At the conclusion of this exercise, the learner will be prepared to:
- Discuss the special considerations related to the pharmacological management of severe or uncontrolled asthma with new biologic medications.
- Outline the current best practices in the treatment of asthma exacerbations.
- Define the special asthma populations that require unique consideration, including pregnant women, older patients, patients with comorbid obesity or anxiety, and adolescents.
- Clarify the timing and rationale for referral of an asthma patient to a specialist.
Asthma is a chronic inflammatory airway disorder characterized by airway hyperresponsiveness and recurrent episodes of acute symptoms such as wheezing, coughing, chest tightness, and/or shortness of breath (SOB) that affects between 235 and 300 million people worldwide (Lynn & Kushto-Reese, 2015; World Health Organization [WHO], 2019). According to the Centers for Disease Control and Prevention (CDC), asthma affects more than 24 million Americans and is responsible for over 430,000 hospitalizations, 1.6 million emergency department (ED) visits, and over 10 million office visits to medical providers annually. Asthma costs more than $62 billion annually to treat and causes over 13 million missed school days, and 14 million missed workdays in the United States alone. Amongst patients diagnosed with asthma, roughly half of adults and 40% of pediatric patients are not well controlled (Hsu et al., 2018). When discussing asthma, the term control refers to the presence of symptoms, any limitations in daily activities, and general quality of life (Bostantzoglou et al., 2015).
Severe asthma may be difficult to treat. Especially in eosinophilic asthma patients, steroid resistance and steroid-related adverse effects are significant treatment hurdles. Scientists have suggested blocking interleukin 5 (IL-5) and IL-13 activity in these patients as a way of reducing steroid resistance, improving steroid sensitivity, and improving treatment response (Dunican & Fahy, 2017). There are a number of new treatment options on the horizon for asthma, including new biologics that target cytokines involved in the inflammatory cascade such as immunoglobulin E (IgE), IL-4, IL-5, and IL-13, as well as a relatively new procedure called bronchial thermoplasty. Omalizumab (Xolair) is an FDA-approved medication for moderate to severe asthma in patients age six and older that functions as a monoclonal antibody that binds IgE. While it has been shown to reduce exacerbations as well as eosinophil counts, there are patients that do not respond as expected (deGroot et al., 2015). The National Asthma Education and Prevention Program (NAEPP) last published guidelines, called the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3), in 2007. Omalizumab (Xolair) is the only newer biologic to be recommended in the EPR-3 treatment guidelines; they recommend it be considered in step 5 or 6 for those asthma patients over the age of 12 with allergies. It is delivered as a subcutaneous injection every two to four weeks. (National Heart, Lung, and Blood Institute [NHLBI], 2012). The Global Initiative for Asthma (GINA, 2018), a collaborative report between the WHO and the NHLBI, was last updated and published in 2018. GINA guidelines also mention omalizumab (Xolair) as an optional adjunct treatment in step 5 for patients over the age of five with moderate or severe allergic asthma uncontrolled on step 4 treatment (GINA, 2018). The 2014 European Respiratory Society and the American Thoracic Society (ERS/ATS) guidelines regarding the treatment of severe asthma mention that omalizumab (Xolair) should be considered and trialed in patients with severe allergic asthma (Chung et al., 2014).
Dupilumab (Dupixent) is a monoclonal antibody to the IL-4𝞪 receptor that has been shown to significantly reduce exacerbations and improve lung function and asthma control in moderate to severe eosinophilic asthma patients (deGroot et al., 2015). It is thought to function by blocking IL-4 and IL-13 activity. It is given via subcutaneous injection every two weeks and is currently FDA-approved as an adjunct for asthma patients 12 and older. A small study was published in 2018, featuring 210 patients age 12 and above with severe asthma. All participants in this study had a history of systemic steroid use in the previous six months, and daily use of at least 500 µg of fluticasone (Flovent, Advair, Arnuity Ellipta) or equivalent in the last four weeks. Patients were dosed with 300 mg dupilumab (Dupixent) or placebo subcutaneously every two weeks for 24 weeks. During that time, corticosteroid doses were reduced every four weeks from week 4-20 and then kept stable from week 20-24. The dupilumab (Dupixent) group was able to reduce steroid dosage by an average of ~70% through the course of the study; 80% were able to reduce their steroid doses by 50% or greater. Within the treatment arm of the study, 69% of patients were able to reduce their daily steroid dose to 5mg or less per day, and 48% were able to discontinue oral steroids by week 24. The placebo group was able to reduce steroid dosage by an average of 41%; only 50% were able to reduce their steroid doses by 50% or greater. Just 33% of the control group was able to reduce their steroid usage to 5mg or less daily, and 25% were able to discontinue oral steroids by week 24. The treatment group had 59% fewer severe exacerbations than the control group and a significantly better forced expiratory volume (FEV1). Injection site reaction and transient blood eosinophilia were the most commonly reported adverse effects (Rabe et al., 2018). In a contemporaneous year-long study of over 1,900 patients with uncontrolled asthma, a dose of 200 mg and 300 mg of dupilumab (Dupixent) every two weeks was compared to placebo. Both doses led to a significant decrease in exacerbation rate and improvement in FEV1 and a more marked improvement in those with a serum eosinophil count greater than 300 cells/µL. The most common adverse effects were injection site reaction and eosinophilia (Castro et al., 2018).
