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. 2024 Aug 28;38(1):81–84. doi: 10.1080/08998280.2024.2395213

Respiratory failure in a patient with exhaled nitric oxide >300 ppb and subsequent response to dupilumab

Howard Crisp 1,
PMCID: PMC11657067  PMID: 39712414

Abstract

Multiple biologic agents are approved for the treatment of severe persistent asthma not controlled by inhaled corticosteroid/beta-agonist therapy. Appropriate phenotyping can aid in picking the right biologic for the right patient. Here is a unique case of a patient with severe asthma and respiratory arrest, with fraction of exhaled nitric oxide >300 ppb whose asthma became completely controlled with dupilumab.

Keywords: Asthma, dupilumab, FeNO, fractional exhaled nitric oxide testing, nitric oxide, respiratory insufficiency

KEY POINTS

  • Elevated fraction of exhaled nitric oxide (FeNO) levels reflect type-2 inflammation mediated by interleukin (IL)-13.

  • Elevated FeNO levels predict enhanced response to inhaled corticosteroids as well as to dupilumab, which blocks IL-4 and IL-13 signaling.

CME

CME Information: https://ce.bswhealth.com/BUMC_Proceedings_CME_info

Credit Claim Process: To claim CME for this activity, read the entire article and go to ce.bswhealth.com/2025BUMC_Proceedings_Jan_asthma. You will register for the course, pay any relevant fee, take the quiz, complete the evaluation, and claim your CME credit.

Dates for credit: January 1, 2025, to January 1, 2026.

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CASE SUMMARY

A man in his 40s presented to an allergy clinic in the southern United States to establish care in the early summer. He had a history of allergic rhinitis, sinus surgery for nasal polyps, and a history of asthma with an exacerbation a few years earlier that required a family member to call an ambulance and resulted in emergency department care without hospital admission. Although he had two prior courses of oral steroids for asthma exacerbations in the prior year, he had not been prescribed an inhaled corticosteroid (ICS). The patient had quit smoking cigarettes 8 years earlier.

At presentation to the allergy clinic, the patient had not had access to albuterol for at least a month and was having chest tightness and dyspnea that awakened him from sleep every night. He denied any daytime symptoms and did not have symptoms while in the office. His medications at the time were once-daily montelukast 10 mg, fexofenadine 180 mg, fluticasone 50 mcg nasal spray, saline sinus irrigation, and omeprazole 20 mg. He had no known drug allergies.

The patient had a normal physical exam, including normal respirations without wheeze and normal anterior rhinoscopy without visible polyposis. Spirometry showed a forced expiratory volume in the first second (FEV1) 112% of predicted, forced vital capacity (FVC) 125% of predicted, and an FEV1/FVC ratio of 0.72. The fraction of exhaled nitric oxide (FeNO) was >300 ppb (NIOX VERO, measurement range 5 to 300 ppb).

Due to nightly asthma symptoms and very elevated FeNO, the patient was started on a high-dose ICS and long-acting beta-agonist (LABA) combination with the first dose given under observation in the clinic. His albuterol was also refilled.

Unfortunately, despite adherence to his medications, he was in his office 2 days later and developed chest tightness that did not respond to albuterol. The only specific trigger he could recall was that it was a bad air quality day. His supervisor called 911. Emergency medical personnel administered albuterol by nebulization, intramuscular epinephrine, and assisted breathing by bag-valve-mask. At the emergency department he was noted to be conscious but not answering questions. Lung exam revealed wheezing with poor air movement. His venous pH was 6.97 with a partial pressure of carbon dioxide >100, and he was intubated shortly after arrival. Initial ventilator settings were assist-control, tidal volume 400 mL, positive end expiratory pressure 2 mm Hg, with mean airway pressure 13 mm Hg. His condition quickly improved after intubation. Additional treatments included methylprednisolone 125 mg intravenously followed by 60 mg every 12 hours, magnesium 2 g intravenously, and ipratropium and albuterol by nebulization. He was extubated the following day and discharged from the hospital another day later on oral prednisone 40 mg daily, montelukast, and high-dose ICS/LABA.

