CONTENTS
- Symptoms & asthma assessment
- Asthma phenotypes
- T2-high (IL4, IL5, IL13, Eos)
- T2-low
- Diagnostic tests
- Diagnosis
- Rubrics for treatment
- Specific therapies
- Related topics
- Questions & discussion
abbreviations used in this chapter:
- SABA = Short-Acting Beta Agonist.
- LABA = Long-Acting Beta Agonist.
- SAMA = Short-Acting Muscarinic Antagonist.
- LAMA = Long-Acting Muscarinic Antagonist.
- ICS = Inhaled corticosteroid.
abbreviations used in the pulmonary section: 4
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AFB: Acid Fast Bacilli
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase Syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- CF: Cystic fibrosis 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MAC: Mycobacterium Avium complex 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OHS: Obesity hypoventilation syndrome 📖
- OP: Organizing pneumonia 📖
- OSA: Obstructive sleep apnea 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: tumor necrosis factor
- UIP: Usual Interstitial Pneumonia 📖
hallmark symptoms attributable to asthma
- (1) Wheeze.
- (2) Chest tightness.
- (3) Dyspnea:
- May be episodic or ongoing.
- May cause nocturnal awakening with dyspnea (can mimic paroxysmal nocturnal dyspnea due to heart failure).
- (4) Cough:
- Especially worse at night.
- May be the only symptom (cough-variant asthma).
- One of the above four symptoms are reported in >90% of patients with asthma. (ERS handbook, 3rd ed.)
a hallmark of asthma is variability in symptoms over time
- Often symptoms are worse at night, or early in the morning.
- Symptoms may be triggered by:
- Allergens.
- Irritants (e.g., perfume, car exhaust, smoking).
- Cold air.
- Exercise (not immediately; often 5-10 minutes following exercise).
- Viral infection.
- Work-related exposures (e.g., grain dust, animal dander). (37703556)
- Symptoms may be alleviated by an inhaled bronchodilator.
asthma assessment
- History of exacerbations:
- Usual pattern (e.g., rapidity of onset).
- Duration and frequency of exacerbations.
- Severity (admission to ED vs. hospital vs. ICU).
- Prior intubations?
- Current pattern of symptoms:
- Frequency of nocturnal awakening?
- Frequency of rescue bronchodilator use?
- Activity limitation?
Patients can often be sub-classified into groups with more homogeneous biology and clinical features. However, these phenotypes remain generalizations which are not immutable. For example, a patient may transition between phenotypes over time, or could display some attributes from two different phenotypes. (Shah 2019)
clinical aspects
- This often occurs in patients with a personal or family history of other allergies:
- Allergic rhinitis (hay fever).
- Atopic dermatitis (eczema).
- Urticaria.
- This often presents early in life. Late-onset hypereosinophilic asthma may occur, but an allergic phenotype becomes less likely with later age at onset. (36682372)
investigations
- Eosinophil levels > ~150-300/uL suggest atopic asthma.
- IgE levels may be elevated.
- Exhaled nitric oxide levels may be elevated.
- Patients may display a wheal-and-flare reaction to some allergens and/or have high levels of allergen-specific IgE antibodies. (36100569)
treatment
- Inhaled steroid is often very effective.
- Leukotriene receptor inhibitors 📖 may be more useful in these patients.
- Biologic therapies 📖 may be useful for patients with severe disease.
- Allergy immunotherapy (AIT): Desensitization may be considered for some patients.
- Skin prick testing or IgE testing may be used to identify and avoid offending allergens.
- Immunotherapy can be utilized for patients with:
- Mild to moderate persistent asthma (not uncontrolled asthma – where it is potentially dangerous). FEV1 should be >70% predicted prior to allergen exposure. (ERS handbook 3rd ed.)
- Symptoms relate to allergen exposure.
- Documented allergen sensitivity (based on skin prick testing or IgE).
- No contraindications (which include pregnancy, unstable cardiovascular disease, beta-blocker use, active systemic autoimmune disorders, active malignancy, severe psychiatric disease, immunodeficiency). (ERS handbook 3rd ed.)
- Evidence supports a reduction in rescue inhaler use and long-term medication use. However, evidence doesn't show a clear improvement in exacerbations or FEV1. (36682372) Overall, emerging data suggests that biological therapies are more strongly evidence-based for these patients.
basics
- This is also known as NSAID-exacerbated respiratory disease, or aspirin-induced asthma.
- It is associated with a T2-high physiology.
epidemiology
- AERD effects ~7% of patients with asthma, and 15% with severe asthma. (29395357)
- It mainly affects adults (median age of onset is ~30 years old). (30207919)
- It can occur in patients with or without atopy.
symptoms
Samter's triad
- This triad was involved in the original description of AERD.
- It is a combination of:
- Nasal polyps.
- Asthma.
- Aspirin/NSAID sensitivity.
AERD may evolve gradually
- It may begin with perennial vasomotor rhinitis.
- Aspirin sensitivity may develop. Certain alcoholic beverages may also cause milder hypersensitivity reactions. (30207919)
- Hyperplastic rhinosinusitis, nasal polyposis, and/or recurrent sinusitis may develop.
- If nasal polyps are surgically removed, they often recur rapidly. (30207919)
- Progressive asthma occurs (although rhinosinusitis may continue to be more bothersome than asthma).
reaction to aspirin/NSAIDs
- ⚠️ This may be life-threatening.
- Chronicity: Reaction occurs 15 minutes to 4 hours after ingestion (typically within <90 minutes).
- Clinical features are usually predominantly respiratory, but may include: (30207919)
- Upper airway involvement: nasal congestion, rhinorrhea, sneezing.
- Lower airway involvement: cough, wheeze, laryngospasm.
- Gastrointestinal symptoms: nausea, abdominal pain.
- Cutaneous features: facial flushing, urticaria, conjunctival irritation.
diagnosis of AERD
historical features that can help evaluate the likelihood of AERD:
- Features suggestive of AERD: (30207919)
- Respiratory symptoms within 90 minutes of ingesting an NSAID or aspirin, especially:
- On multiple occasions.
- Moderate or severe symptoms (e.g., requiring hospitalization).