Mepolizumab (Nucala) is a humanized monoclonal antibody to IL-5 that is FDA-approved for adjunctive therapy for severe eosinophilic asthma in patients 12 and older. It is a subcutaneous injection given every four weeks. It struggled to show clinical effect in early studies, but in patients with severe eosinophilic asthma, it was shown to significantly reduce exacerbations, improve control, reduce the need for steroid use, as well as reduce sputum and blood eosinophilia (deGroot et al., 2015). In a major study regarding mepolizumab (Nucala) published in NEJM in 2014, 539 patients between the ages of 12-82 received either mepolizumab (Nucala) or placebo every four weeks for 32 weeks. The results showed a roughly 50% reduction in exacerbation rate in the study patients, as well as a significant increase in FEV1, improvement in quality of life (QOL) and asthma control scores, and a decrease in eosinophil counts. The most frequently reported adverse effects in this study were nasopharyngitis and headache (Ortega et al., 2014).
Reslizumab (Cinqair) is a humanized monoclonal IgG4 antibody to IL-5 that is FDA-approved for patients over the age of 18 with uncontrolled asthma as adjunctive therapy. It has been shown to reduce exacerbations by as much as 50-60% in phase II trials, as well as improve function and asthma control scores (deGroot et al., 2015). It is dosed as an intravenous (IV) medication every four weeks. Two randomized clinical trials were done, encompassing 953 patients between the ages of 12-75 with diagnosed asthma, at least one exacerbation in the last twelve months, and an eosinophil count of at least 400 cells/µL. The combined results of these two trials showed an over 40% decrease in the annual rate of exacerbations in the treatment group versus the control group (Castro et al., 2015). Benralizumab (Fasenra) is a humanized monoclonal antibody to the IL-5𝞪 receptor on eosinophils given via subcutaneous injection. It is FDA-approved as adjunctive therapy for severe eosinophilic asthma patients 12 and older. In a recent study, 220 adult patients with severe asthma on oral steroids for the previous six months and elevated eosinophil blood counts were randomized to receive either placebo or subcutaneous benralizumab (Fasenra) 30mg every four or eight weeks for 28 weeks. The treatment groups showed a median reduction of 75% in oral steroid dose by the completion of the study, compared to just a 25% reduction seen in the control group. Both treatment groups had a significant reduction in exacerbation rate as well, and a stronger effect was seen in the 8-week dosing group. No significant effect was seen in asthma control scores, QOL, or FEV1 at 28 weeks (Nair et al., 2017). GINA guidelines (2018) mention the optional use of mepolizumab (Nucala), reslizumab (Cinqair), or benralizumab (Fasenra) as part of step 5 treatment in severe eosinophilic asthma patients uncontrolled on step 4 treatment (GINA, 2018). EPR-3 guidelines make a general warning for providers administering these newer biologics that all patients be monitored after administration; providers should be prepared to treat an adverse reaction of anaphylaxis should it occur (NHLBI, 2012).