Additional laboratory tests in the emergency department and hospital showed an eosinophil count of 290 cells/dL (prior to receiving corticosteroids) and immunoglobulin E (IgE) level of 115.9 kU/L. To evaluate for eosinophilic granulomatosis with polyangiitis, which has rarely been associated with leukotriene antagonist use, antineutrophil cytoplasmic antibodies were checked and were negative. A urine drug screen and chest x-ray in the emergency department were normal.

Five days after discharge, while on prednisone and high-dose ICS/LABA, the patient still had an elevated FeNO of 126 ppb with supranormal spirometry (FEV1 131% predicted, FVC 148% predicted, FEV1/FVC 0.73).

While a longer trial of ICS/LABA therapy would have been appropriate, due to his high-risk status a biologic agent was started and his maintenance inhaler was also stepped up to a high-dose ICS/LABA/long-acting muscarinic antagonist (LAMA) combination. While he was a candidate for multiple asthma biologics, an elevated FeNO is associated with enhanced response to dupilumab.1,2 He received dupilumab 600 mg subcutaneously in the office that day and continued 300 mg subcutaneously every other week at home. High-resolution chest computed tomography performed 10 days after discharge showing minimal bronchial wall thickening and minimal air trapping.

One month after discharge, he was doing well on high-dose ICS/LABA/LAMA, montelukast, and dupilumab. He was no longer on oral steroids, and his FeNO had declined to 29 ppb. Percutaneous allergy skin testing at that time showed marked sensitization to grass pollens and mountain cedar (wheal sizes 15 to 30 mm). Grass pollen levels were moderately elevated during the week of his exacerbation, which may have contributed to his asthma flare. His asthma remained well controlled 1.5 months later on dupilumab, and he then began subcutaneous allergy immunotherapy with a twice-weekly build-up schedule. He reached his full maintenance dose within 4 months and spaced out to monthly intervals.

At his next follow-up, he was not having any further asthma symptoms or albuterol use. He has remained on dupilumab, ICS/LABA/LAMA, and allergy immunotherapy with well-controlled asthma and no further asthma exacerbations for 2 years of follow up.

CLINICAL QUESTIONS

  1. A 30-year-old man presents to the office for follow up with severe persistent asthma that remains uncontrolled despite high-dose ICS/LABA/LAMA therapy. He has had multiple asthma exacerbations in the prior year and his asthma is only controlled when he is on oral corticosteroids. His FeNO is 52 ppb. He had previously normal allergy skin testing and serum eosinophils of 100 cells/mcL prior to his most recent course of corticosteroids. Which of the following is the best next therapy for him?
    1. Omalizumab
    2. Mepolizumab
    3. Reslizumab
    4. Dupilumab
  2. Which of the following characteristics or biomarkers predict enhanced response to dupilumab?

    1. Male gender

    2. FeNO >50 ppb

    3. Blood eosinophils <300 cells/mcL

    4. Body mass index >30 kg/m2

Answers are provided at the end of the article.

DISCUSSION

Asthma is a chronic respiratory disease characterized by bronchial hyperresponsiveness that includes different patient phenotypes and endotypes. The type 2 inflammation high endotype is associated with elevated exhaled nitric oxide, blood and tissue eosinophilia, elevated serum IgE, and comorbidities such as allergic rhinitis, chronic sinusitis with nasal polyps, and atopic dermatitis.3 Research on the specific cytokines involved in type 2 inflammation has led to a variety of targeted treatments for asthma (Table 1).4,5 Omalizumab targets IgE. Mepolizumab, benralizumab, and reslizumab target the interleukin-5 (IL-5) pathway. Tezepelumab targets thymic stromal lymphopoietin. Dupilumab inhibits the IL-4 receptor alpha subunit and thereby inhibits both IL-4 and IL-13 signaling, which are mediators of type 2 inflammation. While IgE, blood eosinophils (driven by IL-5), and FeNO (driven by IL-13) each reflect type 2 inflammation, there is great heterogeneity between patients. One-third of patients with severe asthma may have elevation of only a single biomarker.6 As in this patient, differentiating the subtypes of type 2-high asthma is essential to picking the most effective treatment.

