Nitric Oxide Airway Measurements

18 March 2024
Nitric Oxide Airway Measurements

 

Question
When are nitric oxide airway measurements useful? Is it worth me buying a machine to measure it?

 

Answer (2024)
By Cesar Galvan Calle, MD (Lima, Peru)

Nitric oxide (NO) acts as an internal mediator, playing a role in various cellular and tissue functions, including the respiratory system. In this context, it regulates the tone of bronchial smooth muscles, influences neurotoxicity, modulates mucus transport, and contributes to surfactant production (1).

Fractional exhaled nitric oxide (FeNO) serves as a biomarker used to identify potential type 2 inflammation in both the upper and lower airways. It is commonly employed in asthma treatment, offering significant advantages over other tests related to inflammation, such as blood eosinophil count, due to its non-invasive nature, ease of application, and well-tolerance in both adult and pediatric patients (2).

Concerning asthma diagnosis, adults and children experiencing asthmatic symptoms with low FeNO concentrations may suggest that eosinophilic inflammation is less likely. In such cases, alternative diagnoses like non-allergic asthma, gastroesophageal reflux, or vocal cord dysfunction could be considered (2), as recommended for some years by the guidelines of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) (3).

High baseline FeNO levels in severe asthma patients starting biologic therapy predict better clinical control and fewer exacerbations, highlighting its biomarker potential for biologic response (4). A meta-analysis from 2023 found that FeNO-guided asthma treatment plays a crucial role in predicting the response to treatment, although a specific protocol on cut-off points has not yet been fully established. Additionally, the treatment has the potential to reduce the number of patients experiencing at least one exacerbation by 39% and lower the frequency of exacerbations by 33% based on findings from six Randomized Controlled Trials studies (5). Another notable benefit lies in its ability to identify improper inhaler use during asthma treatment. If FeNO levels do not decrease upon initiating inhaler use, this may indicate issues as simple as incorrect technique on the part of the patient (6).

Measuring FeNO values could be valuable in patients with chronic rhinosinusitis and rhinitis, as there exists a correlation between exhaled nitric oxide levels and nasal and sinus mucosal inflammation, along with symptom severity (7). Additionally, FeNO may serve as an indicator in occupational asthma inflammation, given its correlation with methacholine hyperreactivity. Although there is no consensus on the cut-off point for diagnosis, its use is recommended 24 hours after occupational exposure (8). In patients with chronic obstructive pulmonary disease (COPD), a slight increase in FeNO levels has been observed. However, a definitive association between exacerbated COPD and FeNO levels is yet to be established (9).

A cost-effectiveness study, simulating asthma treatment based on current standards of care and comparing these standards with the addition of FeNO, revealed that incorporating FeNO into the treatment regimen could lead to a yearly reduction in patient costs by $409 and an enhancement in health-adjusted quality of life (10). Therefore, the investment in a FeNO measurement device is justified, depending on the type of patients you treat. This measurement is useful for monitoring inflammation, assisting in the diagnosis and management of asthma, as well as considering other possible diagnoses.

