Severe Asthma Management
SEVERE ASTHMA MANAGEMENT

An estimated 3.7% of asthma patients have severe asthma. Throughout the process of diagnosis, treatment, and follow-up, it is imperative to always 1) investigate for comorbidities, differential diagnoses, and refer to specialists as appropriate, 2) stop ineffective add-on therapies, and 3) confirm absence of modifiable factors (incorrect inhaler technique, poor adherence, smoking or comorbidities).

GINA ASTHMA TREATMENT GUIDELINES
  STEP 1 STEP 2 STEP 3 STEP 4 STEP 5
6–11yrs ≥12yrs 6–11yrs ≥12yrs 6–11yrs ≥12yrs 6–11yrs ≥12yrs 6–11yrs ≥12yrs

Preferred controller

  PRN low dose ICS-formoterol7 Daily low dose ICS Daily low dose ICS or PRN low dose ICS-formoterol7 Low dose ICS-LABA or medium dose ICS Low dose ICS-LABA Medium dose ICS-LABA. Refer to expert advice Medium dose ICS-LABA Refer for phenotypic assessment ± add-on therapy (eg, anti-IgE) High dose ICS-LABA. Phenotypic assessment ± add-on therapy8
Other controller Low dose ICS taken whenever SABA is taken9, or daily low dose ICS Low dose ICS taken whenever SABA is taken9 Daily LTRA or low dose ICS taken whenever SABA is taken9 Daily LTRA or low dose ICS taken whenever SABA is taken9 Low dose ICS + LTRA Medium dose ICS or low dose ICS + LTRA10 High dose ICS-LABA, or add-on tiotropium, or add-on LTRA High dose ICS, add-on tiotropium, or add-on LTRA10 Add-on anti-IL5, or add-on low dose OCS, but consider side-effects Add-on low dose OCS, but consider side-effects
Preferred reliever PRN SABA PRN low dose ICS-formoterol7 PRN SABA PRN low dose ICS-formoterol7 PRN SABA PRN low dose ICS-formoterol for patients prescribed maintenance and reliever therapy PRN SABA PRN low dose ICS-formoterol for patients prescribed maintenance and reliever therapy PRN SABA PRN low dose ICS-formoterol for patients prescribed maintenance and reliever therapy
Other reliever   PRN SABA   PRN SABA   PRN SABA   PRN SABA   PRN SABA
PHARMACOLOGICAL TREATMENTS FOR SEVERE ASTHMA
Inhaled Corticosteroids
Low (mcg)11 Medium (mcg)11 High (mcg)11 Notes
6–11yrs ≥12yrs 6–11yrs ≥12yrs 6–11yrs ≥12yrs
beclomethasone dipropionate (standard particle) MDI 100–200 200–500 >200–400 >500–1000 >400 >1000 The choice of medication, device, and dose for each individual patient should be based on assessment of symptom control, risk factors, patient preference, and practical issues (eg, cost, ability to use the device, adherence). Once good symptom control has been maintained for 3mos, carefully titrate ICS dose to the minimum dose that will maintain symptom control and minimize exacerbation risk while reducing potential side-effects.
beclomethasone dipropionate (extrafine particle) MDI 50–100 100–200 >100–200 >200–400 >200 >400
budesonide DPI 100–200 200–400 >200–400 >400–800 >400 >800
ciclesonide MDI 80 80–160 >80–160 >160–320 >160 >320
fluticasone furoate DPI 50 100 50 100 200
fluticasone propionate DPI 50–100 100–250 >100–200 >250–500 >200 >500
MDI 50–100 100–250 >100–200 >250–500 >200 >500
mometasone furoate DPI 200 200 400
MDI 100 200–400 100 200–400 200 >400
Biologics
Generic Brand Strength Dosing Notes
Anti-IgE
omalizumab Xolair 75mg/0.5mL, 150mg/mL; 150mg/vial <6yrs: Not established. ≥6yrs: Base dose and frequency on baseline serum total IgE level and body weight. Give by SC inj over 5–10secs. 75–375mg every 2 or 4wks; max 150mg per inj site. Trial duration: ≥4mos Eligibility: sensitization to inhaled allergen, AND total serum IgE and body weight within local range, AND more than a specified number of exacerbations within the last year Predictors of (+) response: blood eosinophils ≥260/μL or FeNO ≥20ppb, allergen-driven symptoms, childhood-onset asthma
Anti-IL5/5R
mepolizumab Nucala 100mg/mL, 100mg/vial <6yrs: Not established. 6–11yrs(use vials only): 40mg SC once every 4wks. ≥12yrs: 100mg SC once every 4wks. Trial duration: ≥4mos Eligibility: more than a specified number of severe exacerbations within the last year, AND blood eosinophils ≥300/μL Predictors of (+) response: higher blood eosinophils, higher number of severe exacerbations in previous year, adult-onset asthma, nasal polyposis, maintenance OCS at baseline
benralizumab Fasenra 30mg/mL <12yrs: Not established. ≥12yrs: 30mg SC once every 4wks for the first 3 doses, then once every 8wks thereafter.
reslizumab Cinqair 100mg/10mL <18yrs: Not established. ≥18yrs: Give by IV infusion over 20–50mins. 3mg/kg once every 4wks.
Anti-IL4R