Table 1.

Biologic agents approved for the treatment of asthma

Name Antibody target Indicated phenotype Phenotype markers Other predictive markers
Omalizumab
Immunoglobulin E
Allergic
Positive allergy skin test or specific IgE to a perennial allergen
History of allergy-driven symptoms
Mepolizumab IL-5 Eosinophilic Blood eosinophils >150 cells/microL Higher blood eosinophils
Higher number of severe exacerbations
Reslizumab
 
     
Benralizumab
IL-5 receptor
 
 
 
Dupilumab IL-4 receptor alpha subunit Eosinophilic
Blood eosinophils >150 cells/microL
Higher FeNO
 
 
Steroid dependent
No markers required
Higher eosinophils (but <1500)
Tezepelumab Thymic stromal lymphopoietin Any phenotype No markers required Higher FeNO
Higher blood eosinophils

FeNO indicates fraction of exhaled nitric oxide.

Nitric oxide synthase enzymes in the lungs convert L-arginine to L-citrulline and nitric oxide. IL-13 causes upregulation of inducible nitric oxide synthase, yielding increased nitric oxide in exhaled air. FeNO can be measured to give a direct biomarker of type 2 inflammation mediated by IL-13. The American Thoracic Society defines a low FeNO as <25 ppb, intermediate as 25 to 50 ppb, and high as >50 ppb in adult patients, but other cutoffs have also been suggested.7

Patients with elevated FeNO levels are more likely to have uncontrolled asthma symptoms, self-reported wheezing, increased short-acting beta-agonist use, recent asthma attacks and emergency room visits, and increased risk of future asthma exacerbations requiring oral corticosteroids.8–11 For patients not currently on an ICS, an elevated FeNO identifies patients with a higher likelihood to respond to ICS.12 While multiple biologic agents are approved for the treatment of type 2-high severe asthma that is inadequately controlled with an ICS/LABA, those with an elevated FeNO are particularly likely to respond to dupilumab.1,2,4

In this patient, once his asthma was well controlled on dupilumab, he was offered allergy immunotherapy because he was highly allergic to grass pollens, which are typically elevated in the spring and summer and may have contributed to his underlying asthma and allergic rhinitis. Allergy immunotherapy is the only disease-modifying treatment available for allergic rhinitis and allergic asthma. Immunotherapy has been shown to enable step-down in asthma therapy for patients with mild to moderate asthma, but is contraindicated in those with uncontrolled asthma.13 Since the advent of asthma biologics, many patients who would have not previously been candidates for allergy immunotherapy may now receive this treatment once their asthma is well controlled.14 Whether allergy immunotherapy will enable these patients to eventually discontinue their biologic, however, is not yet known. In a randomized trial for the treatment of allergic rhinitis, subcutaneous allergy immunotherapy was superior to dupilumab alone, but the addition of dupilumab to allergy immunotherapy appeared to reduce adverse events.15

This is the first case report of a patient with FeNO >300 ppb and severe asthma completely controlled with dupilumab and ICS/LABA/LAMA therapy. In National Health and Nutrition Examination Survey data of 12,408 patients from 2007 to 2010, only one patient was found to have FeNO >300 ppb, so elevations to this degree are quite rare.11

ANSWERS TO THE CLINICAL QUESTIONS

Question 1, d. Dupilumab is approved for patients who require oral corticosteroids to maintain control of their asthma. Patients with an elevated FeNO are also likely to respond to dupilumab. Omalizumab is for allergic asthma, but this patient had normal allergy testing. Mepolizumab and reslizumab are for eosinophilic asthma, but this patient has serum eosinophils <150 cells/mcL.5

Question 2, b. FeNO >50 ppb is associated with enhanced response to dupilumab. Eosinophils >300 (not <300) are also associated with enhanced response. Dupilumab’s effectiveness tends to be independent of gender and body mass index.1

Disclosure statement/Funding

The planner and faculty for this activity have no relevant financial relationships to disclose. The author reports no funding. The patient consented to publication of this case report.

