Contents

Search

asthma

A chronic illness characterized by airway inflammation* & hyper- responsiveness* of the tracheobronchial tree to diverse stimuli. The clinical course is one of exacerbations & remissions*, but without inevitable progression. * Triad of asthma 1) airway inflammation 2) bronchial hyper-responsiveness 3) reversibility Classification: 1) mild intermittent a) symptoms < 3 times/week b) asymptomatic c) normal peak expiratory flow between exacerbations d) nocturnal symptoms < 3 times/month e) FEV1 >= 80% f) FEV1/FVC normal 2) mild persistent a) symptoms > twice weekly, but < daily b) nocturnal symptoms > 2 times/month c) FEV1 >= 80% d) FEV1/FVC normal 3) moderate persistent a) daily use of short-acting beta-2 adrenergic agonists b) acute exacerbations > once weekly c) nocturnal symptoms > once weekly d) FEV1 60-80% e) FEV1/FVC reduced <= 5% [3] 4) severe persistent a) continual symptoms that limit physical activity b) nocturnal symptoms frequent c) FEV1 < 60% d) FEV1/FVC reduced > 5% [3] e) multiple exacerbations/year f) need for high-dose inhaled glucocorticoids or oral glucocorticoids g) inability to step down therapy without compromising asthma control h) history of multiple hospitalizations for asthma or multiple endotracheal intubations [3] 5) exercise-induced asthma Also see alternative classification of asthma Etiology: 1) genetic predisposition interacts with additional factors (below) 2) most childhood asthma exacerbations are caused by viral infections, esp. rhinovirus, RSV & influenza virus[3,50] 3) exercise-induced asthma (also cold air) - endurance swimmers with high prevalence of asthma [74] 4) GERD-induced asthma [26] a) 80% of adult asthma with some reflux b) innervation of lower esophagus (vagus) is same as innervation of lungs c) theophylline, EtOH & tobacco increase reflux 5) sinobronchial-induced asthma a) pollens b) dust & dust mites c) animal dander d) cockroaches* 6) occupational asthma: a) allergy to Latex b) industrial agents c) fumes d) household cleaning products including green products, cleaning sprays & disinfecting wipes [134] 7) pharmaceutical agents a) beta-adrenergic antagonists can worsen asthma b) ACE inhibitors can cause coughing in asthmatics c) aspirin & other NSAIDs can cause acute, severe asthma d) acetaminophen in children & adolescents not a risk [36] - association with use for respiratory tract infections [36] 8) nitrogen dioxide exposure [10] 9) mycoplasma or chlamydia may be associated with attack, especially 1st attack in children [13] 10) smoke & smoking 11) *peanut allergy [68]? 12) alterations in intestinal flora, specifically lower levels of Faecalibacterium, Lachnospira, Veillonella, & Rothia genera, at 3 months of age, associated with antibiotic use, caesarian section & infant formula, linked to risk of developing asthma [75] 13) exposure to indoor environmental allergens, tobacco smoke, & viruses may predispose to asthma [3] 14) menopause is a risk factor for new-onset asthma (RR=3.4) [77] * exposure to cockroach, mouse, & cat allergens before age 1 diminish likelihood of asthma at age 3 [60] * exposure to dogs & farm animals during infancy reduces risk of asthma at age 6 years (13% for dog exposure; 52% for farm animal exposure) [76] * also see asthma syndrome Epidemiology: - 5-8% of adult population in U.S. [3], increased % in elderly (> 65 years), women, Blacks & those living in poverty [3] - more common in boys than in girls until adolescence - more women develop asthma as adults, especially nonallergic asthma [51] - asthma control may worsen during menstruation [51] - infants whose parents clean their pacifiers by sucking on them are at lower risk for developing asthma [52] - exposure to bacterial endotoxin early in life inhibits allergic inflammation by stimulating the innate immune system thus diminishing risk of asthma in children raised on farms (traditional vs large-scale mechanized farming) [86] - 1/3 of adult onset asthma may represent misdiagnosis [93] - diagnosis without confirmatory spirometry contibutory [93] - in ambient nitrogen dioxide & PM2.5 1993-2014 in Southern Califronia were associated with lower asthma incidence in children [117] - no associations for ozone or PM10 Pathology: 1) mucous gland hypertrophy with mucous hypersecretion & mucous plugs 2) epithelial desquamation & replacement primarily with proliferating goblet cells 3) loss of normal epithelial barriers to respiratory irritants & exposure of nerve endings 4) widening of basement membrane 5) intraepithelial leukocytes & mast cells (inflammation) 6) mast cell degranulation 7) eosinophilic infiltration of submucosa - in asphyxic asthma, neutrophils predominate in airways 8) round cell infiltration of bronchial submucosa 9) bronchial hyper-responsiveness (pathognomonic feature) - asthmatics are 100 times more sensitive to the broncho- constricting effects of LTD4 than normal individuals 10) obstruction of airflow by secretions & edema of bronchial mucosa 11) disruption of elastic fibers [2] Genetics: (also see OMIM database entries) 1) G protein-coupled receptor for asthma susceptibility (GPRA) gene 2) asthma-associated alternatively spliced gene 1 3) susceptibility to asthma associated with: a) defects in DPP10 b) defects in ADAM33 c) defects in TBX21 d) polymorphism(s) in PHF11 e) single nucleotide polymorphisms at 17q21 [50] 4) other implicated genes: MS4A2, PLA2G7 Clinical manifestations: 1) symptoms may be intermittent, seasonal, related to workplace or activity - occur in response to various stimuli (see etiology) 2) upper respiratory symptoms may be initial presentation in older adults [3,115] 3) intermittent dyspnea, wheezing, cough, chest tightness 4) hyperinflation; use of accessory muscles 5) impaired lung expansion 6) decreased fremitus 7) hyperresonant; low diaphragm to percussion 8) prolonged expiration 9) nasal polyps Laboratory: - arterial blood gas (hospitalized patients) - pCO2 is often low - a normal or mildly elevated pCO2 in severe asthma may be a sign of respiratory muscle fatigue & impending respiratory failure [3] - complete blood count (CBC) - absolute eosinophil count* [3] - sputum cytology: 53% with sputum eosinophilia [38] - sputum eosinophils* [54] - IgE in serum* [3] - low serum 25-hydroxyvitamin D has been associated with more-frequent asthma exacerbations, airway hyper-responsiveness, & decreased lung function, but vitamin D supplementation is not helpful [59] - fractional exhaled nitric oxide (FeNO) [124] - not for directing treatment of asthma in the general population [3] * identifies individual eligible for biologic agents (see management) Special laboratory: 1) pulmonary function testing: a) often a reduction in FEV1 > than any reduction in FVC - decreased FEV1/FVC b) improvement in FEV1 or FVC following inhalation of a bronchodilator (>= 12% & 200 mL) [3] c) more severe obstruction resulting in air trapping is identified by an increased residual volume d) DLCO is typically normal or elevated in patients with asthma e) flow volume loop may distinguish intrathoracic from extrathoracic airway obstruction [95] f) may be discrepancy between results of spirometry & symptoms in school-age children [62] - spirometry useful in these cases [62] g) PFT findings do not correlate with patient's subjective symptoms [118] h) every 2 years [24] i) normal spirometry does not rule out asthma j) irreversible airflow obstruction, restrictive pattern (FEV1/FVC > 0.8) 2) methacholine challenge: known airway irritant a) a negative test rules out asthma b) a positive test does not establish diagnosis [3] c) useful in patients with cough & normal spirometry [3,48] 3) peak flow meter (useful at home, emergency department) 4) spirometry before & after workplace exposure useful for diagnosis of occupational asthma [3] 5) allergen