![13
RINITE ALLERGICA RINOSINUSITE
OSTRUZIONE ADENOIDEA (bambini)
FIBROSI CISTICA
Riduzione rispetto ai valori normali (valori dimezzati) verosimilmente a
causa dello stress ossidativo (trasformazione di NO in nitrocomposti)
COPD
Meno utilizzato nella BPCO rispetto all’asma, I livelli sono di solito
normali o solo leggermente aumentati, tranne durante le riacutizzazioni.
La misurazione si effettua eseguendo misurazioni dell’NO esalato a
differenti flussi [MEFT] che permette di separare l’NO flusso-
indipendente e l’NO periferico (CALV) derivato dagli alveoli e
probabilmente dalle piccole vie aeree (possibile utililità in follow up
BPCO come espressione dell’infiammazione delle piccole vie aeree e
correlato con gravità malattia)
DISCINESIA CILIARE PRIMARIA
La determinazione dell’ossido nitrico (NO) nasale può essere effettuata fin
dai primi mesi di vita. Nella Discinesia Ciliare Primaria i livelli di NO nasale
sono tipicamente ridotti (inferiori a 25 ppb) per la mancanza della
fisiologica produzione di NO.](https://image.slidesharecdn.com/201911-omodeo-191130194223/85/201911-Omodeo-Significato-e-ambiti-di-utilizzo-del-FeNO-ossido-nitrico-esalato-8-320.jpg)
201911 - Omodeo - Significato e ambiti di utilizzo del FeNO (ossido nitrico esalato)
- 1. SIGNIFICATI E AMBITI DI UTILIZZO DEL FENO (OSSIDO NITRICO ESALATO) Pinuccia Omodeo Allergologia – SC Malattie Apparato Respiratorio - ALESSANDRIA
- 2. OSSIDO NITRICO: STORIA • L’ossido nitrico (NO/monossido d’azoto): radicale libero dalla breve emivita considerato essenzialmente come pericoloso inquinante ambientale (smog – fumo di sigaretta) prima degli anni 70/80 • Anni 80 scoperta della produzione endogena di NO e funzioni biologiche dello stesso: – A basse concentrazioni: funzioni fisiologiche per sviluppo polmone; e funzione di neurotrasmettitore del sistema nervoso non-adrenergico non-colinergico – Ad alte concentrazioni: mediatore infiammazione e azione nei meccanismi citotossici/citostatici di difesa verso patogeni e cells tumorali • Nel 1991 prima misura FeNO con chemiluminescenza • Gustafsson LE et al. Biochem Biophys Res Commun 1991 Dec 16;181(2):852-7 • Nel 1993: prima dimostrazione dell’incremento di FeNO nei pazienti asmatici rispetto ai controlli • Alving K et all. Eur Respir J 6: 1368-70
- 3. 4 A livello polmonare la NOS è presente in diverse cellule, tra cui le cellule nervose, le cellule epiteliali, i macrofagi alveolari ed altre cellule infiammatorie. cNOS (costitutive) NOS1 (neuronal NOS) NOS3 (endothelial NOS) Neurotrasmissione Regolazione del flusso sanguigno locale. NOS2 (inducibile) Stimoli infiammatori e infettivi Produzione di grosse quantita’ di NO L-ARGININA L-CITRULLINA NO NO SINTETASI L’ossido nitrico viene prodotto attraverso l’azione di sistemi enzimatici chiamati ossido nitrico sintasi (NOS) e regola diverse funzioni biologiche dell’organismo: pressione arteriosa, respirazione, coagulazione sanguigna, killing batterico, prevenzione del cancro e funzione cerebrale.
- 4. Le iNOS sono presenti nelle cellule solo dopo attivazione da parte di endotossine e di citochine pro-infiammatorie. Più recente è il riconoscimento del ruolo essenziale delle citochineTh2 (IL4 e IL13) nell’up-regolare iNOS nell’ep. bronchiale, via STAT-6
- 5. NOS inducibile L’espressione di NOS2 risulta aumentata nelle cellule epiteliali respiratorie di pazienti con l’asma e viene ridotta dall’uso di ICS. Modificato da Luviksodottir, 2012 Ricciardolo et all. Physiol Rev 2004: 84: 731–765
- 6. MISURA del FeNO • Concentrazione espressa in ppb • Valori flusso-dipendenti: misurazione a valori di flusso esp. di 50ml/s per almeno 10 secondi (3 mis. riproduc.) • Per ridurre «contaminazione» nasale eseguire singola espirazione a flusso costante contro una resistenza respiratoria (chiusura palato molle) • Valori normali e elevati: < 25 ppb (20 ppb nei bambini) e > a 50 ppb (35 ppb nei bambini) . LINEE GIUDA ATS - Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children—2005. Am J Respir Crit Care Med 160: 2104–2117, 2005. ATS/ERS. Am J Respir Crit Care Med. 2005;171(8):912-930. ERS/ATS Task Force. Measurement of exhaled nitric oxide in children. Eur RespirJ 20: 223–237, 2002.