- Respiratory symptoms triggered by alcoholic beverages.
- Anosmia with nasal polyposis.
- Respiratory symptoms within 90 minutes of ingesting an NSAID or aspirin, especially:
- Features inconsistent with AERD: (30207919)
- Asthma is present, but sinus CT scan is normal.
- Nasal polyps and asthma began in childhood.
laboratory studies
- Eosinophilia:
- Typically the blood eosinophil count is >300/uL. (Piggott 2022)
- About half of patients have eosinophilia (>500/uL), which correlates with the severity of chronic rhinosinusitis. (29395357) Of course, this is neither specific nor sensitive (since patients with asthma may have eosinophilia).
radiology
- Sinus CT scan may be useful, since a normal sinus CT scan essentially excludes AERD. (30207919)
differential diagnosis
- Allergic reaction may occur to individual NSAIDs. Such reactions wouldn't be expected to extend across the entire medication class (e.g., a patient might be able to tolerate some NSAIDs and not others).
oral aspirin challenge
- This is the essential diagnostic procedure.
- Oral aspirin challenge should be performed only with a proper structure to ensure accuracy and safety.
- If oral challenge is positive, this can be followed immediately by oral aspirin desensitization (discussed further below).
management of AERD
general aspects of management
- If not desensitized, aspirin and any non-COX2 NSAIDs should be avoided.
- Highly selective COX-2 inhibitors are safe to use from a respiratory standpoint (e.g., celecoxib).
- Acetaminophen at a dose of 1,000 mg or higher causes modest COX-1 inhibition and triggers mild reactions in a third of patients. (30207919)
- Standard asthma therapies should be used (e.g., inhaled steroid is often effective).
- Intranasal steroids may provide additional benefit.
- Modulation of the leukotriene pathway is often effective in this patient population:
- Zileuton is an oral inhibitor of 5-lipoxygenase, which globally inhibits leukotriene synthesis. This may be the single most potent leukotriene pathway modifying agent for AERD.
- Leukotriene-receptor antagonists (e.g., montelukast, zafirlukast) may have good efficacy. However, these block only some leukotriene receptors (e.g., Leukotriene-1 receptors).
- Dupilumab may be effective for both asthma and rhinosinusitis symptoms. 📖
aspirin desensitization
- Benefits are numerous: (30207919)
- Reduced sinus infections and steroid use.
- Improvement in rhinosinusitis and asthma.
- Improved sense of smell.
- Improved quality of life.
- Protection from reaction to NSAIDs.
- Technique for desensitization:
- Optimize asthma prior to desensitization.
- Start at low doses of aspirin (40 mg/day) and gradually escalate the dose over 1-3 days. Target a dose of ~325-650 mg BID aspirin. If symptoms occur, treat them and hold a dose but continue desensitization the following day at the same dose.
- Maintenance of desensitization:
- Daily aspirin must be continued, at a dose of 325-650 mg BID. (30207919)
- Concurrent use of a proton pump inhibitor may reduce the risk of gastrointestinal ulceration.
- Desensitized state will persist for no more than ~2-5 days. Full sensitivity may return ~7 days after discontinuing aspirin. If aspirin is stopped for more than 1-2 days, it is advisable to repeat desensitization (starting at a low dose).
pathophysiology of AERD
- Aspirin/NSAIDs block metabolism of arachidonic acid via the COX pathway; this has two problematic consequences:
- (#1) It reduces protective PGE2 (prostaglandin E2).
- (#2) It increases the metabolism of arachidonic acid via the lipoxygenase pathway, thereby elevating leukotriene levels (which cause mast cell activation). LTE4 may be especially problematic, as this may cause pulmonary eosinophilia. (30207919)
- IgE isn't involved, but eosinophils are involved. Unlike atopic asthma, patients may have persistent sputum eosinophilia even after steroid therapy. (Shah 2019)
pathophysiology
- Involves TH17 overactivity (a subset of helper T-cells).
- Some patients may have neutrophilic inflammation, whereas others may have a paucigranulocytic sub-phenotype.
clinical aspects
- May begin in adulthood, sometimes in correlation with smoking or viral infection.
- Patients may tend to have some fixed airway obstruction. Symptoms may be more persistent over time, with less fluctuation.
treatment
- Usual asthma therapies may be utilized.
- Patients may respond less well to steroid.
- Azithromycin may be useful, especially for patients with neutrophilic inflammation. (36100569)
- Tezepelumab ⚡️ may be utilized as a biological therapy in the context of non-Th2-high inflammation.
pathophysiology
- This may involve low-grade systemic inflammation (metabolic inflammation) with elevated levels of IL-6, IL-1, and TNF-⍺.
- Obstructive sleep apnea may increase bronchial reactivity.
- Occasional obese patients may have T2-high disease (elevated levels of IL-4, IL-5, and eosinophils). However, this is overall less likely. Unfortunately, blood eosinophil counts function poorly as a biomarker of T2 airway inflammation in obese patients.
clinical aspects
- Often begins in adulthood.
- May correlate with obesity, sleep apnea, and metabolic syndrome.
- Patients may tend to have some fixed airway obstruction.
- Asthma control is often difficult.
treatment
- Endotype-targeted therapies:
- Weight loss is ideal, if possible. Even loss of a relatively small amount of weight (>5%) may cause metabolic improvements that associate with improved asthma control. Bariatric surgery has been shown to reduce airway hyperresponsiveness.
- Intercurrent sleep apnea should be treated.
- Depression should be treated.
- Usual asthma therapies:
- Overall, patients should be treated using the same algorithms as lean patients. However, bronchodilators and inhaled steroid may be somewhat less effective.
- Steroid exposure may exacerbate metabolic syndrome and obesity. Consequently, steroid exposure should be limited as much as possible. For example, use of PRN inhaled formoterol/steroid as a reliever medication may safely limit steroid use (more on this below 📖). (29768149)
- Theophylline may cause a paradoxical response, with increased exacerbations. (16939998)
Most hospitals won't have access to measurement of exhaled NO. Additionally, the use of nitric oxide monitoring is limited by lack of evidence that it improves outcomes.
levels
- Normal exhaled NO is 3-7 PPB (parts per billion).