skin testing - 70-90% of patients positive [3] 6) echocardiogram (difficult to control asthma) Radiology: 1) chest X-ray (difficult to control asthma) 2) bone-density scan: patients on chronic corticosteroids Complications: - increased risk of obstructive sleep apnea in adults with asthma [64] (RR=2.7) - 15% with aspirin-exacerbated respiratory disease [65] - increased risk of fractures with systemic glucocorticoids [101] - no increased risk of fractures with inhaled glucocorticoids - increased likelihood of tobacco use (28% vs 24%) among high school students [107] - increased risk for atrial fibrillation (RR=1.4, RR=1.7 for uncontrolled asthma) [109] - increased cardiovascular risk among those with persistent asthma [129] - increased risk of cancer (RR=1.36) [130] Differential diagnosis: 1) chronic eosinophilic pneumonia 2) allergic bronchopulmonary aspergillosis 3) Churg-Strauss angiitis 4) GERD (may aggravate asthma) [3] 5) chronic obstructive pulmonary disease (COPD) 6) vocal cord dysfunction (inspiratory & expiratory wheezing) - may be exacerbations & remissions - wheezing over the proximal airways - may mimic or co-exist with asthma [123] 7) heart failure 8) bronchiectasis 9) mechanical airway obsruction, upper airway obstruction - obtain flow-volume loops during excerbation 10) cystic fibrosis [2] 11) asthma syndrome * consider other diagnoses with asthma is difficult to control [3] Management: 1) see acute asthma (asthma exacerbation) &/or status asthmaticus - quick relief or rescue therapy, albuterol MDI/HFA (all patients) - glucocorticoids are the most effective class of asthma control medications [3] - do not use long-acting beta2 agonist alone due to increased risk of death when used without inhaled glucocorticoid or other asthma control medication [3] 2) goals of asthma management: a) reduce chronic airway inflammation b) alleviate symptoms of disease c) prevent exacerbations d) eliminate contributing medications - beta-blockers (including ophthalmic agents) - aspirin, NSAIDs if patient is sensitive e) identify precipitating conditions - the most common cause of corticosteroid-dependent asthma is non-compliance with medications, especially inhaled corticosteroids - ensure proper technique for using inhalers [3] f) during an acute exacerbation, additional goals include: - ensure adequate gas exchange - reduce the work of breathing g) chronic management goals also include: - avoid side affects of medications - identify precipitants of exacerbations - allergen skin testing may be indicated - manage factors contributing to poor asthma control - smoking - rhinitis [47] h) assess asthma control through use of validated questionnaires [3] - see asthma control questionnaire i) written asthma management plan that helps patients recognize symptoms of an asthma exacerbation & begin self treatment [3] j) inhaler skills training & adherence essential [3] - see meter dose inhaler 3) Global Initiative for Asthma guidelines (1 of 3 combinations) a) inhaled glucocorticoid-formoterol combination as needed or low-dose inhaled glucocorticoid whenever albuterol is used b) daily inhaled glucocorticoid +/- long-acting beta2 agonist (formoterol) plus short-acting beta2 agonist (albuterol) as needed - maintenance & reliever use of inhaled glucocorticoid/formoterol superior to using albuterol as a rescue inhaler [128] c) maintenance & rescue with low-dose budesonide-formoterol [3] 4) stepwise management based on classification a) mild intermittent & mild persistent asthma treated similarly [127] - if symptoms usually < twice monthly, or just not daily, as needed low-dose inhaled glucocorticoid/formoterol - if symptoms > twice monthly or daily - daily low-dose inhaled glucocorticoid plus as needed low-dose inhaled glucocorticoid/formoterol - low-dose inhaled glucocorticoid/formoterol as maintenance & reliever therapy is simpler - inhaled budesonide associated with fewer severe asthma attacks in patients with early, mild asthma, even in those with infrequent symptoms (industry- sponsored study) [91] - albuterol monotherapy no longer recommended [127] - more intensive treatment for more severe disease b) moderate asthma - inhaled glucocorticoid/formoterol as maintenance & reliever therapy [127] - consideration for oral corticosteroids as needed - consider omalizumab (Xolair) in patients with allergies [3] - useful for patients with eosinophilia or elevated serum IgE [3] c) exercise-induced asthma - for infrequent symptoms, albuterol MDI, cromylin, or neocromodil 15-30 minutes prior to exercise - for symptoms > twice weekly, leukotriene inhibitor or treat according to 1-4 (above) d) difficult to control asthma - life style modifications - trial of acid suppression with a proton pump inhibitor for potential GERD [3] - tiotropium added to inhaled glucocorticoid may improve symptoms & pulmonary function [28] - long-acting muscarinic antagonist (LAMA) + long-acting beta2-agonist (LABA) added to medium or high-dose inhaled glucocortocoid [124] 5) other observations/strategies - avoid: long-acting beta2-agonist (LABA) as single agent - avoid; use of as needed albuterol as monotherapy 6) anti-inflammatory agents - glucocorticoids - inhaled glucocorticoids for maintenance - prophylaxis: beclomethasone MDI 2 puffs QID, triamcinolone MDI 2 puffs QID flunisolide MDI 2 puffs BID - high dose (4X prophylactic dose)* for acute exacerbations in combination with beta-adrenergic receptor agonists [5]; 2X dose not effective [14]; 4X prophylactic dose not helpful for children but may modestly benefit older patients [103] - reduce to prophylactic dose after acute exacerbation resolves [9] - consider step-down or discontinuation if asthma well-controlled without need for rescue albuterol inhaler, adverse effects (thrush, hoarseness) [3], use lowest dose consistent with adequate asthma control [3] - consider use of spacer [3] - low-dose inhaled glucocorticoid monotherapy is better than all other single-agent strategies for preventing asthma exacerbations [61] - systemic therapy for acute exacerbations - methylprednisolone IV 60-125 mg every 6 hours (unlike prednisone, does not require hepatic metabolism for glucocorticoid activity) - prednisone: initially: 40-60 mg QD (more effective if divided BID), 1 mg/kg PO QD in children [11], < 2 weeks of therapy does NOT require taper - methylprednisolone: Medrol DosePack, Depo-Medrol 80-160 mg IM, if non-compliance is an issue - glucocorticoids do not affect course of disease [22] - high-dose inhaled glucocorticoids do not replace oral glucocorticoids for acute exacerbations [23] - maintenance glucocorticoids stunt growth in children [30] - intermittent high-dose inhaled budesonide at the onset of respiratory tract disease as effective as low-dose daily inhaled glucocorticoids in preschool children [35] - patients with sputum eosinophilia seem to respond better to glucocorticoids than those without [38] - as-needed inhaled glucocorticoids may be an option in some patients who are motivated to take inhaled glucocorticoids along with albuterol [44,45] - most patients do not use daily inhaled glucocorticoids when asymptomatic - older patients with 2-fold risk for glucocorticoid treatment failure as younger patients [71] - cromolyn sodium MDI 2 puffs QID (not 1st line) - nedocromil sodium MDI 2 puffs QID (not 1st line) 7) agents for use with poor response to glucocorticoids - omalizumab (Xolair) recombinant humanized monoclonal anti-IgE antibody - elevated serum IgE [3]; serum IgE 30-700 mU/uL [3] - may be superior to methotrexate, gold salts, cyclosporine, troleamdromycin 250 mg PO QD (hepatotoxic) [3] - modestly lowers frequency of severe asthma exacerbations in patients inadequately controlled on standard therapy [3,33] - IL5 inhibitors - benralizumab (Fasenra) for asthma with eosinophilia (> 300/uL) associated with diminished oral glucocorticoid use in patients with severe asthma [94,132] - mepolizumab (IL-5 inhibitor) for asthma with blood eosinophils > 150-300/uL [3] - reslizumab for severe asthma exacerbations despite appropriate asthma therapy - dupilumab (Dupixent, IL-4 inhibitor) for uncontrolled glucorticoid-dependent eosinophilic asthma [107] 8) bronchodilators a) provide symptomatic relief but do not treat underlying airway inflammation b) beta-adrenergic receptor agonists (1st line agents) - inhaled selective beta-2 agonists - provide symptomatic relief but do not affect underlying airway inflammation - albuterol MDI, albuterol nebulizer (use with glucocorticoid) [139] - MDI with spacer more effective in reducing hospitalization in children [15] - heliox may be useful [19] - long-acting beta-2 agonist MDI (NOT for monotherapy) - salmeterol (Serevent) or formoterol (Foradil) - for use in conjunction with inhaled steroid - no increase in mortality with use of long-acting beta-2 agonist [17] - recommended step-up therapy for asthma that is not controlled on inhaled glucocorticoid alone [39] - long-term maintenance therapy in children [43] - controversy about long-term maintenance therapy[46] - addition of azithromycin 500 mg PO 3x/week associated with fewer asthma exacerbations in patients on dual maintenance therapy [96,138] - epinephrine SQ 0.3-0.5 mL of a 1:1000 solution - rescue medication for life-threatening asthma - 3 doses 15 minutes apart may be given - maximum dose 1 mg - isoproterenol (Isuprel) - isoetharine (Bronkosol) nebulizer c) theophylline & aminophylline d) heliox may be useful in conjunction with bronchodilators 9) anticholinergic agents (muscarinic antagonists) - tiotropium (Spiriva) as add-on to inhaled glucocorticoid for uncontrolled asthma [28,34] - tiotropium (Spiriva) as add-on to inhaled glucocorticoid plus long-acting beta-adrenergic receptor agonist for uncontrolled asthma [43] - a subset of patients who do not respond to long-acting beta-adrenergic receptor agonists will respond to tiotropium [53] 10) combination therapy: a) fluticasone/salmeterol (Advair) b) budesonide/formoterol (Symbicort) [24,87] c) formoterol/mometasone (Dulera) d) adding a long-acting beta-2 adrenergic agonist (LABA) to an inhaled glucocorticoid is more effective than doubling the glucocorticoid dose [3] in adults - inhaled glucocorticoid with long-acting beta agonist lowers risk of severe asthma attack [61,87] - fluticasone/salmeterol noninferior to fluticasone monotherapy in the risk for serious asthma-related events [84] e) albuterol/budesonide superior to albuterol monotherapy[139] f) in children, LABA added to an inhaled glucocorticoid - not inferior to doubling the dose of glucocorticoid, but may result in more frequent hospitalizations [29] - does not increase risk of serious adverse asthma outcomes [88] g) combination rescue with beclomethasone plus albuterol without maintenance glucocorticoids may be an option for children as this approach avoids stunted growth associated with maintenance glucocorticoids [30] h) adding a long-acting muscarinic antagonist (LAMA) to an inhaled glucocorticoid is more effective than glucocorticoid alone but may not be better than adding LABA [104] i) triple therapy glucocorticoid/LABA/LAMA - not better than glucocorticoid/LABA or glucocorticoid/LAMA [104] - associated with improved lung function & fewer exacerbations vs glucocorticoid/LABA [120,125] - recommended for cases of uncontrolled asthma [124] - no improvement over glucocorticoid/LABA in mortality or quality of life [125] j) fluticasone/vilanterol once daily may be beneficial [100] 11) magnesium sulfate: 1-2 g IV over 20 min [8] 12) leukotriene receptor antagonists (prophylaxis) a) agents - montelukast (Singulair) 5-10 mg PO QD (see MOSAIC trial) - zafirlukast (Accolate) 20 mg PO BID b) indications - aspirin-sensitive asthma - exercise-induced asthma - virus-induced wheezing [3] c) addition of leukotriene receptor antagonist to inhaled glucocorticoid NOT of benefit [7,73] d) leukotriene antagonists likely work well as monotherapy in real-world settings because of their ease of use [31,73] 13) zileuton (Zyflo), a 5-lipoxygenase inhibitor 14) theophylline: a) use with caution or not at all b) toxicity may result from drug interactions 15) antihistamines are NOT contraindicated 16) routine use of proton pump inhibitor not indicated [27] - proton pump inhibitors do not improve symptoms of asthma [37] 17) aerobic exercise - helps improve asthma symptoms & systemic inflammation in patients with moderate-to-severe asthma [70] - reduces likelihood of uncontrolled asthma [137] 18) weight reduction in obese patients improves airway hyper-responsiveness & symptom control [72] 19) biologic agents used for treatment of asthma [3] - omalizumab (anti-IgE, elevated serum IgE) - mepolizumab (anti-IL5, eosinophilia) - reslizumab (anti-IL5, eosinophilia) - benralizumab (anti-IL5, eosinophilia) - dupilumab (anti-IL4, eosinophilia) - seems to prevent asthma exacerbations more effectively than other agents [136] - tezepelumab (Tezspire) FDA-approved for treatment of severe asthma - inhibits thymic stromal lymphopoietin - 79% clinical response, 24% remission with biologic agent [133] 20) subcutaneous immunotherapy recommended [124] - sublingual immunotherapy not recommended [124] - useful when a single trigger is identified [3] 21) bronchial thermoplasty FDA-approved as adjunctive therapy for patients who remain symptomatic despite optimal medical management [3] 22) azithromycin 500 mg PO 3x/week associated with higher rates of remission than placebo (51% vs 39%) in patients on dual maintenance therapy [96,138] 23) other unproven therapy - homeopathic therapy for dust mite allergy not useful [6] - soy isoflavones not useful [9] - vitamin D supplementation is not helpful [59] - high dose vitamin D during pregnancy does not reduce risk of asthma in offspring [121] 24) follow-up a) inhaled glucocorticoid may cause thrush, hoarseness & osteopenia b) low threshold for prescribing calcium, vitamin D, early DEXA scan in older adults with glucocorticoid exposure c) vaccines - pneumococcal vaccine (PneumoVax) age >= 2 years - Covid-19 vaccine - annual influenza vaccine 25) patient education: a) self management skills based on classification b) poor control is often due to improper use of inhalers c) asthma medication in hand at discharge improve outcomes [83] 26) environmental control a) air-conditioning in a tightly closed home is most effective b) air filters may be of some value - high-efficiency particulate air [HEPA] filters [90] - HEPA vacuums in combination with other measures [102] c) only industrial quality masks are capable of excluding pollen particles d) controlling common indoor asthma triggers as effective as asthma medications, including allergens due to - pets, dust mites, rodents, mold, - pollutants (secondhand smoke, particulate matter from gas stoves & other appliances [90] e) frequent bathing of animals or complete avoidance f) mold abatement g) pest control [102] h) avoid smoking & second hand smoke i) allergen-proof mattresses & pillow cases [90] j) multicomponent measures may be of benefit, single ]measures are not [102] 27) diet - supplements containing 2.4 g of fish oil or olive oil (placebo) starting at 22-26 weeks gestation until 1 week after delivery reduced diagnosis of asthma in offspirng (17% vs 24%) at 3-5 years of age [92] 28) home visits from trained community health workers providing asthma education & social services support may cost-effective for lower-income adults [63] Comparative biology: - mice fed high-fiber diet especially soluble fiber with less mucus production & airway hyperreactivity in response to dust mite allergen exposure [55] (see dietary fiber)