- 7. Factors Affecting Exhaled NO Measurements • Pharmacologic – Papaverin – Oxymetazoline – Sodium nitroprusside – L-arginine – ACE inhibitors (enalapril) • Physiologic and procedural – Arginine ingestion, nitrite/nitrate- enriched food • Environmental, occupational – Air pollution (NO, ozone) – Electromagnetic field generated by cellular phone (nasal NO) • Infections – Upper respiratory infections • Pharmacologic – Oxymetazoline – NOS inhibitors • Physiologic and procedural – Repeated spirometry – Physical exercise – Menstrual cycle – Sputum induction – Body temperature reduction • Habitual – Smoking – Alchol ingestion
- 8. 13 RINITE ALLERGICA RINOSINUSITE OSTRUZIONE ADENOIDEA (bambini) FIBROSI CISTICA Riduzione rispetto ai valori normali (valori dimezzati) verosimilmente a causa dello stress ossidativo (trasformazione di NO in nitrocomposti) COPD Meno utilizzato nella BPCO rispetto all’asma, I livelli sono di solito normali o solo leggermente aumentati, tranne durante le riacutizzazioni. La misurazione si effettua eseguendo misurazioni dell’NO esalato a differenti flussi [MEFT] che permette di separare l’NO flusso- indipendente e l’NO periferico (CALV) derivato dagli alveoli e probabilmente dalle piccole vie aeree (possibile utililità in follow up BPCO come espressione dell’infiammazione delle piccole vie aeree e correlato con gravità malattia) DISCINESIA CILIARE PRIMARIA La determinazione dell’ossido nitrico (NO) nasale può essere effettuata fin dai primi mesi di vita. Nella Discinesia Ciliare Primaria i livelli di NO nasale sono tipicamente ridotti (inferiori a 25 ppb) per la mancanza della fisiologica produzione di NO.
- 9. 14 IL FENO ESALATO NELLA PATOLOGIA ASMATICA DIAGNOSI MONITORAGGIO DELL’INFIAMMAZIONE CONTROLLO TRATTAMENTO
- 10. Misurazione del FeNO nell’asma: • Vantaggi • Non invasivo, ripetibile • Basso costo • Dati quantitativi • Correla con altri markers infiammazione eosinofilica: ➢ sputum eosinophil count ➢ airway hyperresponsiveness ➢ bronchodilator response ➢ asthma symptoms • Limiti • Dipende dalla collaborazione del paziente (non eseguibile sotto i 4-5 anni) • Influenzato dallo stato della alte vie • Non correla con l’infiammazione neutrofilica • Falsi negativi nei paziente in terapia con ICS
- 11. Guide to interpretation of FENO values in patients with Airway Disease FENO Low Normal Intermediate High Eosinofilic inflamation unlikely unlikely Present but mild Significant < 5ppb 5-25ppb 25-50ppb > 50ppb Consider: Smoker Children If symptomatic review diagnosis If asymptomatic and on treatment Patient compliant Dose reduction? Interpretation based on clinical presentation Symptomatic patients likely to respond to anti- inflammatory treatment If on ICS Check compliance Consider allergen load, imminent exacerbation Thorax 2006
- 12. 18 Diagnosi L’aumento della FENO, un marcatore delle vie aeree specifico di infiammazione a prevalenza eosinofila, non è esclusivo dell’asma ma può essere utilizzato con > 90% di specificità per la diagnosi di asma sia in adulti che in bambini. Tuttavia, devono essere tenuti in conto i livelli più bassi di NO in pazienti trattati con corticosteroidi inalatori (ICS), dato che ciò riduce la sensibilità dell’NO come strumento diagnostico. Al contrario, normali livelli di FENO permettono di distinguere i pazienti con tosse cronica non asmatica.
- 13. © Global Initiative for Asthma www.ginasthma.org ◼ In children ≤5 years with recurrent coughing and wheezing ▪ Elevated FeNO recorded >4 weeks from any URTI predicts physician-diagnosed asthma at school age (Singer 2013) ▪ Elevated FeNO at age 4 increases the odds for wheezing, physician-diagnosed asthma and ICS use by school age, independent of clinical history and presence of specific IgE (Caudri JACI 2010) Exhaled nitric oxide (FeNO) What’s new in GINA 2018?