- Diagnosis of asthma:
- >30 PPB supports the presence of asthma.
- Therapy of known asthma:
- <25 PPB suggests that steroid may not be effective.
- >50 PPB suggests improvement from steroid. (36682372)
sensitivity
- Sensitivity is variable overall.
- Sensitivity is higher for patients with active asthmatic symptoms (as high as 88%).
- NO is elevated by Th2-inflammation, so it is predominantly sensitive for atopic asthma.
- NO levels correlate with eosinophilic inflammation, sputum eosinophils, and serum IgE levels.
- Inhaled steroid reduces nitric oxide, so persistently elevated nitric oxide may suggest nonadherence with inhaled corticosteroid. (ERS handbook 3rd ed.)
- Exhaled NO lacks sensitivity to detect noneosinophilic asthma phenotypes.
specificity: causes of elevated NO include:
- Asthma.
- Allergic rhinitis.
- Bronchiectasis.
- Viral respiratory tract infection.
- Lupus.
- Lung transplantation rejection.
- Primary or secondary pulmonary eosinophilic disorders, for example:
- Non-asthmatic eosinophilic bronchitis.
- EGPA (eosinophilic granulomatosis with polyangiitis).
- Cirrhosis.
- Ingestion of nitrate-rich foods.
physical examination findings in asthma
- Wheezing is diffusely located (throughout the chest) and classically polyphonic (containing multiple different tones).
- Wheezing may be louder on expiration.
- Among critically ill patients, poor airflow may cause wheezing to be absent (“silent chest”). This is an ominous finding.
- Additional information:
examination findings that are inconsistent with asthma
- Large airway obstruction:
- The primary sign of large airway obstruction is that patients often have stridor (rather than true wheezing). Stridor is easily heard from across the room, whereas small airway wheezing cannot be. (Further discussion of stridor is here: 📖.)
- Auscultation may be loudest over the throat.
- Focal wheezing: If wheezing is localized within the lung, this raises the possibility of endobronchial tumor, foreign body, or mucus plugging.
blood eosinophilia in asthma
- Eosinophils are predominantly located in tissues, so blood levels may not correlate perfectly with tissue levels.
- Elevated blood eosinophil levels may be a reflection of T2-high types of asthma (e.g., atopic asthma). This is clinically relevant, as it may guide personalized therapeutic interventions.
- <100 eosinophils/uL suggests a lack of airway eosinophilia (but doesn't exclude this possibility).
- >150-300 eosinophils/uL suggests the presence of airway eosinophilia (e.g., eosinophils in sputum).
- >400 eosinophils/uL may predict a 42% elevation in the risk of a severe exacerbation in the coming year. (Piggott 2022)
- (More on blood eosinophilia: 📖)
immunoglobulin E level (IgE)
- Normal IgE levels are <360 ng/mL (<150 IU/ml or kU/L).
- IgE in asthma may vary from zero to >2,000 ng/ml (>834 IU/ml).
- Higher levels of IgE suggest atopic asthma (aka T2-high endotypes).
- Omalizumab ⚡️ is approved for patients with both:
- IgE levels between 30-700 IU/mL.
- Documented reaction to perennial aeroallergen (e.g. dust mites, mold, animal dander, cockroaches), based on either skin tests showing wheal-and-flare response or specific IgE levels against that antigen.
- Very high IgE levels don't necessarily indicate an alternative diagnosis. However, markedly elevated IgE levels may be consistent with a diagnosis of ABPA (allergic bronchopulmonary aspergillosis).
- (More on IgE: 📖)
basics
- A peak flow meter is a very simple device which measures the peak airflow that the patient can generate. Patients may have these devices at home to track the severity of their asthma.
- Peak flow may provide an objective measurement of airflow impairment. It may be especially useful for patients with poor ability to sense their degree of airflow obstruction.
- Potential utility may include:
- Diagnosis of asthma: diurnal variability of >15% over four or more days is 97% specific for diagnosing asthma in a suggestive clinical context. (36100569)
- Triage: This could help determine the need for inpatient admission among some patients where the optimal disposition is clinically unclear.
- Longitudinal management: Tracking peak flow longitudinally as an outpatient may allow for early detection of disease instability, which can facilitate more proactive management.
limitations
- 🛑 Peak flow measurements can exacerbate bronchospasm, so it's not helpful for patients who are obviously very sick. For example, if you're considering whether a patient should be admitted to the ICU or the hospital floor, then peak flow has minimal role.
- Peak flow will be reduced by poor effort.
- Peak flow may be reduced by other active pulmonary problems (e.g., pneumothorax, effusion, pneumonia). Thus, a reduced peak flow doesn't necessarily indicate that the patient has an asthma exacerbation – it merely indicates that something is wrong with their lungs.
conversion of absolute peak flow into % predicted
- Absolute values may be compared to the percent predicted value using this online calculator 🧮
- Additionally, comparison to a patient's prior values may be helpful (if they are known).
interpreting peak flow: some rough benchmarks
- Peak flow >70% predicted is consistent with mild asthma (e.g., patients who may be appropriate for discharge home).
- Peak flow <40% is suggestive of severe asthma.
- If peak flow is low and doesn't improve with therapy, this is a poor prognostic sign.
diagnosis of asthma
- Responsiveness to bronchodilators or methacholine supports the diagnosis of asthma, but isn't entirely specific for asthma.
- Failure to respond to methacholine provides strong evidence against the diagnosis of asthma. However, patients with asthma can have a negative methacholine challenge if they are currently asymptomatic (e.g., in the context of exercise-induced asthma, early occupational asthma, or recent steroid therapy). (Murray 2022) (Further discussion of methacholine bronchoprovocation: 📖)
- Evaluation of the flow-volume loop is essential to exclude upper airway obstruction or vocal cord dysfunction as a cause of “wheezing.” (In actuality, what is reported as “wheezing” in patients with upper airway obstruction is often stridor.) (Further discussion of flow-volume loops: 📖)
- DLCO should be preserved. A low DLCO implies an alternative or additional diagnosis (e.g., emphysema). (Further discussion of DLCO: 📖)
monitoring disease severity
- Serial PFTs may be useful to evaluate disease severity over time.