Interactions

disease interactions

Related

alternative classification of asthma assessment of severity of acute asthma asthma-related traits conditions that may present as refractory asthma industrial agents that can cause asthma provocation inhalation challenge test; methacholine challenge test referral of asthmatic patients

Useful

metered dose inhaler (MDI)

Specific

acute asthma; asthma exacerbation adult-onset asthma asthma during pregnancy asthma in the elderly asthma syndrome eosinophilic asthma exercise-induced asthma mild-persistent asthma occupational asthma reactive airway dysfunction syndrome (RADS)

General

obstructive lung disease type 1 hypersensitivity; immediate hypersensitivity (allergy) bronchospastic pulmonary disease chronic lung disease

Database Correlations

OMIM correlations MORBIDMAP 608595

References

  1. Manual of Medical Therapeutics, 28th edition, Ewald & McKenzie (eds) Little, Brown & Co, 1995, pg 236-40
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 12-19, 740
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1146
  5. Prescriber's Letter 8(5):29 2001
  6. Journal Watch 22(8):63, 2002 Lewith GT et al Use of ultramolecular potencies of allergen to treat asthmatic people allergic to house dust mite: double blind randomised controlled clinical trial. BMJ 324:520, 2002 PMID: 11872551
  7. Journal Watch 22(16):129, 2002 Ducharme FM et al Anti-leukotrienes as add-on therapy to inhaled glucocorticoids in patients with asthma: systematic review of current evidence. BMJ 324:1545, 2002 PMID: 12089089
  8. Journal Watch 22(19):151-52, 2002 Siverman RA et al IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest 122:489, 2002 PMID: 12171821 - Noppen M Magnesium treatment for asthma: where do we stand? Chest 122:396, 2002 PMID: 12171805
  9. Journal Watch 23(14):114, 2003 Hawkins G et al Stepping down inhaled corticosteroids in asthma: randomised controlled trial. BMJ 326:1115, 2003 PMID: 12763981 http://bmj.com/cgi/content/full/326/7399/1115
  10. Journal Watch 23(14):114, 2003 Chauban AJ et al Personal exposure to nitrogen dioxide (NO2) and the severity of virus-induced asthma in children. Lancet 361:1939 2003 PMID: 12801737
  11. What is the Optimal Dose of Oral Corticosteroids in Children with Acute Exacerbations of Asthma? Prescriber's Letter 11(2):9 2004 Detail-Document#: 200224 (subscription needed) http://www.prescribersletter.com - Journal Watch 24(5):40, 2004 Harrison TW et al Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 363:271, 2004 PMID: 14751699
  12. Journal Watch 24(11):91, 2004 Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P, Makela S, Rehn M, Pirskanen A, Rautanen A, Zucchelli M, Gullsten H, Leino M, Alenius H, Petays T, Haahtela T, Laitinen A, Laprise C, Hudson TJ, Laitinen LA, Kere J. Characterization of a common susceptibility locus for asthma- related traits. Science. 2004 Apr 9;304(5668):300-4. PMID: 15073379 - Couzin J. Genetics. Two new asthma genes uncovered. Science. 2004 Apr 9;304(5668):185-7. No abstract available. PMID: 15073340
  13. Journal Watch 24(13):105-106, 2004 Biscardi S, Lorrot M, Marc E, Moulin F, Boutonnat-Faucher B, Heilbronner C, Iniguez JL, Chaussain M, Nicand E, Raymond J, Gendrel D. Mycoplasma pneumoniae and asthma in children. Clin Infect Dis. 2004 May 15;38(10):1341-6. Epub 2004 Apr 29. PMID: 15156467 - Hartert TV, Edwards K. Antibiotics for asthma? Clin Infect Dis. 2004 May 15;38(10):1347-9. Epub 2004 Apr 29. PMID: 15156468
  14. Prescriber's Letter 11(3):14 2004 Detail-Document#: 200302 (subscription needed) http://www.prescribersletter.com
  15. Journal Watch 24(19):154, 2004 Castro-Rodriguez JA, Rodrigo GJ. beta-agonists through metered-dose inhaler with valved holding chamber versus nebulizer for acute exacerbation of wheezing or asthma in children under 5 years of age: a systematic review with meta-analysis. J Pediatr. 2004 Aug;145(2):172-7. PMID: 15289762 - Smyth RL, Jones A. Treatment of acute wheezing episodes in young children. J Pediatr. 2004 Aug;145(2):151-2. No abstract available. PMID: 15289758
  16. Prescriber's Letter 11(11): 2004 Single-Dose Intramuscular Methylprednisolone in the Treatment of Asthma Exacerbations Detail-Document#: 201119 (subscription needed) http://www.prescribersletter.com
  17. Journal Watch 25(6):49, 2005 Anderson HR, Ayres JG, Sturdy PM, Bland JM, Butland BK, Peckitt C, Taylor JC, Victor CR. Bronchodilator treatment and deaths from asthma: case-control study. BMJ. 2005 Jan 15;330(7483):117. Epub 2004 Dec 23. PMID: 15618231 http://bmj.bmjjournals.com/cgi/content/full/330/7483/117
  18. Garcia Garcia ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos P. Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study. Pediatrics. 2005 Aug;116(2):360-9. PMID: 16061590
  19. Kim IK, Phrampus E, Venkataraman S, Pitetti R, Saville A, Corcoran T, Gracely E, Funt N, Thompson A. Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations: a randomized, controlled trial. Pediatrics. 2005 Nov;116(5):1127-33. PMID: 16263999
  20. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
  21. Nelson HS et al, The salmeterol multicenter asthma research trial: A comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol Chest 2006, 129:15 PMID: 16424409
  22. Guilbert TW et al, Long-term inhaled corticosteroids in preschool children at at high risk for asthma N Engl J Med 2006; 354:1985 PMID: 16687711 - Bisgaard H et al, Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006; 354:1998 PMID: 16687712 - Gold DR & Fuberg A Inhaled corticosteroids for young children with wheezing. N Engl J Med 2006; 354:2058 PMID: 16687719
  23. Schuh S et al, High-dose inhaled fluticasone does not replace oral prednisone in children with mild to moderate acute asthma. Pediatrics 2006, 118:644 PMID: 16882819
  24. Rabe KF et al, Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: A randomized controlled, double-blind study. Lancet 2006, 368:744 PMID: 16935685 - Pedersen S. Budesonide plus formoterol for relieve therapy for asthma. Lancet 2006, 368:707 PMID: 16935666
  25. Prescriber's Letter 14(10): 2007 StepWise Asthma Management Asthma Guideline Summary Patient Handout Detail-Document#: 231004 (subscription needed) http://www.prescribersletter.com
  26. Mastronarde JG et al, for the American Lung Association Asthma Clinical Research Centers Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009 Apr 9; 360:1487 PMID: 19357404
  27. Prescriber's Letter 16(6): 2009 Do Proton Pump Inhibitors (PPIs) Improve Asthma? Detail-Document#: 250609 (subscription needed) http://www.prescribersletter.com - Kiljander TO et al. Effect of esomeprazole 40 mg once or twice daily on asthma: A randomized, placebo-controlled study. Am J Respir Crit Care Med 2010 May 15; 181:1042. PMID: 20110554
  28. Peters SP et al Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma N Engl J Med 2010 September 19, 2010 PMID: 20979471 http://www.nejm.org/doi/full/10.1056/NEJMoa1008770
  29. Vaessen-Verberne AAPH et al. Combination therapy salmeterol/fluticasone versus doubling dose of fluticasone in children with asthma. Am J Respir Crit Care Med 2010 Nov 15; 182:1221 PMID: 20622031 - Arnold DH and Hartert TV. What we need to know about long-acting beta 2-agonists: Deja vu all over again? Am J Respir Crit Care Med 2010 Nov 15; 182:1219. PMID: 21079266
  30. Martinez FD et al Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial The Lancet, Early Online Publication, 15 February 2011 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62145-9/fulltext
  31. Price D et al, Leukotriene Antagonists as First-Line or Add-on Asthma-Controller Therapy N Engl J Med 2011; 364:1695-1707 PMID: 21542741 http://www.nejm.org/doi/full/10.1056/NEJMoa1010846 - Dahlen SE et a; Asthma Treatment Guidelines Meet the Real World N Engl J Med 2011; 364:1769-1770 PMID: 21542748 http://www.nejm.org/doi/full/10.1056/NEJMe1100937