There are other biologics that are either in development phases of study or not yet approved for use in the US. Lebrikizumab is a humanized monoclonal IgG4 antibody to IL-13. It was shown to improve FEV1 in a subgroup of patients with moderate to severe asthma and elevated periostin levels at baseline. In phase II and III trials in patients with mild to moderate asthma, it did not significantly improve FEV1 in patients not receiving inhaled corticosteroid (ICS) therapy (those on short-acting ß-agonist [SABA] only) versus placebo (Korenblat et al., 2017). Tralokinumab is also a humanized monoclonal IgG4 antibody to IL-13. In a large trial with patients with moderate to severe asthma, it failed to show significant improvement in asthma control scores (the primary endpoint) but did significantly improve FEV1 as well as reduce the amount of ß-agonist use (deGroot et al., 2015). In phase III trials STRATOS 1 and 2, it reduced the rate of exacerbations but failed to reach significance. Results did seem to favor its use in those patients with elevated FeNO levels (Panettieri et al., 2018). Pitrakinra (Aerovant) is a human recombinant form of IL-4 that inhibits the activity of IL-4 as well as IL-13. In a phase II trial with patients diagnosed with moderate to severe asthma, this inhaled medication was shown to modestly reduce the number of exacerbations in certain subgroups (deGroot et al., 2015). Tezepelumab is a subcutaneously injected medication that is currently in phase III trials for patients with severe, uncontrolled asthma that are currently receiving ICS as well as at least one additional controller medication with suboptimal results. Phase III studies are not set to be completed until 2023, although phase II studies indicated positive findings. It works by blocking the effects of thymic-stromal lymphopoietin (TSLP), a cytokine that is released when the epithelium is irritated by an allergen or another antigen one step upstream from IL-4 and IL-13 (Salgo et al., 2018).
In those patients with highly symptomatic asthma but less eosinophilic inflammation, in addition to increased amounts of bronchodilators, some have suggested low-dose azithromycin (Zithromax; Bostantzoglou et al., 2015). The AZALEA trial, published in JAMA in 2016, showed disappointing results. This was a randomized, double-blind, placebo-controlled trial conducted in the UK with 199 asthma patients who required urgent or emergent care for an asthma exacerbation requiring systemic corticosteroids. They were discharged with either placebo or azithromycin (Zithromax) tablets. The results showed no significant difference in asthma scores, QOL, lung function at follow-up, or time to a 50% reduction in symptoms per patient report between the two groups (Johnston et al., 2016). The 2014 ERS/ATS guidelines on severe asthma mirrored this sentiment by recommending that macrolide antibiotics not be used for the treatment of asthma (Chung et al., 2014).
Treatment of Exacerbations
The 2007 EPR-3 guidelines (NHLBI, 2012) suggest first assessing the severity of the exacerbation utilizing a physical exam, the patient's report of symptoms, and signs of breathlessness or SOB (audible wheezing, retractions, accessory muscle use, etc.). In patients over the age of five, lung function testing such as spirometry or a peak flow meter may also be used to quantify the amount of limitation in lung function if possible. Supplemental oxygen should be used to treat any existing hypoxemia. Continuous or repeated inhaled SABA (+/- inhaled ipratropium bromide [Atrovent] if severe) should be used to reduce airflow obstruction caused by bronchoconstriction. Ipratropium bromide (Atrovent) is a short-acting muscarinic antagonist (SAMA) that acts as a bronchodilator by antagonizing acetylcholine receptors, similar to tiotropium bromide (Spiriva), which is a long-acting muscarinic antagonist (LAMA). Systemic steroids should be started in patients with moderate to severe exacerbation, or with suboptimal response to SABA treatment, in order to treat the underlying inflammation. The initial assessment should be repeated periodically to assess the response to treatment. Patients who present to the ED for care or are ultimately hospitalized should be discharged with medications (SABA, oral corticosteroids, +/- ICS), a referral for follow-up, an asthma discharge plan, and any patient education that may apply, such as inhaler use/technique and environmental trigger exposure (NHLBI, 2012). GINA guidelines (2018) list some "alarm bells" that providers should look for in patients with asthma exacerbations, which include drowsiness, confusion, and silent chest. They provide the following guidance on admission to the hospital versus discharge home from the ED:
- If pre-treatment FEV1 or peak expiratory flow (PEF) is less than 25% of predicted or personal best, or post-treatment FEV1 or PEF is less than 40% of predicted or personal best, hospitalization is recommended.
- If post-treatment lung function is 40–60% of predicted, a discharge may be possible after considering the patient's risk factors and availability of follow-up care.
- If post-treatment lung function is greater than 60% of predicted or personal best, discharge is recommended after considering risk factors and the availability of follow-up care.
- Factors associated with an increased likelihood of the need for admission include:
- Female sex, older age, and non-white race;
- Use of more than eight ß2-agonist puffs in the previous 24 hours;
- The severity of the exacerbation (e.g., need for resuscitation or rapid medical intervention on arrival, respiratory rate above 22 bpm, oxygen saturation less than 95%, final PEF less than 50% of predicted);
- Past history of severe exacerbations (e.g., intubations, asthma admissions);
- Previous unscheduled office and emergency department visits requiring the use of oral corticosteroids (GINA, 2018).