The primary role of radiology in asthma is either revealing an alternative diagnosis or identification of complications (e.g., pneumothorax).
chest radiograph
- Chest radiograph in asthma will generally be normal. The purpose of obtaining a chest radiograph is exclusion of alternative or superimposed pathology (e.g., pneumothorax, tracheal obstruction).
- During an asthma exacerbation, some degree of hyperinflation might be expected.
- Bronchial wall thickening may generate ring shadows, due to bronchi visualized on-end (usually near the hilar area). (Shepard 2019)
CT scan – utility in asthma diagnosis
- CT scan can help diagnose asthma mimics, including:
- Central airway lesions (e.g., endobronchial or endotracheal tumors).
- Foreign body.
- Tracheobronchomalacia.
- CT scan may help evaluate for other diseases associated with asthma (e.g., allergic bronchopulmonary aspergillosis).
CT scan: potential findings in asthma
- (1) Airflow obstructive features are most characteristic:
- Mosaic attenuation may result from small airway obstruction. This will be highlighted on expiratory CT scan. (Other causes of mosaic attenuation: 📖)
- Hyperinflation.
- (2) Bronchial wall abnormalities can occur:
- Bronchial wall thickening.
- Increased thickness correlates with disease severity. (Rosado-de-Christenson 2022)
- Differential diagnosis of bronchial wall thickening: 📖
- Occasional tree-in-bud abnormalities or small centrilobular opacities may occur. However, these shouldn't be diffuse or dramatic.
- Mild, cylindrical bronchiectasis may occur. However, varicose bronchiectasis is more suggestive of ABPA (allergic bronchopulmonary aspergillosis). (More on radiological typology of bronchiectasis here: 📖)
- Bronchial wall thickening.
- Atelectasis due to mucus plugging is often seen.
- Cysts may rarely occur (due to focal hyperinflation).
- Differential diagnoses:
- Bronchiolitis obliterans may be radiographically identical to asthma. (Rosado-de-Christenson 2022)
- Other forms of bronchiolitis (e.g., infectious bronchiolitis).
⚠️ Patients are often labeled as having asthma, when they do not in fact have asthma. Whenever possible, review prior data to confirm the diagnosis of asthma (ideally pulmonary function tests).
the diagnosis of asthma generally involves a few components
- (1) History suggestive of asthma:
- One or more hallmark symptoms (cough, dyspnea, chest tightness, wheezing).
- Symptoms are often episodic in nature, sometimes with a defined trigger (e.g., cold air, exercise, airborne irritants, or allergens).
- (2) Objective evidence of reversible airflow obstruction:
- (3) Evaluation doesn't suggest an alternative diagnosis.
differential diagnosis of asthma includes:
- Upper airway obstruction, including:
- Vocal cord dysfunction.
- Tracheal stenosis.
- Tracheobronchomalacia.
- Foreign body.
- Carcinoid tumor (may also cause diffuse wheeze).
- Bronchiectasis (including cystic fibrosis).
- Small airway disease:
- Asthma.
- COPD (including emphysema and chronic bronchitis).
- Viral bronchitis (may cause wheeze, dyspnea, and cough with bronchial reactivity for up to 6 weeks).
- Bronchiolitis of various etiologies (especially bronchiolitis obliterans).
- Anaphylaxis, mastocytosis.
- Eosinophilic bronchitis.
- Interstitial lung diseases can sometimes cause obstructive physiology:
- LAM (lymphangioleiomyomatosis).
- PLCH (pulmonary Langerhans cell histiocytosis).
- Sarcoidosis.
- Heart failure (wheeze and airway hyperreactivity can occur in heart failure).
- Pulmonary embolism.
(#1) Consider an alternative or superimposed diagnosis
- Upper airway obstruction, especially vocal cord dysfunction.
- Eosinophilic lung disease associated with asthma:
- ABPA (allergic bronchopulmonary aspergillosis).
- EGPA (eosinophilic granulomatosis with polyangiitis).
- CEP (chronic eosinophilic pneumonia).
- (The differential diagnosis of asthma is explored further in the section above.)
(#2) Consider causes of poor asthma control (“treatable traits”)
- Nonadherence to asthma medications, e.g.:
- Unable to afford.
- Poor inhaler technique.
- Confusion about how medications should be taken (e.g., inhaler device polypharmacy). (36100569)
- Irritant exposure (e.g., crack, marijuana, tobacco).
- Persistent allergen exposure (e.g., occupational, pollen, mold).
- GERD (gastroesophageal reflux disease). However, treatment of GERD usually has little effect on mild-to-moderate asthma. (ERS handbook 3rd ed.)
- Allergic rhinitis, nasal polyps:
- Intranasal steroid may improve asthma control.
- Leukotriene inhibitor may treat asthma as well as rhinitis.
- Aspirin desensitization may help patients with nasal polyps and aspirin sensitivity. 📖
- Obesity (potential to treat with weight loss; possibly bariatric surgery).
- Obstructive sleep apnea.
- Anxiety, panic disorder (may be misdiagnosed as an asthma exacerbation). (Shah 2019)
- Medications that could exacerbate asthma:
- Aspirin or NSAIDs (among sensitive patients). 📖
- Beta-blockers, predominantly nonselective beta-blockers.
- Some chemotherapies (e.g., IL-2, methotrexate).
- Protamine.
- Dipyridamole for cardiac stress test.
investigation to consider in suboptimal asthma control
- Review with the patient:
- Adherence and technique with inhalers.
- New allergen exposure, pets, changes in environment.
- Medication review.
- Symptoms of gastroesophageal reflux disease.
- Symptoms of rhinitis/sinusitis.
- Investigations:
- Chest imaging.
- CBC with differential (? marked eosinophilia).
- IgE level.
bronchodilators
- Acutely ill patients may have difficulty using metered dose inhalers, so nebulized therapy is preferred.
- A typical regimen might be scheduled albuterol/ipratropium nebulized q4-6 hours, with additional PRN albuterol.
systemic steroid
- Patients will often receive an initial dose of IV methylprednisolone in the emergency department (e.g., 60-125 mg). Subsequently, an intermediate-dose steroid burst is often sufficient (e.g., 40-50 mg/day prednisone for five days).