  32. Dhuper S et al. Efficacy and cost comparisons of bronchodilatator administration between metered dose inhalers with disposable spacers and nebulizers for acute asthma treatment. J Emerg Med 2011 Mar; 40:247. PMID: 19081697
  33. Hanania NA et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: A randomized trial. Ann Intern Med 2011 May 3; 154:573 PMID: 21536936
  34. Kerstjens HAM et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial. J Allergy Clin Immunol 2011 May 31 PMID: 21636120 http://www.jacionline.org/article/S0091-6749(11)00677-4/fulltext
  35. Zeiger RS et al Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing N Engl J Med 2011 Nov 24; 365:1990. PMID: 22111718 http://www.nejm.org/doi/full/10.1056/NEJMoa1104647
  36. Beasley RW et al Acetaminophen Use and Risk of Asthma, Rhinoconjunctivitis and Eczema in Adolescents: ISAAC Phase Three. Am J Respir Crit Care Med. 2010 Aug 13. PMID: 20709817 - McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics 2011 Dec; 128:1181 PMID: 22065272 - Cheelo M et al Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis. Arch Dis Child. 26 November 2014 PMID: 25429049 http://adc.bmj.com/content/early/2014/11/07/archdischild-2012-303043
  37. Writing Committee for the American Lung Association Asthma Clinical Research Centers Lansoprazole for Children With Poorly Controlled Asthma JAMA. 2012;307(4):373-380 PMID: 22274684 http://jama.ama-assn.org/content/307/4/373.full - Martinez FD Children, Asthma, and Proton Pump Inhibitors: Costs and Perils of Therapeutic Creep JAMA. 2012;307(4):406-407 PMID: 22274689 http://jama.ama-assn.org/content/307/4/406.extract
  38. McGrath KW et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012 Mar 15; 185:612 PMID: 22268133
  39. Wells KE et al. The relationship between combination inhaled corticosteroid and long-acting beta-agonist use and severe asthma exacerbations in a diverse population. J Allergy Clin Immunol 2012 May; 129:1274 PMID: 22281166 - Pedersen S and O'Byrne PM. Combination inhaled corticosteroid and long-acting beta2-agonist use and severe asthma exacerbations. J Allergy Clin Immunol 2012 May; 129:1280. PMID: 22464645
  40. Pavord ID et al. Mepolizumab for severe eosinophilic asthma (DREAM): A multicentre, double-blind, placebo-controlled trial. Lancet 2012 Aug 18; 380:651 PMID: 22901886
  41. Practical Guide for the Diagnosis and Management of Asthma National Heart, Lung, & Blood Institute (NHLBI) http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf http://www.nhlbi.nih.gov/health/prof/lung/asthma/practgde/practgde.pdf - BRITISH GUIDELINE ON THE MANAGEMENT OF ASTHMA http://www.sign.ac.uk/guidelines/fulltext/63/index.html (corresponding NGC guideline withdrawn July 2015) - Asthma: University of Michigan http://cme.med.umich.edu/pdf/guideline/asthma05.pdf - Institute for Clinical Systems Improvement (ICSI) Diagnosis and outpatient management of asthma http://www.icsi.org/knowledge/browse_bydate.asp?catID=29 - Global Initiative for Asthma (GINA) http://www.ginasthma.com/GuidelinesResources.asp?l1=2&l2=0
  42. Brozek JL et al Long-Acting beta-2-Agonist Step-off in Patients With Controlled Asthma Systematic Review With Meta-analysis Archive of Internal Medicine Aug 2012 PMID: 22928176 http://archinte.jamanetwork.com/article.aspx?articleid=1352787 - Chan CM and Shorr AF Black Clouds and Black Boxes Comment on "Long-Acting beta-2-Agonist Step-off in Patients With Controlled Asthma" Archive of Internal Medicine Aug 2012 PMID: 22928180 http://archinte.jamanetwork.com/article.aspx?articleid=1352791
  43. Kerstjens HAM et al Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012 Sep 27; 367:1198 PMID: 22938706 http://www.nejm.org/doi/full/10.1056/NEJMoa1208606 - Bel EH. Tiotropium for asthma - Promise and caution. N Engl J Med 2012 Sep 27; 367:1257. PMID: 22938707 http://www.nejm.org/doi/full/10.1056/NEJMe1209381
  44. Calhoun WJ et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: The BASALT randomized controlled trial. JAMA 2012 Sep 12; 308:987 PMID: 22968888 - O'Connor GT and Reibman J. Inhaled corticosteroid dose adjustment in mild persistent asthma. JAMA 2012 Sep 12; 308:1036. PMID: 22968893
  45. Prescriber's Letter 19(11): 2012 Using Inhaled Corticosteroids PRN for Asthma Detail-Document#: 281125 (subscription needed) http://www.prescribersletter.com
  46. Prescriber's Letter 19(11): 2012 Safety of Long-Acting Beta-Agonists in Asthma PDF: Stepwise Approach for Managing Asthma (Children) (NIH Asthma Guidelines 2007) PDF: Stepwise Approach for Managing Asthma (Adolescents/Adults)(NIH Asthma Guidelines 2007) Detail-Document#: 281126 (subscription needed) http://www.prescribersletter.com
  47. Haughney J, Price D, Kaplan A Achieving asthma control in practice: understanding the reasons for poor control. Respir Med. 2008 Dec;102(12):1681-93 PMID: 18815019
  48. Dicpinigaitis PV. Chronic cough due to asthma: ACCP evidence-based clinical practice guidelines. Chest. 2006 Jan;129(1 Suppl):75S-79S. PMID: 16428696
  49. Lazarus SC. Clinical practice. Emergency treatment of asthma. N Engl J Med. 2010 Aug 19;363(8):755-64 PMID: 20818877
  50. Caliskan M et al. Rhinovirus wheezing illness and genetic risk of childhood- onset asthma. N Engl J Med 2013 Mar 27 PMID: 23534543 http://www.nejm.org/doi/full/10.1056/NEJMoa1211592
  51. Rao CK et al. Characteristics of perimenstrual asthma and its relation to asthma severity and control: Data from the Severe Asthma Research Program. Chest 2013 Apr; 143:984 PMID: 23632943 http://journal.publications.chestnet.org/article.aspx?articleid=1461073
  52. Physician's First Watch, May 7, 2013 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Hesselmar B et al Pacifier cleaning practices and risk of allergy development. Pediatrics May 6, 2013 PMID: 23650304 http://pediatrics.aappublications.org/content/early/2013/04/30/peds.2012-3345.full.pdf+html
  53. Peters SP et al. Predictors of response to tiotropium versus salmeterol in asthmatic adults. J Allergy Clin Immunol 2013 Nov; 132:1068 PMID: 24084072 http://www.jacionline.org/article/S0091-6749(13)01218-9/abstract
  54. Chung KF et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014 Feb 1; 43:343 PMID: 24337046 http://erj.ersjournals.com/content/43/2/343
  55. Trompette A et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014 Feb; 20:159 PMID: 24390308 - Huffnagle GB. Increase in dietary fiber dampens allergic responses in the lung. Nat Med 2014 Feb 6; 20:120 PMID: 24504401
  56. Prescriber's Letter 21(4): 2014 Dexamethasone for Childhood Asthma Exacerbations Detail-Document#: 300407 (subscription needed) http://www.prescribersletter.com
  57. Morales DR et al. Adverse respiratory effect of acute beta-blocker exposure in asthma: A systematic review and meta-analysis of randomized controlled trials. Chest 2014 Apr; 145:779 PMID: 24202435 http://journal.publications.chestnet.org/article.aspx?articleid=1767055 - Morales DR, Jackson C, Lipworth BJ Adverse respiratory effect of acute beta-blocker exposure in asthma: a systematic review and meta-analysis of randomized controlled trials. Chest. 2013 Nov 7 PMID: 24202435
  58. Jones SC, Iverson D, Burns P Asthma and ageing: an end user's perspective--the perception and problems with the management of asthma in the elderly. Clin Exp Allergy. 2011 Apr;41(4):471-81. PMID: 21395876
  59. Castro M et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: The VIDA randomized clinical trial. JAMA 2014 May 28; 311:2083. PMID: 24838406 http://jama.jamanetwork.com/article.aspx?articleid=1873132
  60. Lynch SV et al Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. Journal of Allergy and Clinical Immunology. June 6, 2014 PMID: 24908147 http://www.jacionline.org/article/S0091-6749%2814%2900593-4/fulltext