References

  1. Antosova M, Mokra D, Pepucha L, Plevkova J, Buday T, Sterusky M, et al. Physiology of nitric oxide in the respiratory system. Physiol Res. 2017;66(Suppl 2):S159-s72.
  2. Murugesan N, Saxena D, Dileep A, Adrish M, Hanania NA. Update on the Role of FeNO in Asthma Management. Diagnostics. 2023;13(8):1428.
  3. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171(8):912-30.
  4. Pianigiani T, Alderighi L, Meocci M, Messina M, Perea B, Luzzi S, et al. Exploring the Interaction between Fractional Exhaled Nitric Oxide and Biologic Treatment in Severe Asthma: A Systematic Review. Antioxidants (Basel). 2023;12(2).
  5. Korevaar DA, Damen JA, Heus P, Moen MJ, Spijker R, van Veen IH, et al. Effectiveness of FeNO-guided treatment in adult asthma patients: A systematic review and meta-analysis. Clin Exp Allergy. 2023;53(8):798-808.
  6. Heffler E, Carpagnano GE, Favero E, Guida G, Maniscalco M, Motta A, et al. Fractional Exhaled Nitric Oxide (FENO) in the management of asthma: a position paper of the Italian Respiratory Society (SIP/IRS) and Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). Multidiscip Respir Med. 2020;15(1):36.
  7. Olonisakin TF, Moore JA, Barel S, Uribe B, Parker DM, Bowers EMR, et al. Fractional Exhaled Nitric Oxide as a Marker of Mucosal Inflammation in Chronic Rhinosinusitis. Am J Rhinol Allergy. 2022;36(4):465-72
  8. Oțelea MR, Fell AKM, Handra CM, Holm M, Filon FL, Mijakovski D, et al. The value of fractional exhaled nitric oxide in occupational diseases - a systematic review. J Occup Med Toxicol. 2022;17(1):14.
  9. Lu Z, Huang W, Wang L, Xu N, Ding Q, Cao C. Exhaled nitric oxide in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2018;13:2695-705.
  10. Brooks EA, Massanari M. Cost-Effectiveness Analysis of Monitoring Fractional Exhaled Nitric Oxide (FeNO) in the Management of Asthma. Manag Care. 2018;27(7):42-8.

Answer (2019)
By Glenis K. Scadding MD, FRCP

Nitric oxide (NO) is produced from the amino acid arginine via the enzyme nitric oxide synthase.

It is a potent biological mediator which has a regulatory role in many cellular and tissue functions. In the upper and lower airways, NO is involved in regulatory, protective, defensive functions, but can have damaging effects. NO forms part of innate immunity, being constitutively generated at high concentrations in the paranasal sinuses.

Nitric oxide levels may reflect the inflammatory status of both the upper and lower airways. Measurement of exhaled bronchial nitric oxide is a useful, non-invasive tool in the diagnosis and management of eosinophilic asthma, since it is normally low unless nitric oxide synthase is induced by the inflammatory response. Normal levels indicate that lower airways eosinophilic inflammation is absent or controlled by therapy. NO levels may also help in the diagnosis of chronic cough.

Nasal nitric oxide is more complex since two factors are involved: high continually present sinus NO enters the nose via the ostiomeatal complex, but the nasal mucosa can also form inducible nitric oxide in an inflammatory response. Therefore nasal NO may be normal, raised or lowered in disease states. However measurement may be a useful tool in the diagnosis and management of patients with chronic rhinosinusitis, nasal polyps, and cystic fibrosis, as well as in the diagnosis of primary ciliary dyskinesia (PCD), where nasal NO is very low. In conditions where the ostiomeatal complex is blocked (such as nasal polyps) nasal NO tends to be low and to improve with nasal corticosteroids, correlating with the improvement in polyp grade. Further research is aimed at investigating the role of nitric oxide in allergic rhinitis, where results are variable, but tend to be elevated in active disease and lowered by nasal corticosteroids.

Measuring both bronchial and nasal nitric oxide may assist the combined management of upper and lower airways: for example in the coughing child normal exhaled NO (from the lower airways) suggests that the pathology is more likely to be in the upper respiratory tract.

Whether NO measurements are useful in your practice depends on the patients whom you are seeing. (FENO) values obtained using a portable analyzer correlate well with those obtained using an established laboratory analyzer and can be used to discriminate asthmatic from non-asthmatic patients. This may facilitate the measurement of asthmatic airway inflammation in primary care.

I have found NO very helpful in subjects with both upper and lower airway conditions, where they can obviate the need for a repeat CT scan, alert one to the likelihood of PCD or cystic fibrosis or to the fact that a patient is not using their inhaled corticosteroids in sufficient quantity.

There are guidelines for making the measurements accurately.