- The optimal steroid dose is unknown, with guidelines often recommending a dose of 0.5-1 mg/kg/day, or 40-80 mg/day prednisone. (Shah 2019)
additional therapies
- Adjunctive therapies should generally be continued.
- 2 grams of IV magnesium is reasonable.
- Initiation of a leukotriene receptor inhibitor (e.g., montelukast) could be considered (with a primary goal of improving chronic asthma control following discharge from the hospital).
transition to home bronchodilators and inhaled steroid
- As patients improve and start approaching discharge, it may be helpful to transition them towards their home regimen.
- Their outpatient regimen should be reviewed and modified as necessary (see the section below).
- Appropriate technique with inhalers should be reviewed with the patient. Respiratory therapists are extremely helpful in coaching patients on the best techniques.
controller medications
- Controller medications are intended to achieve and maintain good control of asthma over the longer term.
- Controller therapies should be utilized regardless of whether the patient is having symptoms (e.g., in a preventative fashion).
- Controller therapy should be escalated or de-escalated in a stepwise fashion depending on disease activity, as outlined below.
reliever medications
- Reliever therapy is used as-needed (PRN), based on symptoms. Reliever therapy should ideally not be utilized frequently (frequent need for reliever medications is a reflection of poor asthma control).
- Albuterol has traditionally been used for rescue therapy. Albuterol has rapid onset and is usually effective at relieving transient bronchoconstriction.
- Ideally patients should only require rescue albuterol 0-2 times per week. More frequent use of albuterol may reflect inadequate asthma control, which could benefit from a step-up in the aggressiveness of controller medications.
- Frequent use of albuterol may cause desensitization, increasing the risk of clinical deterioration that becomes refractory to bronchodilators. Frequent use of albuterol without adequate inhaled steroid is a risk factor for hospitalization.
- PRN formoterol-steroid (preferred):
- Formoterol is a long-acting beta-2 agonist, which has a rapid onset of effect. Due to its rapid onset, formoterol may be used for PRN bronchodilation.
- The combination of formoterol plus an inhaled steroid in a single inhaler has been shown to be a winning strategy. This combines a reliever medication (formoterol) with an inhaled steroid – thereby ensuring that patients don't receive high doses of beta-agonist in the absence of adequate steroid. If asthma control is suboptimal, PRN use of formoterol-steroid will automatically up-titrate the patient's inhaled steroid dose.
- SMART therapy refers to using a single medication as rescue and maintenance therapy (e.g., formoterol-steroid may scheduled and also used PRN – thus functioning as both a controller and also a reliever medication). This simplifies management and improves patient adherence.
- Available formulations of formoterol/steroid include:
- Formoterol/budesonide is combined in Symbicort™️.
- Formoterol/mometasone is combined in Dulera™️.
- Formoterol/beclomethasone is combined in Fostair™️ (not available in the United States).
stepping up/down
- For uncontrolled asthma, escalate therapy.
- For asthma controlled >3 months, de-escalation may be cautiously considered.
Based on which reliever medication is used, two tracks may be used to combine different medications:
Track 1 (preferred) – Inhaled steroid-formoterol used as a reliever
step #1-2 controller
- No scheduled controller medication.
- PRN low-dose steroid-formoterol is the only therapy.
- Example: Budesonide 160 mcg/formoterol 4.5 mcg, 1 inhalation PRN. (37703556)
step #3 controller
- Scheduled low-dose steroid-formoterol is used as a controller.
- (Adjunctive: May consider addition of Leukotriene receptor agonist.)
- Example: Budesonide 160 mcg/formoterol 4.5 mcg or Beclomethasone 84.6 mcg/formoterol 5 mcg, 1 inhalation once or twice daily PLUS 1 inhalation PRN. (37703556)
step #4 controller
- Scheduled medium-dose steroid-formoterol is used as a controller.
- (Adjunctive: May consider addition of Leukotriene receptor agonist.)
- Example: Budesonide 160 mcg/formoterol 4.5 mcg or Beclomethasone 84.6 mcg/formoterol 5 mcg, 2 inhalations twice daily PLUS 1 inhalation PRN. (37703556)
step #5 controller
- Add-on LAMA.
- Scheduled medium- or high-dose steroid-formoterol.
- Consider addition of Leukotriene receptor agonist.
- Evaluation for asthma phenotype and consideration for biological therapies.
- Example: Budesonide 160 mcg/formoterol 4.5 mcg or Beclomethasone 84.6 mcg/formoterol 5 mcg, 2 inhalations twice daily PLUS 1 inhalation PRN. Also add LAMA +/- leukotriene antagonist. (37703556)
Track 2 (traditional; not preferred) – Albuterol is used as a reliever
step #1 controller
- No scheduled controller.
- For dyspnea, take both albuterol and also take inhaled steroid.
- ⚠️ Albuterol-only treatment is no longer recommended for asthma, given evidence that it increases the risk of exacerbations and mortality. (36100569)
step #2 controller
- Preferred options:
- Low-dose inhaled steroid.
- Alternative:
- Leukotriene receptor antagonist instead of inhaled steroid.
- Adjunctive: Leukotriene receptor agonist as add-on therapy.
step #3 controller
- Preferred:
- Low-dose inhaled steroid + long-acting beta-2 agonist.
- Alternatives:
- Medium-dose inhaled steroid.
- Low-dose inhaled steroid + leukotriene receptor antagonist.
- Adjunctive: Leukotriene receptor agonist as add-on therapy.
step #4 controller
- Preferred:
- Medium-high dose inhaled steroid + long-acting beta-2 agonist.
- Alternative:
- High-dose inhaled steroid + leukotriene receptor agonist.
- High-dose inhaled steroid + LAMA (e.g., tiotropium).
- Adjunctive: Leukotriene receptor agonist as add-on therapy.
step #5 controller
- Preferred:
- Long-acting anticholinergic.
- Medium-high dose inhaled steroid + long-acting beta-2 agonist.
- Also may consider:
- Addition of a leukotriene receptor antagonist or zileuton (a leukotriene synthesis inhibitor).