  61. Loymans RJB et al. Comparative effectiveness of long term drug treatment strategies to prevent asthma exacerbations: Network meta-analysis. BMJ 2014 May 13; 348:g3009 PMID: 24919052 http://www.bmj.com/content/348/bmj.g3009
  62. Schifano ED et al. Mismatch between asthma symptoms and spirometry: Implications for managing asthma in children. J Pediatr 2014 Sep 1 PMID: 25175496 http://www.jpeds.com/article/S0022-3476%2814%2900650-7/abstract
  63. Krieger J, Song L, Philby M Community health worker home visits for adults with uncontrolled asthma: The HomeBASE Trial randomized clinical trial. JAMA Intern Med 2014 Nov 24 PMID: 25419871 http://archinte.jamanetwork.com/article.aspx?articleid=1939375
  64. Teodorescu M et al Association Between Asthma and Risk of Developing Obstructive Sleep Apnea. JAMA. 2015;313(2):156-164 PMID: 25585327 http://jama.jamanetwork.com/article.aspx?articleid=2089354
  65. Rajan JP et al. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. J Allergy Clin Immunol 2015 Mar; 135:676. PMID: 25282015 http://www.jacionline.org/article/S0091-6749%2814%2901192-0/abstract
  66. The NNT: Long-Acting Beta-Agonists with Inhaled Corticosteroids vs. Inhaled Steroids Alone for Adults with Asthma. http://www.thennt.com/nnt/combination-inhalers-steroids-plus-bronchodilators-for-adult-asthma/ - The NNT: Long-Acting Beta-Agonists with Inhaled Corticosteroids vs. Inhaled Steroids Alone for Children with Asthma http://www.thennt.com/nnt/combined-inhalers-vs-steroid-inhalers-for-childhood-asthma/ - Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev. 2010 Apr 14;(4):CD005533 PMID: 20393943
  67. The NNT: Nebulized Ipratropium Given During an Asthma Attack http://www.thennt.com/nnt/nebulized-ipratropium-for-asthma-attack/ - Cydulka RK, Emerman CL, Muni A. Levalbuterol versuss levalbuterol plus ipratropium in the treatment of severe acute asthma. J Asthma. 2010 Dec;47(10):1094-100 PMID: 20923385 - Salo D, Tuel M, Lavery RF, Reischel U, Lebowitz J, Moore T. A randomized, clinical trial comparing the efficacy of continuous nebulized albuterol (15 mg) versus continuous nebulized albuterol (15 mg) plus ipratropium bromide (2 mg) for the treatment of acute asthma. J Emerg Med. 2006 Nov;31(4):371-6. PMID: 17046476
  68. American Thoracic Society. Public Release. May 17, 2015 Many children with asthma have reaction to peanuts, but do not know it. http://www.eurekalert.org/pub_releases/2015-05/ats-mcw050515.php
  69. Smith LJ et al. Effect of a soy isoflavone supplement on lung function and clinical outcomes in patients with poorly controlled asthma: A randomized clinical trial. JAMA 2015 May 26; 313:2033 PMID: 26010632 http://jama.jamanetwork.com/article.aspx?articleid=2297169
  70. Orciari Herman A, Sadoughi S, Saitz R Benefits of Aerobic Training in Adults with Asthma Detailed Physician's First Watch, June 11, 2015 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Thorax article (link broken)
  71. Dunn RM et al Impact of Age and Gender on Response to Asthma Therapy. Am J Respir Crit Care Med. First published online 11 Jun 2015 PMID: 26068329 http://www.atsjournals.org/doi/abs/10.1164/rccm.201503-0426OC
  72. Pakhale S et al. Effects of weight loss on airway responsiveness in obese adults with asthma: Does weight loss lead to reversibility of asthma? Chest 2015 Jun 1; 147:1582 PMID: 25763936
  73. Miligkos M et al Leukotriene-Receptor Antagonists Versus Placebo in the Treatment of Asthma in Adults and Adolescents: A Systematic Review and Meta-Analysis. Ann Intern Med. Published online 22 September 2015 PMID: 26390230 http://annals.org/article.aspx?articleid=2443064
  74. Mountjoy M et al. Prevalence and characteristics of asthma in the aquatic disciplines. J Allergy Clin Immunol 2015 Sep; 136:588. PMID: 25819982 http://www.jacionline.org/article/S0091-6749%2815%2900186-4/abstract
  75. Arrieta MC, Stiemsma LT, Dimitriu PA et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med 2015 Sep 30; 7:307ra152. PMID: 26424567 - Dominguez-Bello MG and Blaser MJ. Asthma: Undoing millions of years of coevolution in early life? Sci Transl Med 2015 Sep 30; 7:307fs39. PMID: 26424565
  76. Fall T, Lundholm C, Ortqvist AK et al Early Exposure to Dogs and Farm Animals and the Risk of Childhood Asthma. JAMA Pediatr. 2015;169(11):e153219 PMID: 26523822 http://archpedi.jamanetwork.com/article.aspx?articleid=2467334
  77. Triebner K, Johannessen A, Puggini L et al. Menopause as a predictor of new-onset asthma: A longitudinal Northern European population study. J Allergy Clin Immunol 2016 Jan; 137:50. PMID: 26435006
  78. Forno E, Celedon JC. Health disparities in asthma. Am J Respir Crit Care Med. 2012 May 15;185(10):1033-5. PMID: 22589306 Free PMC Article
  79. Lajunen TK, Jaakkola JJ, Jaakkola MS. The synergistic effect of heredity and exposure to second-hand smoke on adult-onset asthma. Am J Respir Crit Care Med. 2013 Oct 1;188(7):776-82 PMID: 23981189
  80. Martinez FD, Vercelli D. Asthma. Lancet. 2013 Oct 19;382(9901):1360-72. PMID: 24041942
  81. von Mutius E, Hartert T. Update in asthma 2012. Am J Respir Crit Care Med. 2013 Jul 15;188(2):150-6. PMID: 23855691
  82. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138. PMID: 17983880
  83. Bell LM Asthma Medication in Hand at Discharge Improves Outcomes. Physician's First Watch, Feb 24, 2016 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Hatoun J, Bair-Merritt M, Cabral H, Moses J Increasing Medication Possession at Discharge for Patients With Asthma: The Meds-in-Hand Project. Pediatrics. March 2016 PMID: 26912205 http://pediatrics.aappublications.org/content/early/2016/02/22/peds.2015-0461
  84. Stempel DA et al Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone. N Engl J Med. March 6, 2016 PMID: 26949137 http://www.nejm.org/doi/full/10.1056/NEJMoa1511049 - Martinez FD Safety of Fluticasone plus Salmeterol in Asthma - Reassuring Data, but No Final Answer. N Engl J Med. March 6, 2016 PMID: 26946980 http://www.nejm.org/doi/full/10.1056/NEJMe1601040
  85. Raimondi GA, Gonzalez S, Zaltsman J, Menga G, Adrogue HJ. Acid-base patterns in acute severe asthma. J Asthma. 2013 Dec;50(10):1062-8. PMID: 23947392
  86. Stein MM et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med 2016 Aug 4; 375:411. PMID: 27518660 http://www.nejm.org/doi/10.1056/NEJMoa1508749 - Chatila TA. Innate immunity in asthma. N Engl J Med 2016 Aug 4; 375:477 PMID: 27518667 http://www.nejm.org/doi/10.1056/NEJMe1607438
  87. Peters SP et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. N Engl J Med 2016 Sep 1; 375:850 PMID: 27579635 http://www.nejm.org/doi/10.1056/NEJMoa1511190
  88. Stempel DA et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med 2016 Sep 1; 375:840. PMID: 27579634 http://www.nejm.org/doi/10.1056/NEJMoa1606356 - Bush A, Frey U. Safety of long-acting beta-agonists in children with asthma. N Engl J Med 2016 Sep 1; 375:889. PMID: 27579641 http://www.nejm.org/doi/10.1056/NEJMe1608508
  89. 2016 GINA Report. Global Strategy for Asthma Management and Prevention. http://ginasthma.org/2016-gina-report-global-strategy-for-asthma-management-and-prevention/
  90. Matsui EC, Abramson SL, Sandel MT et al Indoor Environmental Control Practices and Asthma Management. Pediatrics Oct 2016, e20162589; PMID: 27940791
  91. Reddel HK, Busse WW, Pedersen S et al Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet Nov 29, 2016 PMID: 27912982 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31399-X/fulltext - Papi A, Fabbri LM Management of patients with early mild asthma and infrequent symptoms. Lancet Nov 29, 2016 PMID: 27912984 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32111-0/fulltext