References

  • 1.Busse WW, Paggiaro P, Muñoz X, et al. Impact of baseline patient characteristics on dupilumab efficacy in type 2 asthma. Eur Respir J. 2021;58(4):2004605. doi: 10.1183/13993003.04605-2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Pavord ID, Deniz Y, Corren J, et al. Baseline FeNO independently predicts the dupilumab response in patients with moderate-to-severe asthma. J Allergy Clin Immunol Pract. 2023;11(4):1213–1220.e2. doi: 10.1016/j.jaip.2022.11.043. [DOI] [PubMed] [Google Scholar]
  • 3.Busse WW, Kraft M, Rabe KF, et al. Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation. Eur Respir J. 2021;58(2):2003393. doi: 10.1183/13993003.03393-2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Buhl R, Bel E, Bourdin A, et al. Effective management of severe asthma with biologic medications in adult patients: a literature review and international expert opinion. J Allergy Clin Immunol Pract. 2022;10(2):422–432. doi: 10.1016/j.jaip.2021.10.059. [DOI] [PubMed] [Google Scholar]
  • 5.Global Initiative for Asthma . Global Strategy for Asthma Management and Prevention, 2024. Updated May 2024. www.ginasthma.org.
  • 6.Frøssing L, Silberbrandt A, Bülow AV, et al. The prevalence of subtypes of type 2 inflammation in an unselected population of patients with severe asthma. J Allergy Clin Immunol Pract. 2021;9(3):1267–1275. doi: 10.1016/j.jaip.2020.09.051. [DOI] [PubMed] [Google Scholar]
  • 7.Loewenthal L, Menzies-Gow A.. FeNO in asthma. Semin Respir Crit Care Med. 2022;43(5):635–645. doi: 10.1055/s-0042-1743290. [DOI] [PubMed] [Google Scholar]
  • 8.Zeiger RS, Schatz M, Zhang F, et al. Elevated exhaled nitric oxide is a clinical indicator of future uncontrolled asthma in asthmatic patients on inhaled corticosteroids. J Allergy Clin Immunol. 2011;128(2):412–414. doi: 10.1016/j.jaci.2011.06.008. [DOI] [PubMed] [Google Scholar]
  • 9.Dweik RA, Sorkness RL, Wenzel S, et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010;181(10):1033–1041. doi: 10.1164/rccm.200905-0695OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Diamant N, Amirav I, Armoni‐Domany K, et al. High fractional exhaled nitric oxide levels in asthma patients: does size matter? Pediatr Pulmonol. 2021;56(6):1449–1454. doi: 10.1002/ppul.25333. [DOI] [PubMed] [Google Scholar]
  • 11.Malinovschi A, Fonseca JA, Jacinto T, et al. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol. 2013;132(4):821–827.e5. doi: 10.1016/j.jaci.2013.06.007. [DOI] [PubMed] [Google Scholar]
  • 12.Lehtimäki L, Csonka P, Mäkinen E, et al. Predictive value of exhaled nitric oxide in the management of asthma: a systematic review. Eur Respir J. 2016;48(3):706–714. doi: 10.1183/13993003.00699-2016. [DOI] [PubMed] [Google Scholar]
  • 13.Demoly P, Makatsori M, Casale T, Calderon M.. The potential role of allergen immunotherapy in stepping down asthma treatment. J Allergy Clin Immunol Pract. 2017;5(3):640–648. doi: 10.1016/j.jaip.2016.11.024. [DOI] [PubMed] [Google Scholar]
  • 14.Malipiero G, Melone G, Puggioni F, et al. Allergen immunotherapy and biologics in respiratory allergy: friends or foes? Curr Opin Allergy Clin Immunol. 2021;21(1):16–23. doi: 10.1097/ACI.0000000000000707. [DOI] [PubMed] [Google Scholar]
  • 15.Corren J, Saini SS, Gagnon R, et al. Short-term subcutaneous allergy immunotherapy and dupilumab are well tolerated in allergic rhinitis: a randomized trial. J Asthma Allergy. 2021;14:1045–1063. doi: 10.2147/JAA.S318892. [DOI] [PMC free article] [PubMed] [Google Scholar]

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