In very severe exacerbations or in those patients who are not responding to the aforementioned treatments, intravenous magnesium sulfate (MgSO4) or helium-oxygen therapy (Heliox) should be considered (NHLBI, 2012). Regarding the use of helium-oxygen therapy (Heliox), GINA guidelines (2018) cite a systematic review of studies comparing this to air-oxygen therapy that found no benefit. The guidelines state that they see no role for this treatment in routine care, but it could be considered in patients not responding to convention treatment. Cost and availability are additional barriers (GINA, 2018). MgSO4, when administered via infusion, has a short half-life (2.7 hours) and functions as a bronchodilator by inhibiting the cellular uptake of calcium, mast cell degranulation, and/or acetylcholine release at motor nerve terminals (Rower et al., 2017). The GINA guidelines (2018) point out that randomized trials in mild-moderate asthma patients showed no benefit with the use of MgSO4, but a single 2 gm IV infusion administered to an adult over 20 minutes has been shown to reduce hospitalization rates in:
- Adult patients with FEV1 less than 25–30% of predicted at presentation;
- Patients with persistent hypoxemia who fail to respond to initial treatment;
- Pediatric patients who fail to improve (FEV1 less than 60% of predicted) after one hour of treatment (GINA, 2018).
For pediatric patients, Rower et al. (2017) found a dose of 50-75 mg/kg IV MgSO4 generally effective in achieving a therapeutic range of 25-40 mg/dL based on a small retrospective study of 54 pediatric patients based in Utah.
Within asthma care, a few special populations warrant some specific treatment recommendations. The EPR-3 (NHLBI, 2012) recommends that pregnant women with asthma be monitored very closely while pregnant. They note that asthma control may change during pregnancy, either by improving or worsening, depending on the patient; this may warrant medication and treatment changes. In general, most medications used in asthma management are acceptable during pregnancy, but they recommend ICS as the preferred long-term controller medication (NHLBI, 2012). GINA guidelines (2018) are a bit more specific, stating that about ⅓ of asthma patients get worse when pregnant, ⅓ improve, and ⅓ do not change much. They warn that exacerbations are more common during pregnancy, especially in the second trimester, and that uncontrolled asthma increases the risk for preeclampsia, preterm delivery, low birth weight, or perinatal mortality. They note that ICS, all ß-agonists, montelukast (Singulair), and theophylline (Theo-24) have been proven to cause no increased risk of fetal abnormality. They recommend the use of SABA as needed during labor in the instance of SOB. Perimenstrual asthma (also called catamenial) affects about 20% of women. Oral contraceptives and/or leukotriene receptor antagonists (LTRAs) may be helpful in these patients (GINA, 2018).
Older adults are at a higher risk of medication interactions. All patients should be warned about the risk of osteopenia or osteoporosis with prolonged corticosteroid use, but older patients may be at increased risk for this complication or its sequelae (NHLBI, n.d.). Older adults also typically see diminishing lung function over time, as well as increased sensitivity to medication adverse effects and decreased medication clearance. The gradual, progressive decline in spirometry results seen in some asthma patients over their lifetime is referred to as fixed airflow limitation and is usually incomplete and reversible with appropriate treatment. GINA guidelines recommend a streamlined regimen and inhalers that are easy to use (GINA, 2018).
Obesity poses an additional risk for asthma patients as it has been shown to make asthma control more difficult to achieve. ICS is the recommended treatment, but their response may be reduced. Patients with obesity should be strongly encouraged to attempt a comprehensive weight loss plan (GINA, 2018).
Anxiety and depression are more prevalent amongst asthma patients, leading to worse asthma control, poor adherence, and decreased QOL if not appropriately treated (cognitive behavioral therapy +/- medications but further research in this particular patient population is needed) (GINA, 2018).
Adolescent patients will see frequent changes in symptoms, control, and therapy needs due to their rapid growth and hormonal changes during this stage. They also recommend seeing all adolescent patients separate from their caregivers at least briefly to ask about smoking (GINA, 2018).
Those diagnosed with exercise-induced bronchospasms (EIB) should first be trialed on SABA as needed prior to exercise, as well as appropriate conditioning and warm-up, or the use of a mask or scarf if cold-induced. Tolerance to ß-agonists is a concern, especially if used more than once daily. Alternatives to SABA include LTRAs or chromones (GINA, 2018). Long-acting ß-agonists (LABAs) are also listed as an option for EIB in the EPR-3 guidelines, but the group cautions against frequent use. EIB patients should be encouraged to exercise regularly, like all asthma patients, despite symptoms (NHLBI, 2012).