  92. Bisgaard H, Stokholm J, Chawes BL et al Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring. N Engl J Med 2016; 375:2530-2539. December 29, 2016 PMID: 28029926 http://www.nejm.org/doi/full/10.1056/NEJMoa1503734 - Ramsden CE Breathing Easier with Fish Oil - A New Approach to Preventing Asthma? PMID: 28029914 N Engl J Med 2016; 375:2596-2598. December 29, 2016 http://www.nejm.org/doi/full/10.1056/NEJMe1611723
  93. Aaron SD, Vandemheen KL, FitzGerald JM et al Reevaluation of Diagnosis in Adults With Physician-Diagnosed Asthma. JAMA. 2017;317(3):269-279 PMID: 28114551 http://jamanetwork.com/journals/jama/article-abstract/2598265 - Hollingsworth HM. O'Connor GT Asthma - Here Today, Gone Tomorrow? JAMA. 2017;317(3):262-263 PMID: 28114530 http://jamanetwork.com/journals/jama/article-abstract/2598243
  94. Nair P, Wenzel S, Rabe KF et al Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. May 22, 2017 PMID: 28530840 http://www.nejm.org/doi/full/10.1056/NEJMoa1703501
  95. Fein A, Morante JE, Shah AM Diagnostic Errors in Patients With Pulmonary Symptoms. Medscape. June 15, 2017 http://www.medscape.com/slideshow/diagnostic-errors-pulmonary-symptoms-6008747
  96. Gibson PG, Yang IA, Upham JW et al Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. July 4, 2017 PMID: 28687413 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31281-3/fulltext - Brusselle G, Pavord I Azithromycin in uncontrolled asthma Lancet. July 4, 2017 PMID: 28687412 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31547-7/fulltext
  97. Fanta CH. Asthma. N Engl J Med. 2009 Mar 5;360(10):1002-14. PMID: 19264689
  98. Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults N Engl J Med 2017; 377:965-976. September 7, 2017 PMID: 28877019 http://www.nejm.org/doi/full/10.1056/NEJMra1608969
  99. Rothaus C Severe and Difficult-to-Treat Asthma in Adults. NEJM Resident 360. Sept 6, 2017 https://resident360.nejm.org/content_items/severe-and-difficult-to-treat-asthma-in-adults
  100. Woodcock A, Vestbo J, Bakerly ND et al. Effectiveness of fluticasone furoate plus vilanterol on asthma control in clinical practice: An open-label, parallel group, randomised controlled trial. Lancet 2017 Sep 10; PMID: 28903864 - Gibson P. Effectiveness trials in asthma: Time to SaLSA? Lancet 2017 Sep 10 PMID: 28903863
  101. Gray N, Howard A, Zhu J et al Association Between Inhaled Corticosteroid Use and Bone Fracture in Children With Asthma. JAMA Pediatr. Published online November 13, 2017 PMID: 29131874 https://jamanetwork.com/journals/jamapediatrics/article-abstract/2661821
  102. Leas BF, D'Anci KE, Apter AJ et al Effectiveness of Indoor Allergen Reduction in Management of Asthma Comparative Effectiveness Review No. 201. (Prepared by the ECRI Institute-Penn Medicine Evidence-based Practice Center under Contract No. 290-2015-0005-I.) AHRQ Publication No. 18-EHC002-EF. Rockville, MD: Agency for Healthcare Research and Quality; February 2018. https://effectivehealthcare.ahrq.gov/topics/asthma-nonpharmacologic-treatment/final-report-indoor-allergen-reduction - Leas BF, D'Anci KE, Apter AJ et al Effectiveness of indoor allergen reduction in the management of asthma: a systematic review. The Journal of Allergy and Clinical Immunology. 13 Feb 2018. PMID: 29452202
  103. Jackson DJ, Bacharier LB, Mauger DT et al. Quintupling inhaled glucocorticoids to prevent childhood asthma exacerbations. N Engl J Med 2018 Mar 8; 378:891. PMID: 29504498 http://www.nejm.org/doi/10.1056/NEJMoa1710988 - McKeever T, Mortimer K, Wilson A et al. Quadrupling inhaled glucocorticoid dose to abort asthma exacerbations. N Engl J Med 2018 Mar 8; 378:902. PMID: 29504499 http://www.nejm.org/doi/10.1056/NEJMoa1714257 - Bardin PG. Escalating inhaled glucocorticoids to prevent asthma exacerbations. N Engl J Med 2018 Mar 8; 378:950. PMID: 29504500 http://www.nejm.org/doi/10.1056/NEJMe1800152
  104. Sobieraj DM, Baker WL, Nguyen E et al Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma. A Systematic Review and Meta-analysis. JAMA. Published online March 19, 2018 PMID: 29554174 https://jamanetwork.com/journals/jama/fullarticle/2675736 - Sobieraj DM, Weeda ER, Nguyen E et al Association of Inhaled Corticosteroids and Long-Acting beta- Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma. A Systematic Review and Meta-analysis. JAMA. Published online March 19, 2018 PMID: 29554195 https://jamanetwork.com/journals/jama/fullarticle/2675737 - Krishnan JA, Au DH. Time to Converge FDA Decisions and Evidence Syntheses for Long-Acting Muscarinic Antagonists and SMART in Guidelines for the Treatment of Asthma. JAMA. Published online March 19, 2018. PMID: 29554261 https://jamanetwork.com/journals/jama/fullarticle/2675735
  105. Rabe KF, Nair P, Brusselle G et al Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. May 21, 2018 PMID: 29782224 Free full text https://www.nejm.org/doi/full/10.1056/NEJMoa1804093 - Castro M, Corren J, Pavord ID et al Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. May 21, 2018 PMID: 29782217 Free full text https://www.nejm.org/doi/full/10.1056/NEJMoa1804092 - Drazen JM, Harrington D. New Biologics for Asthma. N Engl J Med. May 21, 2018 PMID: 29782236 Free full text https://www.nejm.org/doi/full/10.1056/NEJMe1806037
  106. Bateman ED et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018 May 17; 378:1877. PMID: 29768147 - Lazarus SC. On-demand versus maintenance inhaled treatment in mild asthma. N Engl J Med 2018 May 17; 378:1940. PMID: 29768146 - O'Byrne PM et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018 May 17; 378:1865. PMID: 29768149 - Rothaus C As-Needed Budesonide-Formoterol in Mild Asthma. NEJM Resident 360. May 16, 2018 https://resident360.nejm.org/content_items/as-needed-budesonide-formoterol-in-mild-asthma
  107. Reid KM, Forrest JR, Porter L. Tobacco Product Use Among Youths With and Without Lifetime Asthma - Florida, 2016. MMWR Morb Mortal Wkly Rep 2018;67:599-601 https://www.cdc.gov/mmwr/volumes/67/wr/mm6721a2.htm
  108. Amrol DJ Treating Patients When Asthma Symptoms Worsen NEJM Journal Watch. June 12, 2018 Massachusetts Medical Society https://www.jwatch.org/na46894/2018/06/11/treating-patients-when-asthma-symptoms-worsen (subscription needed) http://www.jwatch.org
  109. Cepelis A, Brumpton BM, Malmo V et al Associations of Asthma and Asthma Control With Atrial Fibrillation Risk. Results From the Nord-Trondelag Health Study (HUNT). JAMA Cardiol. Published online July 11, 2018 PMID: 29998294 https://jamanetwork.com/journals/jamacardiology/fullarticle/2687455
  110. Chan-Yeung M, Malo JL. Occupational Asthma N Engl J Med 1995; 333:107-112 https://www.nejm.org/doi/full/10.1056/NEJM199507133330207
  111. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138. PMID: 17983880
  112. McCracken JL, Veeranki SP, Ameredes BT, Calhoun WJ. Diagnosis and Management of Asthma in Adults: A Review. JAMA. 2017 Jul 18;318(3):279-290. Review. PMID: 28719697
  113. Prasad Kerlin M. In the clinic. Asthma. Ann Intern Med. 2014 Mar 4;160(5):ITC3 2-15; PMID: 24737276
  114. Idrees M, FitzGerald JM. Vocal cord dysfunction in bronchial asthma. A review article. J Asthma. 2015 May;52(4):327-35. Review. PMID: 25365113
  115. Al-Alawi M, Hassan T, Chotirmall SH. Advances in the diagnosis and management of asthma in older adults. Am J Med. 2014 May;127(5):370-8. Review. PMID: 24380710
  116. Beasley R, Holliday M, Reddel HK et al Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma. N Engl J Med. May 19, 2019 PMID: 31112386 https://www.nejm.org/doi/full/10.1056/NEJMoa1901963 - Lazarus SC, Krishnan JA, King TS et al Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level N Engl J Med. May 19, 2019 PMID: 31112384 https://www.nejm.org/doi/full/10.1056/NEJMoa1814917 - Wong GWK How Should We Treat Patients with Mild Asthma? PMID: 31112381 https://www.nejm.org/doi/full/10.1056/NEJMe1905354