- Evaluation for phenotype and consideration for biological therapies.
role of inhaled steroid in asthma control
- Inhaled steroid is a fundamental therapy for asthma. It has been shown to improve symptoms, reduce hospitalization, and reduce mortality.
- Predictors of responsiveness to inhaled steroid:
- Eosinophilic inflammation.
- Atopic phenotype.
- Side effects of inhaled steroid:
- Laryngeal or oral candidiasis can occur. The risk may be reduced by gargling after use of inhaled steroid, and the use of a spacer with metered dose inhalers (MDIs).
- Relative adrenal suppression may occur (especially with fluticasone).
- Some formulations of inhaled steroid have been linked to increased pneumonia in COPD. However, this doesn't seem to be a concern in the context of asthma.
inhaled steroid dosing
⚠️ The dose-response curve of inhaled steroid is relatively flat, so high-dose steroid is usually only mildly more effective than medium doses. This explains why addition of a long-acting beta-2 agonist is usually attempted prior to escalating to high dose inhaled steroid. (Fishman 2023)
beclomethasone dipropionate HFA (Qvar™️)
- 40 or 80 ug/actuation.
- Low dose: 80-240 ug/day.
- Medium dose: >240-480 ug/day.
- High dose: >480 ug/day.
- Beclomethasone has relatively low first-pass metabolism (as compared to budesonide and fluticasone), so swallowed beclomethasone may tend to produce relatively more systemic effects. (ERS handbook 3rd ed.)
budesonide DPI (Pulmicort™️)
- 90 or 180 ug/actuation.
- Low dose: 180-600 ug/day.
- Medium dose: >600-1200 ug/day.
- High dose: >1200 ug/day.
- 🏆 Combined with formoterol in Symbicort™️ or Breyna™️ (contains 80 or 160 mcg of budesonide plus 4.5 mcg formoterol). For adults the preferred formulation may be 160 mcg budesonide plus 4.5 mcg formoterol. (37703556) The maximal scheduled dose is two actuations of 4.5/160, twice daily (for a total of 640 mcg/day budesonide) – but additional doses may be used PRN.
ciclesonide HFA (Alvesco™️)
- Low dose: 160-320 ug/day.
- Medium dose: >320-640 ug/day.
- High dose: >640 ug/day.
- May have lowest degree of systemic corticosteroid effect (<1% bioavailability and 99% protein binding).
fluticasone DPI or HFA (Flovent™️)
- Low dose: 100-300 ug/day.
- Medium dose: >300-500 ug/day.
- High dose: >500 ug/day.
- Causes the greatest degree of adrenal suppression.
- Combined with salmeterol in Advair™️.
- Combined with vilanterol in Breo™️.
- Combined with vilanterol and umeclidinium in Trelegy™️.
mometasone furoate (Asmanex™️)
- Low dose: 110-220 ug/day.
- Medium dose: 220-440 ug/day.
- High dose: >440 ug/day.
- Approved for once-daily use (unlike most others, which require BID dosing).
- One study of severe, persistent asthma found that doses up to 1600 mcg/day allowed 76% of patients to completely eliminate oral prednisone. This may be possible because mometasone is the most potent inhaled corticosteroid. (19125898)
- 🏆 Combined with formoterol in Dulera™️ (contains 5 mcg formoterol and either 50/100/200 mcg mometasone). Maximal scheduled dose: two actuations of 5/200, twice daily (for a total of 800 mcg/day mometasone).
triamcinolone (Azmacort™️)
- Low dose: 400-1000 ug/day.
- Medium dose: 1000-2000 ug/day.
- High dose: >2000 ug/day.
role in asthma maintenance therapy
- Long-acting beta-2 agonists may function synergistically with steroids, by causing bronchodilation and improved steroid delivery.
- Long-acting beta-2 agonists should not be used alone (without steroid), as this may be correlated with an increased risk of exacerbations and mortality.
agents and dosing
- Salmeterol (salmeterol/fluticasone in Advair™️).
- Formoterol (formoterol/budesonide in Symbicort™️).
- Formoterol has a rapid onset of action, allowing formoterol/budesonide to be utilized as a PRN agent (a combination of reliever and controller).
- Indacaterol – has an advantage of a duration of action >24 hours, allowing once daily therapy. (ERS handbook 3rd edition)
- Vilanterol.
conceptual schema regarding anticholinergics
- Pathophysiology:
- Anticholinergics may prevent cholinergic reflex bronchoconstriction stimulated by irritants, stress, and cold air.
- Anticholinergics are less effective against allergens or inflammatory mediators (e.g., histamine and leukotrienes).
- General schema for clinical use:
- (1) Anticholinergics are especially helpful in COPD, wherein cholinergic tone may be the only reversible element of airway narrowing. (ERS handbook 3rd edition)
- (2) Long-acting anti-muscarinic agents (LAMAs) still have some utility in asthma.
- They are often less effective in T2-high phenotypes (e.g., allergic/atopic asthma).
- Tiotropium (a LAMA) may be more useful in patients with T2-low phenotypes.
short-acting anticholinergic agents in asthma
- These have not been found to provide benefit in patients with chronic asthma. (15266477)
- Short-acting anticholinergics may be useful for patients hospitalized with an acute asthma exacerbation. 📖
long-acting antimuscarinic agents (LAMAs) in asthma
- Agents include: tiotropium, umeclidinium, aclidinium, revefenacin, glycopyrrolate.
- Tiotropium has been shown to provide benefit as add-on therapy for patients on either inhaled steroid, or on inhaled steroid plus a long-acting beta-agonist. It may improve lung function and increase the time to severe exacerbation. (36100569) Tiotropium may be more helpful for patients with a T2-low phenotype (discussed above).
Acutely ill patients admitted to the hospital are often unable to correctly self-administer metered-dose inhalers or dry-powder inhalers. Consequently, initial management of asthma for hospitalized patients will typically involve a transition to nebulized therapies. As patients recover and approach discharge, it is helpful to transition to a home regimen involving metered-dose inhalers and/or dry powder inhalers (with assistance and education by respiratory therapists). A series of instructional videos regarding inhaler devices may be found at copdfoundation.org.
nebulizers
- Nebulizers have the advantage of being able to administer large doses of medication without any additional work expenditure from the patient.