- 14. 20 Controllo In misurazioni longitudinali, le variazioni della FENO correlavano in maniera significativa non solo con le variazioni degli eosinofili nell’espettorato e con l’iperreattività ma anche con la funzionalità respiratoria ed i sintomi asmatici. Il vantaggio della FENO come “marcatore di perdita di controllo” è che l’aumento della FENO precede la caduta del picco di flusso espiratorio ed i sintomi asmatici. Il monitoraggio dell’asma può essere molto più accurato quando vengono effettuate misurazioni ripetute della FENO piuttosto che singole valutazioni; le variazioni della FENO correlano significativamente non solo con le variazioni degli eosinofili nell’espettorato e con l’iperreattività ma anche con la funzionalità respiratoria ed i sintomi asmatici. Jones SL, et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001; 164:738– 743
- 15. Utility of Available Diagnostic Tests Adapted from: Smith AD et al. Am J Respir Crit Care Med. 2004;169(4):473-478. Sensitivity Specificity Positive Predictive Value Negative Predictive Value (%) (%) (%) (%) Peak flow increase with steroid >15% 24 100 100 69 FEV1 improvement with steroid >15% 12 100 100 66 FEV1 <80% predicted 29 100 100 71 FEV1/FVC <70% 35 100 100 73 Sputum eosinophils >3% 86 88 80 92 FENO50 >20 ppb 88 79 70 92 *
- 16. L’Ossido Nitrico è un Rapido Indicatore di Risoluzione dell’Infiammazione
- 17. 23 FeNO E GLI ALTRI MARKERS DI FLOGOSI ALLERGICA (IgE, SPT, EOSINOFILI, ECP) Correlazione tra: FeNO e IgE totali (Frank TL et al. Relationship between exhaled nitric oxide and childhood asthma. Am J Resp Crit Care Med 1998;158:1032-6.) Sintomi clinici e FeNO nei bambini atopici Aumento degli eosinofili, ECP e FeNO (Rosias PP et al. Childhood asthma: exhaled markers of airway inflammation, asthma control score, and lung function tests. Pediatr Pulmonol 2004;38:107-14) (Leuppi JD, et al.Exhaled nitric oxide levels in atopic children: relation to specific allergic sensitisation, AHR, and respiratory symptoms. Thorax 2002;57:518-23) Livelli di FeNO e la sensibilizzazione ad allergeni perenni e, nei pazienti atopici una correlazione anche tra i valori di FeNO ed il numero di Skin Prick Test positivi
- 18. 24 Trattamento e Compliance La FENO si comporta come marcatore “a rapida risposta” sensibile al trattamento steroideo dato che può essere ridotto in maniera significativa e dose dipendente 6 h dopo la nebulizzazione di una singola dose di budesonide, o entro 2-3 giorni di trattamento regolare con ICS. L’assenza di compliance o la cessazione del trattamento con ICS riporterà i valori di NO rapidamente (3-5 giorni) al livello pretrattamento; grazie alle misurazioni della FENO è possibile ridurre in maniera significativa le dosi di mantenimento dei ICS senza compromettere il controllo dell’asma.
- 19. © Global Initiative for Asthma www.ginasthma.org ◼ FeNO-guided treatment ▪ Updated to reflect new meta-analyses (Petsky Cochrane 2016; Petsky Cochrane 2016) that separately analyzed studies in which the control algorithm was reasonably close to current clinical recommendations, and therefore provided a clinically relevant comparator ▪ Children/adolescents: FENO-guided treatment was associated with significantly fewer exacerbations and lower exacerbation rate than treatment based on current guidelines ▪ Adults: no significant difference in exacerbations with FENO-guided treatment compared with treatment based on current guidelines ▪ FeNO-guided treatment is not recommended for the general asthma population at present ▪ Further studies are needed to identify the populations most likely to benefit, and the optimal frequency of monitoring Exhaled nitric oxide (FeNO) What’s new in GINA 2018?