dupilumab Dupixent 200mg/1.14mL, 300mg/2mL <12yrs: Not established. ≥12yrs: Initially 400mg (two 200mg inj at different sites) SC followed by 200mg every other week; or, initially 600mg (two 300mg inj at different sites) followed by 300mg every other week. For those with oral corticosteroids-dependent asthma or with co-morbid moderate-to-severe atopic dermatitis for which Dupixent is indicated: initially 600mg followed by 300mg every other week. Trial duration: ≥4mos Eligibility: more than a specified number of severe exacerbations within the last year, AND blood eosinophils ≥300/μL or FeNO ≥25ppb, OR requirement for maintenance OCS Predictors of (+) response: higher blood eosinophils, higher FeNO
Inhaled Corticosteroids + Long-Acting Beta2-Antagonist
budesonide/ formoterol Symbicort 80mcg/4.5mcg, 160mcg/4.5mcg <6yrs: Not established. 6–<12yrs: 2 inh of 80/4.5 twice daily (approx. 12hrs apart). ≥12yrs: Initially 2 inh of 80/4.5 or 160/4.5 twice daily (approx. 12hrs apart), based on asthma severity. If inadequate response after 1–2wks using 80/4.5 strength, may switch to 160/4.5 strength. Max 2 inh of 160/4.5 twice daily. Prime by shaking (5 secs) and spraying inhaler 2 times. Discard 3mos after opening foil pouch.
fluticasone furoate/ vilanterol Breo Ellipta 100mcg/25mcg, 200mcg/25mcg ≤17yrs: Not established. ≥18yrs: Initially 1 inh of 100/25mcg or 200/25mcg once daily, based on disease severity and previous asthma therapy. Max 1 inh of 200/25mcg once daily. Discard 6wks after opening foil tray.
fluticasone propionate/ salmeterol Advair HFA 45mcg/21mcg, 115mcg/21mcg, 230mcg/21mcg <12yrs: Not established. ≥12yrs: Initially 2 inh of 45/21 or 115/21 or 230/21 twice daily (approx. 12hrs apart), based on disease severity and previous asthma therapy. If inadequate response after 2wks, use next higher strength. Max 2 inh of 230/21 twice daily. Prime by shaking (5 secs) and spraying inhaler 4 times.
Advair Diskus 100mcg/50mcg, 250mcg/50mcg, 500mcg/50mcg <4yrs: Not established. 4–11yrs: 1 inh of 100/50 twice daily (approx. 12hrs apart). ≥12yrs: Initially 1 inh of 100/50 or 250/50 or 500/50 twice daily (approx. 12hrs apart), based on disease severity and previous asthma therapy. If inadequate response after 2wks, use next higher strength. Max 1 inh of 500/50 twice daily. Discard 1 month after opening foil pouch.
mometasone furoate/ formoterol Dulera 50mcg/5mcg, 100mcg/5mcg, 200mcg/5mcg <5yrs: Not established. 5–<12yrs: 2 inh of 50mcg/5mcg twice daily (AM & PM); max 200mcg/20mcg daily.≥12yrs: Initially 2 inh of 100mcg/5mcg or 200mcg/5mcg twice daily (AM & PM), based on disease severity and previous asthma therapy. If inadequate response after 2wks, may increase dose. Max 2 inh of 200mcg/5mcg twice daily (800mcg/20mcg per day). Prime by shaking and spraying inhaler 4 times.
Leukotriene Receptor Antagonist/Leukotriene Modifier
montelukast Singulair 4mg, 5mg chew tabs <12mos: Not established. 12–23mos: 4mg granule packet once daily in PM. 2–5yrs: 4mg chew tab or granule packet once daily in PM. 6–14yrs: 5mg chew tab once daily in PM. ≥15yrs: 10mg tab once daily in PM. Take granules by mouth within 15mins of opening packet; may dissolve in 5mL of cold or room temperature baby formula or breast milk, or mix in spoonful of soft applesauce, carrots, rice, or ice cream.
4mg granules
10mg tabs
zafirlukast Accolate 10mg, 20mg <5yrs: Not established. 5–11yrs: 10 mg twice daily. ≥12yrs: 20mg twice daily. Take 1hr before or 2hrs after meals.
zileuton Zyflo 600mg <12yrs: Not recommended. ≥12yrs: 600mg four times daily; max 2400mg/day. CR: 1200mg twice daily; max 2400mg/day. Take with meals and at bedtime. CR: take within 1hr after AM and PM meals; swallow whole.
Zyflo CR
Long-Acting Anticholinergic
tiotropium Spiriva Respimat 1.25mcg/ actuation <6yrs: Not established. ≥6yrs: 2 inh of Spiriva Respimat 1.25mcg/actuation (2.5mcg) once daily; max 2 inh/24hrs. Prime by inserting cartridge into inhaler and actuating until aerosol cloud is visible; repeat 3 more times. Discard 3mos after first use.
Short-Acting Beta2-Agonist
albuterol ProAir Digihaler 90mcg/inh <4yrs: Not established. ≥4yrs: 2 inh every 4–6hrs as needed; 1 inh every 4hrs may suffice in some patients Does not require priming. Do not use with a spacer or volume holding chamber. Discard 13mos after opening foil pouch.
ProAir HFA Prime by shaking and spraying inhaler 3 times.
ProAir Respiclick Does not require priming. Do not use with a spacer or volume holding chamber. Discard 13mos after opening foil pouch.
Proventil HFA Prime by shaking and spraying inhaler 4 times.
Ventolin HFA Prime by shaking and spraying inhaler 4 times. Discard 12mos after opening foil pouch.
NOTES