- Nebulizers are useful for acutely ill patients admitted to the hospital.
- Nebulizers are generally less useful for outpatient treatment (they lack portability, depend on an external power source, and require regular cleaning and maintenance). (Fishman 2023) However, for some patients who are able to maintain a nebulizer properly, home nebulization may be very effective.
metered-dose inhaler (MDI)
- Metered-dose inhalers are inexpensive and widely available.
- The device should be actuated at the beginning of a deep, slow inhalation lasting for five seconds, followed by a breath-hold pause of at least five seconds (ideally ten seconds). Patients should be instructed to inhale “slowly, gently, naturally, deeply, and comfortably” and to actuate the device within the first second following initiation of inhalation. (Fishman 2023)
- Spacers improve delivery to the lungs, while reducing drug deposition in the oropharynx. This may simultaneously improve efficacy, while reducing toxicity.
- Specific spacers should be prescribed only with the MDI they are compatible with. (Fishman 2023)
dry powder inhaler (DPI)
- Dry powder inhalers depend on patient efforts to pull drug particles into the lungs. To be effective, patients should inhale forcefully, quickly, and deeply.
- Strengths of DPIs:
- Breath actuation can facilitate synchronous drug release with inspiration.
- Many devices have a dose counter, which helps clarify when a refill is needed.
- Weaknesses of DPIs:
- Effectiveness is dependent on generating an adequate inspiratory flow. Some devices may require high inhalation flows to be effective (~60 L/min). Patients with severe airflow obstruction may be unable to generate sufficient flow to pull the drug into their lungs. (ERS handbook 3rd ed.)
role in asthma maintenance therapy
- Leukotriene receptor antagonists on average are less effective than inhaled steroid or long-acting beta agonists, so they aren't generally used as first- or second-line controller medications. (Shah 2019) However, leukotriene receptor antagonists are extremely well tolerated, so they may be utilized as add-on therapy.
- Leukotriene-receptor antagonists may be especially useful in patients with:
- Aspirin sensitivity.
- Allergen-induced and allergic rhinitis/rhinosinusitis.
- Exercise-induced asthma. (36100569)
agents and dosing
- Montelukast (Singulair™️), 10 mg daily.
- Zafirlukast (Accolate™️), 20 mg BID.
physiology
- Leukotriene D4 normally binds to smooth muscles and causes bronchospasm.
- Leukotriene inhibition causes bronchodilation within hours of the first dose, with a maximal effect within a few days.
- May cause a reduction in peripheral eosinophils.
side effects
- Generally well tolerated.
- Zafirlukast may cause hepatic failure.
- Zileuton inhibits the activity of 5-lipoxygenase. This reduces the synthesis of leukotrienes (figure above).
- One RCT found that zileuton extended release 2400 mg/day was more effective than montelukast 10 mg BID. (22926233)
- Zileuton can cause a reversible chemical hepatitis. (Shah 2019)
- Overall, zileuton is generally reserved for refractory asthma that has a phenotype suggestive of benefit from modulation of the leukotriene pathway. (Murray 2022)
OMAlizumab (anti-IgE)
basics & mechanisms of action
- Omalizumab is a monoclonal anti-IgE antibody, which causes a 95% reduction in IgE levels.
- Its primary mechanism of action is removal of IgE from circulation.
indications
- Severe, refractory asthma with:
- (1) IgE levels between 30-700 IU/mL.
- -AND-
- (2) Documented reaction to perennial aeroallergen (e.g. dust mites, mold, animal dander, cockroaches), including either:
- Skin test showing wheal-and-flare response.
- Specific IgE level against that antigen.
- Also effective for:
contraindications / adverse effects
- Omalizumab is generally well tolerated, but systemic allergic reactions may rarely occur.
- Serum sickness.
MEPOlizumab/RESlizumab (anti-IL5)
basics
- Mechanism: These bind to circulating IL-5 (a cytokine involved in eosinophil activation).
- IL-5 inhibitor efficacy is highly dependent on the peripheral eosinophil count (often using a cutoff of >300 eosinophils/uL).
MEPOlizumab
- Indications:
- Refractory asthma (especially steroid-dependent asthma):
- It may be utilized for severe eosinophilic asthma (trials have required >150 eosinophils/uL at baseline and >300 eosinophils/uL at some point within the last year).
- Mepolizumab may reduce exacerbations and oral steroid use.
- EGPA (eosinophilic granulomatosis with polyangiitis).
- Hypereosinophilic syndrome.
- Chronic rhinosinusitis with nasal polyps. (36283607)
- Refractory asthma (especially steroid-dependent asthma):
- Contraindications/cautions:
- Helminthic infections.
- Hypersensitivity reactions.
- Herpes zoster infections (rare).
RESlizumab
- Indications:
- This is useful for refractory, eosinophilic asthma (with trials requiring >400 eosinophils/uL).
- Higher doses of reslizumab may be administered than of mepolizumab, so it may be considered in patients who don't have a good response to mepolizumab. (Fishman 2023)
- Reslizumab hasn't yet been shown to reduce daily steroid requirement in steroid-dependent patients. (35020986)
- Contraindications / cautions:
- Helminthic infections.
- Anaphylaxis (~0.3%).
BENRAlizumab (anti-eosinophil)
mechanism
- BENRAlizumab binds to the IL5-receptor, causing apoptosis of eosinophils and basophils (with subsequent eosinopenia).
- Longer duration of effect may allow for q8-week dosing (unlike other biologics that require q2- or q4-week dosing). (36283607)
indications
- BENRAlizumab may be used for severe eosinophilic asthma (with best results in patients with >300 eosinophils/uL).
- BENRAlizumab has been shown to promote reduction or withdrawal of steroid if the blood eosinophils are >150/uL. (35020986)
- It also may be effective for chronic rhinosinusitis with nasal polyps. (36283607)
contraindications/cautions
- Helminthic infections.