Occupational asthma refers to patients that are triggered by a chemical or environmental exposure that occurs as part of their regular workday. It generally increases in severity over time. The primary goal of treatment is to limit exposure (GINA, 2018).
Asthmatics that are aspirin-exacerbated typically present with nasal congestion and anosmia, which leads to chronic rhinosinusitis with nasal polyps, and eventually, asthma. They typically describe acute exacerbations within 60-120 minutes of exposure to aspirin or other NSAIDs along with rhinorrhea, nasal obstruction, conjunctival irritation, and flushing of the head and neck. It can be confirmed with an aspirin challenge test in a well-monitored environment with access to emergency equipment if needed. NSAIDs should be avoided in these patients, but COX-2 inhibitors or acetaminophen (Tylenol) are well tolerated typically. Asthma symptoms can be treated with ICS, LTRA, +/- oral corticosteroids, and desensitization therapy (GINA, 2018).
Referral to a Specialist
Recognizing when a patient needs to be referred out to a specialist for more advanced care should be of utmost concern to the provider. In patients age four and under, the EPR-3 guidelines suggest referral with an asthma specialist if step 3 care or higher is required, with consideration at step 2. In older patients, this threshold is step 4 or higher, with consideration in step 3 (NHLBI, 2012). GINA guidelines (GINA, 2018) recommend referral to an asthma specialist at step 5, or in the following circumstances:
- Difficulty confirming or doubts regarding the diagnosis;
- Suspected occupational asthma;
- Persistent uncontrolled asthma or frequent exacerbations (in children age 6-11, despite moderate dose ICS);
- The presence of any risk factors for asthma-related death, such as ICU admission, mechanical ventilation, anaphylaxis, or a confirmed food allergy;
- The risk for or evidence of significant treatment adverse effects (in children, growth delay);
- Symptoms that are suggestive of complications or sub-types of asthma, such as aspirin-exacerbated respiratory disease or allergic bronchopulmonary aspergillosis (GINA, 2018).
When treating patients with severe eosinophilic asthma, it is recommended to refer to an Ear, Nose, and Throat specialist (ENT) to help manage rhinosinusitis and nasal polyposis (de Groot et al., 2015).
Bostantzoglou, C., Delimpoura, V., Samitas, K., Zervas, E., Kanniess, F., & Gaga, M. (2015). Clinical asthma phenotypes in the real world: Opportunities and challenges. Breathe, 11(3), 186–193. https://doi.org/10.1183/20734735.008115
Castro, M., Zangrilli, J., Wechsler, M. E., Bateman, E. D., Brusselle, G. G., Bardin, P., Murphy, K., Maspero, J. F., O’Brien, C., & Korn, S. (2015). Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: Results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. The Lancet Respiratory Medicine, 3(5), 355–366. https://doi.org/10.1016/S2213-2600(15)00042-9
Castro, M., Corren, J., Pavord, I. D., Maspero, J., Wenzel, S., Rabe, K. F., Busse, W. W., Ford, L., Sher, L., Fitzgerald, J. M., Katelaris, C., Tohda, Y., Zhang, B., Staudinger, H., Pirozzi, G., Amin, N., Ruddy, M., Akinlade, B. Khan, A., … Teper, A. (2018). Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. New England Journal of Medicine, 378(26), 2486–2496. https://doi.org/10.1056/NEJMoa1804092
Chung, K. F., Wenzel, S. E., Brozek, J. L., Bush, A., Castro, M., Sterk, P. J., Adcock, I. M., Bateman, E. D., Bel, E. H., Bleecker, E. R., Boulet, L-P., Brightling, C., Chanez, P., Dahlen, S-E. Djukanovic, R., Frey, U., Gaga, M., Gibson, P., Hamid, Q.,… Teague, W. G. (2014). International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. European Respiratory Journal, 43(2), 343–373. https://doi.org/10.1183/09031936.00202013
de Groot, J. C., ten Brinke, A., & Bel, E. H. D. (2015). Management of the patient with eosinophilic asthma: A new era begins. ERJ Open Research, 1(1), 00024–02015. https://doi.org/10.1183/23120541.00024-2015