Key:  ABPA = allergic bronchopulmonary aspergillosis; AERD = aspirin-exacerbated respiratory disease; DPI = dry powder inhaler; FeNO = fractional concentration of exhaled nitric oxide; GINA = Global Initiative for Asthma; ICS = inhaled corticosteroid; inh = inhalation; inj = injection; IgE = immunoglobulin E; IL = interleukin; LABA = long-acting beta2-antagonist; LM = leukotriene modifier; LTRA = leukotriene receptor antagonist; MDI = metered dose inhaler; OCS = oral corticosteroid; ppb = parts per billion; PRN = as needed; SABA = short-acting beta2-agonist

1 Uncontrolled asthma is defined by 1) poor symptom control (frequent symptoms or reliever use, activity limited by asthma, night waking), AND/OR 2) frequent exacerbations (≥2/year) requiring OCS, or serious exacerbations (≥1/year) requiring hospitalization.

2 Difficult-to-treat asthma is defined by 1) patient uncontrolled despite GINA Step 4 or Step 5 treatment, OR 2) patient requires GINA Step 4 or Step 5 treatment to maintain good symptom control and reduce risk of exacerbation.

3 Optimize management by 1) optimizing Step 4 or Step 5 treatment (correct inhaler technique and adherence, switch to ICS-formoterol maintenance and reliever therapy), 2) treat comorbidities and modifiable risk factors, 3) consider non-biologic and non-pharmacologic interventions, 4) consider trial of high dose ICS, if not used.

4 Evidence of type 2 inflammation includes 1) blood eosinophil ≥150/μL, AND/OR 2) FeNO ≥20 ppb, AND/OR 3) sputum eosinophil ≥2%, AND/OR 4) asthma is clinically allergy-driven, AND/OR 5) need for maintenance OCS.

5 Includes sputum induction, high resolution chest CT, bronchoscopy for alternative/additional diagnoses.

6 Non-biologic add-on therapy includes tiotropium, macrolide, LABA, LM/LTRA.

7 Data only available for budesonide-formoterol.

8 Add-on therapy: tiotropium, anti-IgE, anti-IL5/5R, anti-IL4R.

9 6–11yrs: separate ICS and SABA inhalers; ≥12yrs: separate or combination ICS and SABA inhalers.

10 Consider adding house dust mite SL immunotherapy for sensitized patients with allergic rhinitis and FEV1 >70% predicted.

11 Suggested total daily doses for the low, medium, and high dose ICS therapies based on available studies and product information.

REFERENCE

Global Initiative for Asthma (GINA). Global Strategy for Asthma Management And Prevention, 2020. Available from www.ginasthma.org. Accessed July 1, 2020.

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 randomized, double-blind, placebo-controlled trial. Lancet. 2017;390:659-68.

Created 7/2020