- 20. FeNO: update nell’ asma • FeNO predicts the response to biological therapy (anti-IgE. –IL-5, -IL-4/IL13 receptor antibodies) • …but…FeNO values fall only after treatment with anti-IL 13 and anti-IL4/IL- 13 receptor antibodies
- 21. McDowell et al. Allergy 2019
- 22. FeNO e FARMACI BIOLOGICI secondo le GINA Guidelines
- 23. Fig 1 Joseph D et all. JAMA 2016 138, 1296-1298 –DOI 10.1016.jaci.2016,09.002 Copyright © 2016 American Academy of Allergy, Asthma & ImmunologyTerms and Conditions Current application of exhaled nitric oxide in clinical practice
- 25. 33
- 26. 34
- 27. 37
- 28. Che cos’è l’ossido nitrico? L’ossido nitrico viene prodotto attraverso l’azione di sistemi enzimatici chiamati ossido nitrico sintasi (NOS) e regola diverse funzioni biologiche dell’organismo: pressione arteriosa, respirazione, coagulazione sanguigna, killing batterico, prevenzione del cancro e funzioni sessuale e cerebrale. La sua sintesi è mediata, a partire dalla L-arginina convertita in L-citrullina, dall’ossido nitrico sintasi, presente in cinque forme, di cui tre costitutive (eNOS endoteliale con gene sul cromosoma 7; nNOS neuronale con gene sul cromosoma 12 ed mtNOS mitocondriale) e due inducibili (mNOS macrofagica con gene sul cromosoma 17 e OANOS osteo-cartilaginea) . Questo processo avviene in diverse cellule e tessuti: in particolare a livello polmonare la NOS è presente in diverse cellule, tra cui le cellule nervose, le cellule epiteliali, i macrofagi alveolari ed altre cellule infiammatorie. L’ossido nitrico è un regolatore endogeno prodotto dai nervi, dalle cellule endoteliali, epiteliali e da alcune cellule infiammatorie; agisce come mediatore transcellulare in molti e differenti processi biologici 10 (Fig. 2).
- 29. FORMATION OF NO Exhaled Markers of Pulmonary Disease KHARITONOV SA and BARNES PJ. Am J Respir Crit Care Med Vol 163. pp 1693–1722, 2001
- 30. FORMATION OF NO Exhaled Markers of Pulmonary Disease KHARITONOV SA and BARNES PJ. Am J Respir Crit Care Med Vol 163. pp 1693–1722, 2001
- 33. MEASUREMENT OF EXHALED NO • online • offline • Expiratory flow (50ml/s) • Contamination by nasal NO (single breath exhalation against a resistance)
- 35. Ossido nitrico: - storia del FeNO - FeNO e asma - FeNO e asma severo - FeNO e prospettive future
- 44. Barnes PJ. NO or no NO in asthma.Thorax 1996;51:218-220
- 45. Beneficial Effects of NO ◼ Mediates the NANC neural inhibitory responses in human airways and acts as a "braking" mechanism to cholinergic bronchoconstriction. ◼ Surprisingly, inhaled NO is relatively ineffective as a bronchodilator. ◼ NOS inhibitors increase the bronchoconstrictor response to histamine and bradykinin, suggesting that NO is normally protective
- 46. Beneficial Effects of NO ◼ Regulating mucociliary clearance - NOS inhibitor decreases ciliary beat frequency in airway epithelial cells. ◼ Low concentrations of NO may also inhibit plasma exudation. ◼ NO has toxic effects on bacteria, viruses, and parasites
- 47. Harmful Effects of NO ◼ Inflammatory response - increased symptoms and airways obstruction in asthma ◼ Vasodilation - hyperaemia seen in asthmatic airways ◼ Increasing blood flow to leaky post-capillary venules- increasing airway oedema ◼ Vasodilation of the pulmonary vessels - V/Q mismatch ◼ Increased mucus secretion
- 48. Harmful Effects of NO ◼ Eosinophilic inflammation in asthma is driven by Th2 that secrete interleukin 5 (IL-5). ◼ NO may inhibit Th1 that secrete interferon gama as interferon gama suppresses the proliferation of Th2 cells ◼ This would allow expansion and secretion of Th2 lymphocytes which secrete IL-5
- 49. ATS/ERS Guidelines for FeNO Measurement American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med. 2005;171(8):912-930. NPO x 2 hours before No caffeine Hold BDs x 6 hours ATS & ERS FeNO GUIDELINES Use of NO free air (< 5ppb) for inhalation 1999 ATS statement recommended a flow rate of 50 mL/second Exhalation against expiratory resistance
- 50. Guide to interpretation of FENO values in patients with Airway Disease FENO Low Normal Intermediat e High Eozinofilik inflamasyo n unlikely unlikely Present but mild Significant < 5ppb 5-25ppb 25-50ppb > 50ppb Consider: Smoker Children -PCD CF If symptomatic review diagnosis If asymptomatic and on treatment Patient Interpretation based on clinical presentation Symptomatic patients likely to respond to anti-inflammatory treatment If on ICS Check compliance Consider allergen load, imminent exacerbationThorax 2006
- 51. eNO in Asthma ◼ Extensively investigated biomarker for asthma. ◼ Noninvasive ◼ Reproducibility ◼ Correlate with other markers of disease activity ◼ sputum eosinophil count ◼ airway hyperresponsiveness ◼ bronchodilator response ◼ asthma symptoms
- 52. eNO in COPD ◼ Lower than asthma (either smoking or nonsmoking) - not different from normal subjects ◼ Smoking – downregulation of eNOS ◼ increased oxidative stress that may consume NO in the formation of peroxynitrite ◼ unstable COPD - high NO compared with stable COPD - increased neutrophilic inflammation - oxidant/antioxidant imbalance
- 53. eNO in COPD ◼ İncreased in exacerbations ◼ Pulmonary hypertension – cor pulmonale - impaired endothelial NO release - low eNO ◼ COPD patients who response to corticosteroids (those are likely to have coexistent asthma) have an increased eNO. ◼ eNO may be useful in predicting which patients with COPD will respond to long-term inhaled corticosteroid treatment.