Dunican, E. M., & Fahy, J. V. (2017). Asthma and corticosteroids: Time for a more precise approach to treatment. European Respiratory Journal, 49(6), 1701167. https://doi.org/10.1183/13993003.01167-2017
Global Initiative for Asthma. (2018). Global strategy for asthma management and prevention. www.ginasthma.org
Hsu, J., Sircar, K., Herman, E., & Garbe, P. (2018). EXHALE: A technical package to control asthma. National Center for Environmental Health, The Centers for Disease Control and Prevention. https://www.cdc.gov/asthma/pdfs/EXHALE_technical_package-508.pdf
Johnston, S. L., Szigeti, M., Cross, M., Brightling, C., Chaudhuri, R., Harrison, T., Mansur, A., Robison, L., Sattar, Z., Jackson, D., Mallia, P., Wong, E., Corrigan, C., Higgins, B., Ind, P., Singh, D., Thomson, N. C., Ashby, D., & Chauhan, A. (2016). Azithromycin for acute exacerbations of asthma: The AZALEA randomized clinical trial. JAMA Internal Medicine, 176(11), 1630–1637. https://doi.org/10.1001/jamainternmed.2016.5664
Korenblat, P., Kerwin, E., Leshchenko, I., Yen, K., Holweg, C. T. J., Anzures-Cabrera, J., Martin, C., Putnam, W. S., Governale, L., Olsson, J & Matthews, J. G. (2017). Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids. Respiratory Medicine, 134, 143-149. https://doi.org/10.1016/j.rmed.2017.12.006
Lynn, S. J., & Kushto-Reese, K. (2015). Understanding asthma pathophysiology, diagnosis, and management. American Nurse Today, 10(7), 49–51. https://www.myamericannurse.com/wp-content/uploads/2015/07/ant7-Asthma-622.pdf
Nair, P., Wenzel, S., Rabe, K. F., Bourdin, A., Lugogo, N. L., Kuna, P., Barker, P., Sproule, S., Ponnarambil, S., & Goldman, M. (2017). Oral glucocorticoid–sparing effect of benralizumab in severe asthma. New England Journal of Medicine, 376(25), 2448–2458. https://doi.org/10.1056/NEJMoa1703501
National Heart, Lung, and Blood Institute. (n.d.). Asthma. Retrieved January 21, 2020, from https://www.nhlbi.nih.gov/health-topics/asthma
National Heart, Lung, and Blood Institute. (2012). Asthma care quick reference: Diagnosing and managing asthma (NIH Publication No. 12-5075). https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthma_qrg_0_0.pdf
Ortega, H. G., Liu, M. C., Pavord, I. D., Brusselle, G. G., FitzGerald, J. M., Chetta, A., Humbert, M., Katz, L. E., Keene, O. N., Yancey, S. W., & Chanez, P. (2014). Mepolizumab treatment in patients with severe eosinophilic asthma. New England Journal of Medicine, 371(13), 1198–1207. https://doi.org/10.1056/NEJMoa1403290
Panettieri, R. A., Sjobring, U., Peterffy, A., Wessman, P., Bowen, K., Piper, E, Colice, G., & Brightling, C. E. (2018). Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and 2): Two randomised, double-blind, placebo-controlled, phase III clinical trials. The Lancet, 6(7), 511-525. https://doi.org/10.1016/S2213-2600(18)30184-X
Rabe, K. F., Nair, P., Brusselle, G., Maspero, J. F., Castro, M., Sher, L., Zhu, H., Hamilton, J. D., Swanson, B. N., Khan, A., Chao, J., Staudinger, H., Pirozzi, G., Antoni, C., Amin, N., Ruddy, M., Akinlade, B., Graham, N. M. H., Stahl, N., Yancopoulos, G. D., & Teper, A. (2018). Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. New England Journal of Medicine, 378(26), 2475–2485. https://doi.org/10.1056/NEJMoa1804093
Rower, J. E., Liu, X., Yu, T., Mundorff, M., Sherwin, C. M. T., & Johnson, M. D. (2017). Clinical pharmacokinetics of magnesium sulfate in the treatment of children with severe acute asthma. European Journal of Clinical Pharmacology, 73(3), 325–331. https://doi.org/10.1007/s00228-016-2165-3
Salgo, P., Tachdjian, R., Jain, N., & Rosenstreich, D. (2018). Novel therapies under investigation in asthma. MD Magazine Peer Exchange. https://www.mdmag.com/peer-exchange/severe-asthma-treatment/novel-therapies-under-investigation-in-asthma
World Health Organization. (2019). Asthma. https://www.who.int/news-room/q-a-detail/asthma