- Hypersensitivity reactions.
dupilumab: broad type-2 immune suppression via IL4/IL13
basics & mechanism of action
- Dupilumab binds to the alpha-subunit of the IL-4 receptor, causing a dual blockade of IL-4 and IL-13 (figure above). Actions of IL-4 and IL-13 include:
- Activation of B-cells.
- IgE synthesis.
- Eosinophil recruitment.
- Overall, dupilumab suppresses type-2 inflammation more broadly than by simply targeting eosinophils.
indications
- Oral steroid-dependent asthma (regardless of eosinophil count; may help reduce oral steroid). (29782224) Dupilumab is the only asthma biologic approved specifically for oral steroid reduction (although mepolizumab and benralizumab have been shown to reduce oral steroid requirements as well). (36283607)
- Exhaled NO predicts responsiveness.
- Optimal efficacy probably occurs with eosinophil levels 150-1500/uL. (35020986)
- Higher eosinophil levels may suggest improved responsiveness somewhat (but its efficacy is less directly tied to eosinophil count as compared to the IL-5 agents in the section above). (27130691)
- Other indications:
contraindications / cautions
- Dupilumab may cause transient elevation of blood eosinophils during the first four months of therapy, so caution is needed in patients with baseline eosinophilia >1,500/uL. (Murray 2022) Hypereosinophilia is usually asymptomatic, but rare cases of EGPA (eosinophilic granulomatosis with polyangiitis) have been reported. (35020986)
- Helminthic infections.
- Hypersensitivity reactions.
- Conjunctivitis.
Tezepelumab (Thymus)
basics & mechanism of action
- Tezepelumab inhibits thymic stromal lymphopoietin (TSLP). It may act upstream to dampen inflammation, or via effects on mast cells or on smooth airway muscles. (36682372)
- Tezepelumab may be effective in patients regardless of eosinophil count, since it may also target T-cells that orchestrate neutrophilic inflammation. As such, tezepelumab is an attractive option for patients who aren't candidates for other biologic therapies. Tezepelumab is the only biologic agent approved for severe asthma with no phenotype or biomarker limitation. (36283607) However, tezepelumab is most effective in eosinophilic asthma. (36682372)
efficacy
- Reduced exacerbations.
- Symptomatic improvement.
- Improved lung function.
contraindications / cautions
- Potential side effects:
- Pharyngitis.
- Arthralgia.
- Back pain.
theophylline
- The use of theophylline is dubious, given potential toxicity and lack of evidence that it improves patient-centered endpoints.
- For patients on chronic theophylline, levels should be checked (with a target level of 10-20 ug/mL). Theophylline interacts with a variety of medications, so care is required to avoid drug-drug interactions.
- Theophylline may cause a paradoxical worsening of exacerbation frequency among patients with obesity-associated asthma. (16939998)
roflumilast
- Roflumilast is a selective phosphodiesterase type-4 inhibitor with a superior safety profile as compared with theophylline.
- Roflumilast has been shown to improve pulmonary function and symptoms in asthma. (16364159)
basics
- This is fundamentally irritant-induced asthma that occurs following a single, high-level exposure to respiratory irritants (vapor, fumes, or smoke).
epidemiology
- There are numerous causes (including chlorine, ammonia, sulfur dioxide, di-isocyanates, perchloroethylene, acetic or peracetic acid, and hydrogen peroxide). (34022018)
- Causes of exposure include:
- Workplace accident.
- Accidental fire with release of thermal combustion byproducts.
- Atopy is not a risk factor.
symptoms
- Chronicity:
- (1) Symptoms develop within hours of exposure.
- (2) To meet the diagnosis of RADS, symptoms and airway responsiveness should persist for at least three months. Unfortunately, the disorder often persists for over a year, and may be permanent.
- Symptoms mimic those of asthma (e.g., wheezing, dyspnea, chest tightness, cough).
diagnostic testing
- Pulmonary function testing shows obstruction with hyperreactive airways (e.g., positive response to methacholine bronchoprovocation).
management
- Short-acting bronchodilators and inhaled steroid may be beneficial. (Fishman 2023)
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References
- 29395357 Sacco KA, Pongdee T. 52-Year-Old Man With Hyposmia, Rhinorrhea, and Wheezing. Mayo Clin Proc. 2018 Apr;93(4):518-522. doi: 10.1016/j.mayocp.2017.04.019 [PubMed]
- 30207919 White AA, Stevenson DD. Aspirin-Exacerbated Respiratory Disease. N Engl J Med. 2018 Sep 13;379(11):1060-1070. doi: 10.1056/NEJMra1712125 [PubMed]
- 34022018 Fong I, Chew SY, Tan KL. A 27-Year-Old Man With Persistent Breathlessness After an Inhalational Injury. Chest. 2021 Apr;159(4):e197-e201. doi: 10.1016/j.chest.2020.11.044 [PubMed]
- 34743854 Okereke J, Malin M, Koo P. A 31-Year-Old Pregnant Woman With Asthma, Presenting With Worsening Dyspnea, Wheeze, and Hoarseness. Chest. 2021 Nov;160(5):e507-e512. doi: 10.1016/j.chest.2021.06.064 [PubMed]
- 35020986 Brusselle GG, Koppelman GH. Biologic Therapies for Severe Asthma. N Engl J Med. 2022 Jan 13;386(2):157-171. doi: 10.1056/NEJMra2032506 [PubMed]
- 36100569 Witt A, Douglass JA, Harun NS. Overview of recent advancements in asthma management. Intern Med J. 2022 Sep;52(9):1478-1487. doi: 10.1111/imj.15904 [PubMed]
- 36283607 Busse WW, Castro M, Casale TB. Asthma Management in Adults. J Allergy Clin Immunol Pract. 2023 Jan;11(1):21-33. doi: 10.1016/j.jaip.2022.10.015 [PubMed]
- 36682372 Porsbjerg C, Melén E, Lehtimäki L, Shaw D. Asthma. Lancet. 2023 Mar 11;401(10379):858-873. doi: 10.1016/S0140-6736(22)02125-0 [PubMed]
- 37703556 Mosnaim G. Asthma in Adults. N Engl J Med. 2023 Sep 14;389(11):1023-1031. doi: 10.1056/NEJMcp2304871 [PubMed]
Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.