- 54. Primary Ciliary Dyskinesia (PCD) ◼ There are three known conditions with reduced airway NO concentrations: ◼ PCD, first demonstrated by LUNDBERG et al. ◼ Cystic fibrosis (CF) ◼ Systemic sclerosis with pulmonary hypertension ◼ NO is thought to be involved in both the regulation of ciliary motility and host defence.
- 57. Am. J. Respir. Cell Mol. Biol. Vol. 24, pp. 414–418, 2001 Immunohistochemical immunoreactivity for NOSIII antibody. (A) LAM smooth-muscle cells have diffuse moderate staining for NOSIII (L) similar to the adjacent bronchial smooth muscle (B) and endothelium (arrow) (Hematoxylin counterstain; original magnification, 320). (B) LAM smooth-muscle cells (L), bronchiolar smooth muscle (B), and endothelium of multiple vessels (arrows) have immunoreactivity to NOSIII (hematoxylin; original magnification, 340). (C) LAM smooth-muscle cells (L) and adjacent endothelium (arrow) have immunoreactivity to NOSIII (hematoxylin; original magnification, 3200).
- 59. 72
- 60. 73
- 61. Exhaled nitric oxide (FeNO) FeNO is becoming more widely available in some countries All sections on FeNO have been reviewed and updated Decisions about initial asthma treatment GINA recommends at least low dose ICS in almost all patients with asthma, to reduce risk of asthma exacerbations and death SABA-only treatment considered only if symptoms < twice/month, no night waking, and no risk factors for exacerbations In non-smoking patients, FeNO >50 ppb is associated with a good short-term response to ICS in symptoms and lung function There are no studies examining the long-term safety (i.e. for risk of exacerbations) of withholding ICS if initial FeNO is low In patients with a diagnosis or suspected diagnosis of asthma, FeNO can support the decision to start ICS, but cannot safely be recommended for deciding against treatment with ICS What’s new in GINA 2018?
- 62. Exhaled nitric oxide (FeNO) FeNO-guided treatment Updated to reflect new meta-analyses (Petsky Cochrane 2016;Petsky Cochrane 2016) that separately analyzed studies in which the control algorithm was reasonably close to current clinical recommendations, and therefore provided a clinically relevant comparator Children/adolescents: FENO-guided treatment was associated with significantly fewer exacerbations and lower exacerbation rate than treatment based on current guidelines Adults: no significant difference in exacerbations with FENO-guided treatment compared with treatment based on current guidelines FeNO-guided treatment is not recommended for the general asthma population at present Further studies are needed to identify the populations most likely to benefit, and the optimal frequency of monitoring What’s new in GINA 2018?
- 63. Exhaled nitric oxide (FeNO) In children ≤5 years with recurrent coughing and wheezing Elevated FeNO recorded >4 weeks from any URTI predicts physician- diagnosed asthma at school age (Singer 2013) Elevated FeNO at age 4 increases the odds for wheezing, physician- diagnosed asthma and ICS use by school age, independent of clinical history and presence of specific IgE (Caudri JACI 2010) What’s new in GINA 2018?
