplasty
• Asthma occurs when hyperresponsive smooth muscle constricts the airways (see physiology above). Patients with severe asthma often have increased airway smooth muscle mass.
• Bronchial thermoplasty is a procedure where a bronchoscope is used to deliver radiofrequency-generated heat to bronchial smooth muscle that causes the muscle to shrink. Theoretically, this helps to open up airways and decrease hyperresponsiveness.
• Studies that have evaluated bronchial thermoplasty have shown that it has a modest effect on severe asthma. [PMID 24585221] A study that looked at the long-term effects of the procedure found that reductions in severe asthma exacerbations persisted for more than ten years post-procedure. [PMID 33524320]
• Recommendations on its use are presented below

• NHLBI 2020 recommendations
• In individuals aged 18 years or older with persistent asthma, the expert panel conditionally recommends against bronchial thermoplasty (conditional recommendation, low certainty of evidence)
• Individuals aged 18 years or older with persistent asthma who place a low value on harms (short-term worsening symptoms and unknown long-term adverse effects) and a high value on potential benefits (improvement in quality of life, a small reduction in exacerbations) might consider bronchial thermoplasty [18]
• GINA 2019 recommendation
• For adult patients whose asthma remains uncontrolled despite optimization of asthma therapy and referral to a severe asthma specialty center, bronchial thermoplasty is a potential treatment option
• Caution should be used in selecting patients for this procedure. The number of studies is small, people with chronic sinus disease, frequent chest infections or FEV1 < 60% predicted were excluded from the pivotal sham-controlled study, and patients did not have their asthma treatment optimized before bronchial thermoplasty was performed. [15]

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• SEVERE ASTHMA

• Definition
• The definition of severe asthma varies by professional organization. The ATS defines severe asthma as "asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy. The diagnosis of asthma should be confirmed and other possible conditions should be excluded (see differential).
• In general, severe asthma is asthma that remains uncontrolled despite optimal therapy with an ICS, LABA, and LAMA, or asthma that requires the aforementioned and oral steroids to remain controlled.

• Asthma biologics
• A number of biologic therapies are now available for the treatment of asthma. These medications are antibodies that bind and block inflammatory mediators that are involved in airway inflammation. Studies that have evaluated the effects of asthma immunomodulators on asthma are reviewed here - asthma immunomodulators
• Immunomodulators only come in parenteral forms, and they are very expensive. Because of this, they should be reserved for patients with severe asthma.
• Guidelines for their use have been published by the ATS and GINA. The table below provides highlights from those recommendations along with indications from the manufacturer's package insert. Blood eosinophil levels and FeNO values are incorporated into some of the recommendations.

• Reference [15,16,17]

Asthma immunomodulator therapy recommendations
Therapies IL-5 inhibitors Benralizumab (Fasenra®) Mepolizumab (Nucala®) Reslizumab (Cinqair®) IgE inhibitor Omalizumab (Xolair®) IL-4 and IL-13 inhibitor Dupilumab (Dupixent®)
Indications for IL-5 inhibitor therapy ATS - Blood eosinophil count ≥ 150 cells/mcL and prior exacerbations GINA - Blood eosinophil count ≥ 300 cells/mcL and exacerbations in last year Manufacturer package insert/studies Benralizumab (Fasenra®) - blood eosinophil count ≥ 300 cells/mcL Mepolizumab (Nucala®) - blood eosinophils ≥ 150 cells/mcL within 6 weeks of dosing or ≥ 300 cells/mcL within 12 months of enrollment Reslizumab (Cinqair®) - blood eosinophil count ≥ 400 cells/mcL
Indications for IgE inhibitor therapy ATS - Blood eosinophil count ≥ 260 cells/mcL or FeNO ≥ 19.5 ppb GINA - Sensitization on skin prick testing or specific IgE + total serum IgE and weight within dosage range + exacerbations in the last year Omalizumab (Xolair®) package insert - patients who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids
Indications for IL-4/IL-13 inhibitor therapy ATS - adult patients with severe eosinophilic asthma, and for those with severe corticosteroid-dependent asthma regardless of eosinophil levels GINA - Blood eosinophils ≥ 150 cells/mcL or FeNO ≥ 25 ppb + exacerbations in the last year Dupilumab (Dupixent®) package insert - asthma with eosinophilic phenotype or oral corticosteroid dependent asthma

• Macrolide antibiotics
• Macrolide antibiotics include azithromycin, clarithromycin, and erythromycin. Macrolides have antiinflammatory properties in addition to their antibacterial properties. A number of studies have looked at their effects in preventing asthma exacerbations. One of the larger studies is detailed below (see azithromycin for prevention of asthma exacerbation)
• Recent ATS and GINA guidelines include macrolides in their severe asthma treatment recommendations. No dosing recommendations are made in either guideline, but in trials, azithromycin 250 - 500 mg three times a week for 26 - 48 weeks has been used the most.
• ATS 2019 recommendations
• We suggest a trial of macrolide treatment to reduce asthma exacerbations in adult asthmatics on GINA/NAEPP step 5 therapy that remain persistently symptomatic or uncontrolled. We suggest against the use of chronic macrolide treatment in children and adolescents with severe uncontrolled asthma
• The benefits and safety of using macrolides for asthma beyond one year has not been determined [17]
• GINA 2019 recommendations
• A trial of macrolide therapy may be considered in patients with uncontrolled or severe asthma. Before considering add-on off-label therapy with azithromycin in adult patients with uncontrolled or severe asthma, sputum should be checked for atypical mycobacteria, and the risk of increasing antimicrobial resistance at the patient and the population level should be taken into account. [15]