  117. Garcia E, Berhane KT, Islam T et al Association of Changes in Air Quality With Incident Asthma in Children in California, 1993-2014 JAMA. 2019;321(19):1906-1915 PMID: 31112259 https://jamanetwork.com/journals/jama/fullarticle/2733972 - Thurston GD, Rice MB. Air Pollution Exposure and Asthma Incidence in Children: Demonstrating the Value of Air Quality Standards. JAMA. 2019;321(19):1875-1877. PMID: 31112243 https://jamanetwork.com/journals/jama/fullarticle/2733950
  118. Sullivan PW, Ghushchyan VH, Marvel J et al. Association between pulmonary function and asthma symptoms. J Allergy Clin Immunol Pract 2019 Sep/Oct; 7:2319-2325. PMID: 31034996 Free Article https://www.sciencedirect.com/science/article/pii/S2213219819303927
  119. Hardy J, Baggott C, Fingleton J et al. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): A 52-week, open-label, multicentre, superiority, randomised controlled trial. Lancet 2019 Sep 14; 394:919 PMID: 31451207 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31948-8/fulltext - Gauthier M, Wenzel SE. As-needed beta agonist-inhaled corticosteroid in mild asthma. Lancet 2019 Sep 14; 394:897. PMID: 31451208 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31994-4/fulltext
  120. Virchow JC, Kuna P, Paggiaro P et al Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Lancet. Sept 30, 2019 PMID: 31582314 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32215-9/fulltext - FitzGerald JM, Sadatsafavi M Triple therapy in a single inhaler: a new option for uncontrolled asthma. Lancet. Sept 30, 2019 PMID: 31582315 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32216-0/fulltext
  121. Litonjua AA, Carey VJ, Laranjo N et al Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction. N Engl J Med 2020; 382:525-533. Feb 6 PMID: 32023372 https://www.nejm.org/doi/full/10.1056/NEJMoa1906137 - von Mutius E, Martinez FD Vitamin D Supplementation during Pregnancy and the Prevention of Childhood Asthma. N Engl J Med 2020; 382:574-575. Feb 6 PMID: 32023379 https://www.nejm.org/doi/full/10.1056/NEJMe1915082
  122. Amrol DJ A New Approach for Treating Patients with Intermittent Mild Asthma (cites NICE, American Diabetes Association) NEJM Journal Watch. Oct 15,, 2019 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
  123. Lee J, Denton E, Hoy R et al. Paradoxical vocal fold motion in difficult asthma is associated with dysfunctional breathing and preserved lung function. J Allergy Clin Immunol Pract 2020 March 12 PMID: 32173506 https://www.sciencedirect.com/science/article/abs/pii/S2213219820302385 - Stojanovic S, Denton E, Lee J et al. Diagnostic and therapeutic outcomes following systematic assessment of patients with concurrent suspected vocal cord dysfunction and asthma. J Allergy Clin Immunol Pract 2022 Feb; 10:602-608.e1 PMID: 34718212 https://www.jaci-inpractice.org/article/S2213-2198(21)01191-0/fulltext
  124. Cloutier MM, Dixon AE, Krishnan JA et al Managing Asthma in Adolescents and Adults. 2020 Asthma Guideline Update From the National Asthma Education and Prevention Program. JAMA. 2020 Dec 8;324(22):2301-2317 PMID: 33270095 https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2020.21974 - Lovinsky-Desir S, O'Connor GT Evolving Strategies for Long-term Asthma Management. JAMA. 2020 Dec 8;324(22):2265-2267 PMID: 33270088 https://jamanetwork.com/journals/jama/fullarticle/2773481
  125. Kim LMY, Saleh C, Whalen-Browne A et al Triple vs Dual Inhaler Therapy and Asthma Outcomes in Moderate to Severe Asthma. A Systematic Review and Meta-analysis. JAMA. Published online May 19, 2021 PMID: 34009257 https://jamanetwork.com/journals/jama/fullarticle/2780374
  126. Papi S, Chipps BE, Beasley R et al Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. N Engl J Med. 2022. may 15 PMID: 35569035 https://www.nejm.org/doi/10.1056/NEJMoa2203163
  127. Gray SE, Cifu AS, Press VG Therapy for Mild to Moderate Asthma JAMA. Published online July 21, 2022 PMID: 35862052 https://jamanetwork.com/journals/jama/fullarticle/2794730
  128. Kim C et al. Effectiveness of maintenance and reliever therapy using inhaled corticosteroid- formoterol in asthmatics. J Allergy Clin Immunol Pract 2022 Oct; 10:2638. PMID: 35752435 https://www.jaci-inpractice.org/article/S2213-2198(22)00594-3/fulltext - Israel E et al. Reliever-triggered inhaled glucocorticoid in Black and Latinx adults with asthma. N Engl J Med 2022 Feb 26; [e-pub]. PMID: 35213105 https://www.nejm.org/doi/10.1056/NEJMoa2118813
  129. Tattersall MC, Dasiewicz AS, McClelland RL Persistent Asthma Is Associated With Carotid Plaque in MESA. J Am Heart Assoc. 2022. Nov 23 PMID: 36416156 Free article https://www.ahajournals.org/doi/10.1161/JAHA.122.026644
  130. Guo Y, Bian J, Chen Z et al Cancer incidence after asthma diagnosis: Evidence from a large clinical research network in the United States. Cancer Medicine. 2023. March 31 PMID: 36999938 https://onlinelibrary.wiley.com/doi/10.1002/cam4.5875
  131. Corren J, Menzies-Gow A, Chupp G, et al. Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials. Am J Respir Crit Care Med. 2023 Jul 1;208(1):13-24. PMID: 37015033
  132. Jackson DJ, Heaney LG, Humbert M et al. Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): A randomised, multicentre, open-label, phase 4 study. Lancet 2023 Dec 7; [e-pub]. PMID: 38071986 Free article. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02284-5/fulltext
  133. Hansen S et al. Clinical response and remission in patients with severe asthma treated with biologic therapies. Chest 2024 Feb; 165:253 https://journal.chestnet.org/article/S0012-3692(23)05695-7/fulltext PMID: 37925144 Free article
  134. Pacheco Da Silva E et al. Household use of green cleaning products, disinfecting wipes, and asthma control among adults. J Allergy Clin Immunol Pract 2024 Apr; 12:919. PMID: 38151117 https://www.jaci-inpractice.org/article/S2213-2198(23)01392-2/abstract - Tarlo SM. Can airway effects of cleaning agents be prevented? J Allergy Clin Immunol Pract 2024 Apr; 12:927 PMID: 38583927 https://www.jaci-inpractice.org/article/S2213-2198(24)00068-0/fulltext
  135. Global Initiative for Asthma (GINA). The Global Strategy for Asthma Management and Prevention; 2020 https://ginasthma.org/ - Global Initiative for Asthma (GINA). Reports. July 10, 2023 https://ginasthma.org/reports/
  136. Kearney CM et al. Comparative effectiveness of mepolizumab, benralizumab, and dupilumab among patients with difficult-to-control asthma: A multicenter retrospective propensity- matched analysis. Ann Am Thorac Soc 2024 Jun; 21:866. PMID: 38241013 PMCID: PMC11160126 (available on 2025-06-01) https://www.atsjournals.org/doi/10.1513/AnnalsATS.202306-566OC
  137. de Lima FF et al. Physical activity and sedentary behavior as treatable traits for clinical control in moderate-to-severe asthma. J Allergy Clin Immunol Pract 2024 Aug; 12:2047. PMID: 38492665 https://www.jaci-inpractice.org/article/S2213-2198(24)00274-5/abstract
  138. Thomas D, McDonald VM, Stevens S et al Effect of Azithromycin on Asthma Remission in Adults With Persistent Uncontrolled Asthma: A Secondary Analysis of a Randomized, Double-Anonymized, Placebo- Controlled Trial. Chest. 2024 Aug;166(2):262-270. PMID: 38431051 Free article. Clinical Trial. https://journal.chestnet.org/article/S0012-3692(24)00284-8/fulltext - Rhoads SL, Mohan A. A novel examination of azithromycin as a low-cost intervention to achieve remission in asthma. Chest 2024 Aug; 166:241. PMID: 39122292 https://journal.chestnet.org/article/S0012-3692(24)00802-X/fulltext
  139. Rayner DG, Ferri DM, Guyatt GH et al Inhaled Reliever Therapies for Asthma: A Systematic Review and Meta-Analysis. JAMA. 2024 Oct 28:e2422700. . PMID: 39465893 https://jamanetwork.com/journals/jama/fullarticle/2825533