- 64. Type 2 inflammation plays an important role in the pathogenesis of asthma1-3 IL-4 and IL-13 activate multiple cell types and induce multiple mediators involved in inflammation—contributing to airflow limitation and increasing the risk of severe exacerbations1-3
- 65. FeNO (a marker of lung inflammation) Up to 35% reduction from baseline TOTAL AND ALLERGEN-SPECIFIC IgE Up to 70% reduction in total IgE from baseline EOSINOPHILIC LUNG INFLAMMATION despite the presence of normal or increased blood eosinophil levels
- 68. Prevalence of oral corticosteroid use in the German severe asthma population ChristianTaube, Peter Bramlage,Annette Hofer, DörteAnderson ERJ Open Research 2019 5: 00092-2019;DOI: 10.1183/23120541.00092-2019
- 70. Medicine Published in Clinical andTranslational… 2013 DOI:10.1186/2045-7022-3-37 Using fractional exhaled nitric oxide (FeNO) to diagnose steroid- responsive disease and guide asthma management in routine care David B Price, Dermot P Ryan, +8 authors MikeThomas BackgroundFractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation and good predictor of corticosteroid response.AimTo evaluate how FeNO is being used to guide primary care asthma management in the United Kingdom (UK) with a view to devising practical algorithms for the use of FeNO in the diagnosis of steroid-responsive disease and to guide on-going asthma management.MethodsEligible patients (n = 678) were those in the Optimum Patient Care Research… CONTINUE READING
- 71. Severe Asthma: UpdatedTherapy Approach Based on Phenotype and Biomarker Marcia Regina Piuvezam, Laércia Karla Diega Paiva Ferreira,Talissa Mozzini Monteiro, Giciane CarvalhoVieira and Claudio Roberto Bezerra-Santos © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
- 72. FIGURE 3.Traditional and personalized approaches to treating asthma. FeNO, Fractional exhaled nitric oxide; Hx, history; ICS, inhaled corticosteroid; IgE, immunoglobulin E, LABA, long-acting b-agonist; LTRA, leukotriene receptor antagonist; SABA, short-acting bagonist.Adapted with permission from Dunn et al.96 Changing Paradigms in theTreatment of Severe Asthma:The Role of BiologicTherapies 2017American Academy of Allergy,Asthma & Immunology (J Allergy Clin Immunol Pract 2017;5:S1-S14) Rohit K. Katial, MDa , GregW. Bensch, MDb ,WilliamW. Busse, MDc , Bradley E. Chipps, MDd , Joshua L. Denson, MDe,f ,Anthony N. Gerber, MD, PhDe,g , Joshua S. Jacobs, MDh , Monica Kraft, MDi , Richard J. Martin, MDj , Parameswaran Nair, MD, PhD, FRCP, FRCPCk , and Michael E. Wechsler, MDe Denver,Aurora, Colo; Stockton, Sacramento,Walnut Creek, Calif; Madison,Wis;Tucson,Ariz; and Hamilton, Ontario, Canada
- 73. In clinical trials of mAb treatment, elevated FeNO levels were predictive of response to benralizumab (anti-IL-5Ra; ≥50ppb, in combination with elevated peripheral blood eosinophils) (10), omalizumab (anti-IgE; ≥19.5 ppb) (11) and lebrikizumab (anti-IL-13; ≥30 ppb) (12, 13) (reviewed in (1)). FeNO levels were reduced following treatment with lebrikizumab (12-14) or dupilumab (15, 16) (reviewed in (1), however mAbs targeting the IL-5 pathway (e.g. mepolizumab, benralizumab) do not suppress FeNO levels (17). STUDI SU DUPILUMAB E FENO?????
- 78. Three-step algorithm for biological therapy targeted IgE and IL-5 in severe asthma Keiji Oishi 1 & Kazuto Matsunaga2 1 Department of Medicine and Clinical Science, Graduate School of Medicine,Yamaguchi University, Ube,Yamaguchi, Japan 2 Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine,Yamaguchi University, Ube,Yamaguchi, Japan Immunity,Inflammation and Disease (2018)
- 100. Prescribing and medicines optimisation issues Guidance published November 2017 Asthma: diagnosis, monitoring and chronic asthma management NICE guideline NG80
- 101. Terms used (1) Sensitivity How good the test is at correctly identifying people who have the condition If a test has 90% sensitivity It correctly identifies 9 in every 10 people who have the condition true positives It fails to identify 1 in every 10 people who have the condition false negatives 114
- 102. Terms used (2) Specificity How good the test is at correctly identifying people who don’t have the condition If a test has 90% specificity It correctly identifies 9 in every 10 people who don’t have the condition true negatives It misidentifies 1 in every 10 people don’t have the condition false positives 115
- 103. No diseasePercent of population Level (arbitrary units) Disease 100% sensitive: no false negatives (but lots of false positives) −ve Minimum number of false positives and false negatives 100% specific: no false positives (but lots of false negatives) +ve−ve +ve −ve +ve
- 104. The FeNO test (1) • Nitric oxide is produced in the lungs and is present in exhaled breath • It acts as a vasodilator, bronchodilator, neurotransmitter and inflammatory mediator in the lungs and airways • Fractional exhaled nitric oxide (FeNO) is a non-invasive marker of airway inflammation in people with asthma • FeNO levels are raised in people with eosinophilic asthma, which may respond to treatment with corticosteroids • Neutrophilic asthma generally does not respond to corticosteroids NICE diagnostic guidance DG12 (2014) 117
- 105. The FeNO test (2) • 2 FeNO tests are available: NIOX Vero and NObreath • Be aware that the results of spirometry and FeNO tests may be affected in people who have been treated empirically with inhaled corticosteroids • Be aware that a person’s current smoking status can lower FeNO levels both acutely and cumulatively. However, a high level remains useful in supporting a diagnosis of asthma NICE diagnostic guidance DG12 (2014), NICE NG80 recommendations 1.1.7, 1.3.4 118
