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The purpose of this activity is to ensure that all nurses are aware of and able to implement the most up-to-date information regarding the management of severe cases of asthma, exacerbations, and special populations into their practice.

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At the conclusion of this exercise, the nurse 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).

Biologics

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 previous 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. During the 24-week study, 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 significantly reduce steroid use as compared to the placebo group with fewer exacerbations and improved forced expiratory volume (FEV₁) (Rabe et al., 2018). In a contemporaneous year-long study of over 1,900 patients with uncontrolled asthma, both a 200 and 300 mg dosing regimen led to a significant decrease in exacerbation rate and improvement in FEV₁ (Castro et al., 2018). Injection site reaction and transient blood eosinophilia were the most commonly reported adverse effects in both studies (Castro et al., 2018; Rabe 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, 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 as adjunctive therapy for patients over the age of 18 with uncontrolled asthma. 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, the combined results of which 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 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

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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, it reduced the rate of exacerbations but failed to reach significance. Results do 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 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). Studies have not shown to be significantly effective, and 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 are typically ordered in patients with moderate to severe exacerbations, 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 list the following factors associated with an increased likelihood of the need for admission:

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 (FEV₁less 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 based on a small retrospective study of 54 pediatric patients based in Utah.

Special Populations

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

It is crucial to recognize when a patient needs to be referred out to a specialist for more advanced care. 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 patients age five and above, this threshold is step 4 or higher, with consideration at 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).

References

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

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

Asthma Nursing CE Course for RNs and LPNs Part 4: The Management of Severe Asthma: Biologics, Asthma Exacerbations, Special Populations, and Referral Considerations Nursing CE Course

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Single Course Cost: $13.00

Asthma Nursing CE Course for RNs and LPNs Part 4: The Management of Severe Asthma: Biologics, Asthma Exacerbations, Special Populations, and Referral Considerations Nursing CE Course

About this course:

Course preview

Single Course Cost: $13.00

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