 

References

  1. Gustafsson I, Leone A, Persson M, Wiklund N, Moncada S: Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991;181:852–857.
  2. Alving K, Weitzberg E, Lundberg JM: Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993;6:1368–1370.
  3. Moncada S, Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002–2012.
  4.  Djupesland P, Chatkin J, Qian W: Nitric oxide in the nasal airway: a new dimension in otorhinolaryngology. Am J Otolaryngol 2001;22:19–32.
  5.  Hibbs JB Jr: Infection and nitric oxide. J Infect Dis 2002;18(suppl 1):S9–S17.
  6.  Lundberg JO, Weitzberg E, Rinder J, Rudehill A, Jansson O, Wiklund NP, et al: Calcium-independent and steroid-resistant nitric oxide synthase activity in human paranasal sinus mucosa. Eur Respir J 1996;9:1344–1347
  7. Kharitonov S, Alving K, Barnes PJ: Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force. Eur Respir J 1997;10:1683–1693.
  8. Lundberg J, Rinder J, Weitzberg E, Lundberg JM, Alving K: Nasally exhaled nitric oxide in humans originates mainly in the paranasal sinuses. Acta Physiol Scand 1994;152:431–432.
  9. Lundberg JO, Farkas-Szallasi T, Weitzberg E, Rinder J, Lidholm J, Anggaard A, Hökfelt T, Lundberg JM, Alving K: High nitric oxide production in human paranasal sinuses. Nat Med 1995;1:370–373
  10. Lundberg J, Weitzberg E, Nordvall S: Primarily nasal origin of exhaled nitric oxide and absence in Kartagener’s syndrome. Eur Resp J 1994;7:1501–1504.
  11. Kawamoto H, Takeno S, Yajin K: Increased expression of inducible nitric oxide synthase in nasal epithelial cells in patients with allergic rhinitis. Laryngoscope 1999;109:2015–2020.
  12. Croen KD: Evidence for antiviral effect of nitric oxide: inhibition of herpes simplex virus type 1 replication. J Clin Invest 1993;91:2446–2452.
  13. Runer T, Lindberg S: Effects of nitric oxide on blood flow and mucociliary activity in the human nose. Ann Otol Rhinol Laryngol 1998;107:40–46.
  14. Alving K, Janson C, Nordvall L: Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children. Respir Res 2006;7:67.
  15. Menzies D, Nair A, Lipworth BJ: Portable exhaled nitric oxide measurement: comparison with the ‘gold standard’ technique. Chest 2007;131:410–414.
  16. Balfour-Lynn IM, Laverty A, Dinwiddie R: Reduced upper airway nitric oxide in cystic fibrosis. Arch Dis Child 1996;75:319–322.
  17. Kharitonov SA, Chung KF, Evans D, O’Connor BJ, Barnes PJ: Increased exhaled nitric oxide in asthma is mainly derived from the lower respiratory tract. Am J Respir Crit Care Med 1996;153:1773–1780.
  18. Henriksen A, Sue-Chu M, Holmen T, Langhammer A, Bjermer L: Exhaled and nasal NO levels in allergic rhinitis: relation to sensitization, pollen season and bronchial hyperresponsiveness. Eur Respir J 1999;13:301–306.
  19. Colantonio D, Brouillette L, Parikh A, Scadding GK: Paradoxical low nasal nitric oxide in nasal polyposis. Clin Exp Allergy 2002;32:698–701.
  20. Ragab SM, Lund VJ, Saleh HA, Scadding G: Nasal nitric oxide in objective evaluation of chronic rhinosinusitis therapy. Allergy 2006;61:717–724.
  21. Lundberg JO, Maniscalco M, Sofia M, Lundblad L, Weitzberg E: Humming, nitric oxide, and paranasal sinus obstruction. JAMA 2003;289:302–303.
  22. Bush A: Primary ciliary dyskinesia. Acta Otorhinolaryngol Belg 2000;54:317–324.
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  24. Scadding G, Scadding K: Update on the use of nitric oxide as a non-invasive measure of airways inflammation. Rhinology 2009;47:115–120.
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  26. Anonymous. ATS/ERS Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide. Am J Respir Crit Care Med 2005;171:912e30.

 

 

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