- 106. Objective tests recommended in the guideline (1) • Spirometry • Offer to everyone aged 5 and over • Bronchodilator reversibility (BDR) • Offer to adults with obstructive spirometry and consider in children and young people with obstructive spirometry • Fractional exhaled nitric oxide (FeNO) • Offer to adults (people aged 17 and over) • Consider for children and young people (aged 5–16) if there is diagnostic uncertainty: see guideline Section 1.3 119
- 107. No diseasePercent of population FeNO level 40 ppb or more =positive (adults) 35 ppb or more =positive (children and young people) Disease 100% sensitive: no false negatives (but lots of false positives) −ve Minimum number of false positives and false negatives 100% specific: no false positives (but lots of false negatives) +ve−ve +ve −ve +ve
- 108. Diagnosis in adults (1) Order of tests • Measure FeNO first followed by spirometry • Carry out a bronchodilator reversibility (BDR) test if spirometry shows an obstruction • If diagnostic uncertainty remains after FeNO, spirometry and BDR, monitor peak flow variability for 2–4 weeks • If diagnostic uncertainty remains after measuring peak flow variability, refer for a histamine or methacholine direct bronchial challenge test • If this test is unavailable suspect asthma and review diagnosis after treatment Recommendations 1.3.18–1.3.20, Algorithm C 121
- 109. Using objective tests to monitor asthma • Consider using a validated questionnaire (for example, the Asthma Control Questionnaire or Asthma Control Test) to monitor asthma control in adults • Monitor asthma control at each review in adults, young people and children aged 5 and over using either spirometry or peak flow variability testing • Do not routinely use FeNO to monitor asthma control • Consider FeNO measurement as an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids • Do not use challenge testing to monitor asthma control Recommendations 1.14.2–1.14.6 122
- 110. Diagnostic accuracy of FeNO • The sensitivity and specificity of FeNO in adults was high • In children and young people, FeNO had a moderate sensitivity in 1 study and high sensitivity in the other with high specificity in both • FeNO had the best diagnostic accuracy of all the tests that can be conducted in primary care. • The GC agreed that FeNO should appear in every diagnostic pathway as it would be pivotal in making a diagnosis Full guideline page 148 123
- 111. Asthma - diagnosis and monitoring guideline: primary care implementation feasibility project update Adoption & Impact Programme, NICE: Sally Chisholm, Programme Director Jennifer Watts, Associate Director Heather Stephens, Project lead 3rd June 2016 Trade-off between clinical benefits and harms The FeNO test can be performed in around 10 minutes and can be performed within primary care. The sensitivity and specificity of FeNO in adults was high, with the exception of one study with a moderate specificity (cut-off >36ppb70) and one study with a low sensitivity(cut-off >30ppb191). In children/young people, FeNO had a moderate sensitivityin one study197 and high sensitivity in the other163 with high specificity in both. Economic considerations No economic evaluations were included which assessed the use of FeNO as part of a diagnostic pathway. Therefore, an original health economic model was built to assess the cost-effectiveness of different diagnostic pathways for asthma. The model assessed the additional costs of tests against cost-savings from unnecessary asthma medication, and the increased health outcomes from providing correct treatment. FeNO had the best diagnostic accuracy out of all the tests that can be conducted in primary care. Due to this the GC agreed that FeNO should appear in every diagnostic pathway as it would be pivotal in making a diagnosis. In the model, strategies that gave FeNO to all patients in the pathway dominated the strategies that did not. Therefore FeNO is a highly cost-effective component of the diagnostic algorithm. The most cost-effective strategy involved using spirometry, bronchodilator reversibility (BDR), FeNO, peak expiratory flow variability (PEFv) and a methacholine challenge test (MCT) in selected individuals to diagnose asthma. In this strategy, everybody with symptoms of asthma would undergo a spirometry test and a FeNO test, those who had an obstructive spirometry would also receive a BDR test. Only those who had non-obstructive spirometry and conflicting FeNO and PEFv test results would receive a MCT. Adopting this strategy dominated all other strategies apart from those which performed challenge tests at more points in the pathway. The ICERs of adopting these further strategies were above £20,000 per QALY gained. In a sensitivity analysis when the cost of FeNO increased above £93 none of the diagnostic strategies were cost-effective at a £20,000 per QALY threshold and therefore current practice became the most cost-effective strategy. If the cost of FeNO was £93 then the cost-effective ranking of strategies remained unchanged. For the marginal cost of FeNO to rise to £93 the machine would only be used approximately 28 times in a 5 year time span. The GC noted that even for small GP practices under the most conservative assumptions of the number of new diagnoses made each year, this level of use would still be attainable. In children the GC recognised FeNO as having considerable value in a diagnostic pathway as it can be performed at a low cost and the clinical evidence showed it had a high specificity.Apart from children who produce a positive bronchodilator reversibility result, the GC considered that FeNO measurements would add value to all other points in the pathway. The GC noted that as not all children would receive a FeNO test the average unit cost of including FeNO in the proposed diagnostic algorithm would be less.