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• INHALER DEVICES

• Metered-dose inhalers (MDIs)
• Metered-dose inhalers (MDIs) are what is typically referred to as "an inhaler". MDIs deliver a dose of medication when they are activated. The medication may be delivered in the form of an aerosol or powder. In the past, all aerosol MDIs required that the patient press on the canister to deliver an actuation. Now, some aerosol MDIs are breath-actuated meaning they sense when the patient is inhaling and automatically deliver an actuation without being pressed.
• Spacers and VHCs are devices that fit on an MDI and provide a contained reservoir for the emitted aerosol from the MDI. The intent of spacers and VHCs is to improve the delivery of the active medication to the lungs.

• Spacers
• Spacers are simple tubes or extensions that are connected to the end of an inhaler. Spacers contain the aerosol puff after it is emitted.
• Spacers do not have valves that control the flow of air where valved holding chambers do (see below)
• Some spacers connect to the mouthpiece of an inhaler while others have a nozzle receptacle for the canister only
• Some inhalers (e.g. Aerospan®) come with spacers
• In studies, there is a high amount of variability among the performance of individual spacers. With some MDIs, a spacer may improve delivery of a medication, while with another MDI, the same spacer may decrease delivery. Some studies show no benefit of a spacer compared to an MDI alone. [8]
• Whether or not a spacer should be used will depend on the clinical situation. For example, young children who are unable to use an MDI correctly will likely benefit from a spacer or VHC while other patients may not.

• Valved holding chambers (VHC)
• VHCs are devices like spacers that contain the aerosol puff in a reservoir after it is emitted from the MDI
• VHCs differ from spacers in that VHCs have a one-way valve that prevents the patient from exhaling into the chamber
• In studies, there is a high amount of variability among the performance of individual VHCs. With some MDIs, a VHC may improve delivery of a medication, while with another MDI, the same VHC may decrease delivery. Some studies show no benefit of a VHC compared to an MDI alone. [8]
• Whether or not a VHC should be used will depend on the clinical situation. For example, young children who are unable to use an MDI correctly will likely benefit from a spacer or VHC while other patients may not.
• In children, a VHC may be preferred over a spacer when using a face mask [2]
• Some available VHCs include:
• AeroChamber®
• OptiChamber®
• Prochamber®
• Vortex®

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• NEBULIZERS

• A nebulizer is a machine that produces compressed air
• The air is forced into a chamber with a solution that contains the medication
• Interactions in the chamber between the solution and the compressed air produce a mist of droplets that the patient inhales
• The patient may inhale the mist through a facemask or mouthpiece
• Mouthpieces may be more effective in delivering the medication, but uncooperative patients (ex. small children) may not use them properly
• Some studies have compared nebulizers to other delivery devices (spacers, VHCs, MDIs). In general, there is no clear evidence that nebulizers improve drug delivery or clinical outcomes when compared to other delivery devices. In patients who cannot use an MDI correctly (ex. small children), a nebulizer is probably preferred. [9, 13]
• "Blow-by technique" (holding the mask or mouthpiece close to the patient's mouth and nose) is not effective and should not be used [2, 9]
• Only certain asthma medications are available for use in a nebulizer

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• PEAK FLOW METERS (PFM)

• Overview
• A peak flow meter is a device that patients may use at home to measure their lung function
• Peak flow meters can be used in monitoring asthma symptoms, but they are not for the diagnosis of asthma
• The value of using PFMs has varied in clinical trials. It is unclear whether monitoring with PFMs improves outcomes when compared to symptom monitoring alone. PFMs may be more beneficial in patients who are "poor perceivers" of the severity of their asthma symptoms. The NHLBI guidelines state that there is insufficient evidence to recommend their use in all patients. [2]


• Instructions for using a PFM:
• Patient should take a deep breath and blow as hard and fast as they can into the meter. The PFM approximates the force of the exhaled air in liters/min.
• To determine personal best reading, patient should take at least 2 readings/day over 2 - 3 weeks
• Readings can be done at random times and 15 - 20 minutes after using SABA
• Once a personal best reading is determined, the zones below can help guide therapy when a reading is taken
• Green Zone: ≥ 80% of personal best - Good control
• Yellow Zone: 50 - 80% of personal best - Caution - Use SABA and monitor
• Red Zone: < 50% of personal best - Medical alert - Use SABA and call health professional [2]

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• GASTROESOPHAGEAL REFLUX DISEASE (GERD) AND ASTHMA

• Patients with asthma often have coexisting GERD (32 - 84% in studies)
• Symptoms of GERD can overlap with asthma (e.g. cough, chest discomfort)
• Acid reflux can cause bronchoconstriction through microaspiration of stomach contents into the airways. Acid reflux can also irritate the esophagus and upper airway leading to reflex bronchoconstriction. Because of this relation, it has been postulated that GERD may contribute to poorly-controlled asthma.
• A number of studies have looked at the effect of treating poorly-controlled asthmatics with proton pump inhibitors (PPIs). In general, these studies have found no benefit of treating asthmatics for GERD. Subgroup analyses in patients with confirmed reflux disease also have shown no benefit. [10, 11, 12]

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• STUDIES

• STUDY
  School Air Filter Purifiers or Pest Management vs None for Asthma Control, JAMA (2021) [PubMed abstract]
• Design: 2 X 2 factorial design, randomized controlled trial (N=236 | Length = 10 months) in asthmatic children attending urban elementary schools
• Treatment: Classroom HEPA filter purifiers vs Sham purifiers and Integrated pest management vs No management in a 2 X 2 factorial design
• Primary outcome: Number of symptom-days with asthma during a 2-week period. Symptom-days were assessed every 2 months during the 10 months after randomization.
• Results
• Primary outcome: HEPA purifier - 1.6 days, Sham purifier - 1.8 days (IRR 1.47, 95%CI[0.79 to 2.75])
• Primary outcome: Pest management - 1.5 days, None - 1.9 days (IRR 0.71, 95%CI[0.38 to 1.33])
• There was no significant interaction between the two treatments (p=0.18)
• Findings: Among children with active asthma, use of a school-wide integrated pest management program or classroom HEPA filter purifiers did not significantly reduce symptom-days with asthma. However, interpretation of the study findings may need to consider allergen levels, particle exposures, and asthma symptoms at baseline.

• STUDY
  Nocturnal Laminar Airflow vs Sham Device for Atopic Asthma, Thorax (2012) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=312 | Length = 12 months) in asthmatics with confirmed allergy to cat, dog, or dust mite allergen
• Treatment: Nocturnal temperature-controlled laminar airflow (TLA) device vs Sham device placed in patient bedroom
• Primary outcome: Proportion of patients with an increase of ≥ 0.5 points in asthma quality of life score after 1 year of treatment
• Results
• Primary outcome: TLA - 76%, Sham - 61% (p=0.02)
• Findings: Inhalant exposure reduction with TLA improves quality of life, airway inflammation and systemic allergy in patients with persistent atopic asthma. TLA may be a treatment option for patients with inadequately controlled persistent atopic asthma.

• STUDY
  House Dust Mite (HDM) Sublingual Allergen Immunotherapy (SLIT) Tablet vs Placebo in Allergic Asthma, JAMA (2016) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=834 | Length = 12 months) in asthmatics with confirmed house dust mite allergy not controlled with ICS
• Treatment: House Dust Mite SLIT tablet once daily vs Placebo tablet. Two different doses of the SLIT tablet (6 SQ-HDM and 12 SQ-HDM) were given making three treatment groups.
• Primary outcome: Time to first moderate or severe asthma exacerbation during the ICS reduction period.
• Results
• The 6 SQ-HDM and 12 SQ-HDM doses both significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo (hazard ratio [HR]: 0.72 [95% CI, 0.52-0.99] for the 6 SQ-HDM group, p=0.045, and 0.69 [95% CI, 0.50-0.96] for the 12 SQ-HDM group, p=0.03).
• Findings: Among adults with HDM allergy–related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate or severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6 months of 9 to 10 percentage points; the reduction was primarily due to an effect on moderate exacerbations. Treatment-related adverse events were common at both active doses. Further studies are needed to assess long-term efficacy and safety.

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• BIBLIOGRAPHY

• 1 - PMID 24041942 Lancet review
• 2 - NHLBI 2007 asthma guidelines
• 3 - PMID 780004
• 4 - ALA trends in asthma morbidity and mortality
• 5 - PMID 21345099
• 6 - PMID 23634861
• 7 - NHLBI asthma quick reference guide
• 8 - PMID 3530417
• 9 - PMID 24037768
• 10 - PMID 21482834
• 11 - PMID 19357404
• 12 - PMID 22274684
• 13 - PMID 19081697
• 14 - PMID 27518660 - Innate immunity and asthma risk in Amish and Hutterite
• 15 - Global Strategy for Asthma Management and Prevention (2019 update)
• 16 - Update on Selected Topics in Asthma Management: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group, NHLBI draft recommendations (2019)
• 17 - PMID 31558662 - Management of Severe Asthma: A European Respiratory Society/American Thoracic Society Guideline, Eur Respir J (2019)
• 18 - PMID 33270095 - Managing Asthma in Adolescents and Adults 2020 Asthma Guideline Update From the National Asthma Education and Prevention Program, JAMA (2020)