- 112. Economic considerations for FeNO • The recommended strategy (FeNO + spirometry ± BDR and, when there are conflicting results, PEFv and MCT) dominated all other strategies apart from those which performed challenge tests at more points in the pathway • The ICERs of adopting these further strategies were above £20,000 per QALY gained • Depends on the cost of FeNO being £93 or less • For the marginal cost of FeNO to rise to £93 the machine would only be used approximately 28 times in a 5 year time span • The GC noted that even for small GP practices under the most conservative assumptions of the number of new diagnoses made each year, this level of use would still be attainable Full guideline pages 148–149 125
- 113. Asthma - diagnosis and monitoring guideline: primary care implementation feasibility project update Adoption & Impact Programme, NICE: Sally Chisholm, Programme Director Jennifer Watts, Associate Director Heather Stephens, Project lead 3rd June 2016 16.6 Recommendations and link to evidence The FeNO test can be performed in around 10 minutes and can be performed within primary care. The sensitivity and specificity of FeNO in adults was high, with the exception of one study with a moderate specificity (cut-off >36ppb70) and one study with a low sensitivity (cut-off >30ppb191). In children/young people, FeNO had a moderate sensitivity in one study197 and high sensitivity in the other163 with high specificity in both. Economic considerations No economic evaluations were included which assessed the use of FeNO as part of a diagnostic pathway. Therefore, an original health economic model was built to assess the cost-effectiveness of different diagnostic pathways for asthma. The model assessed the additional costs of tests against cost-savings from unnecessary asthma medication, and the increased health outcomes from providing correct treatment. FeNO had the best diagnostic accuracy out of all the tests that can be conducted in primary care. Due to this the GC agreed that FeNO should appear in every diagnostic pathway as it would be pivotal in making a diagnosis. In the model, strategies that gave FeNO to all patients in the pathway dominated the strategies that did not. Therefore FeNO is a highly cost-effective component of the diagnostic algorithm. The most cost-effective strategy involved using spirometry, bronchodilator reversibility (BDR), FeNO, peak expiratory flow variability (PEFv) and a methacholine challenge test (MCT) in selected individuals to diagnose asthma. In this strategy, everybody with symptoms of asthma would undergo a spirometry test and a FeNO test, those who had an obstructive spirometry would also receive a BDR test. Only those who had non- obstructive spirometry and conflicting FeNO and PEFv test results would receive a MCT. Adopting this strategy dominated all other strategies apart from those which performed challenge tests at more points in the pathway. The ICERs of adopting these further strategies were above £20,000 per QALY gained. In a sensitivity analysis when the cost of FeNO increased above £93 none of the diagnostic strategies were cost-effective at a £20,000 per QALY threshold and therefore current practice became the most cost-effective strategy. If the cost of FeNO was £93 then the cost-effective ranking of strategies remained unchanged. For the marginal cost of FeNO to rise to £93 the machine would only be used approximately 28 times in a 5 year time span. The GC noted that even for small GP practices under the most conservative assumptions of the number of new diagnoses made each year, this level of use would still be attainable. In children the GC recognised FeNO as having considerable value in a diagnostic pathway as it can be performed at a low cost and the clinical evidence showed it had a high specificity. Apart from children who produce a positive bronchodilator reversibility result, the GC considered that FeNO measurements would add value to all other points in the pathway. The GC noted that as not all children would receive a FeNO test the average unit cost of including FeNO in the proposed diagnostic algorithm would be less.
- 114. Practical considerations for FeNO • A project was conducted to assess the impact and feasibility of adopting the diagnostic tests (e.g. FeNO and spirometry) recommended, into primary care • The main barrier to implementation cited was the cost of the device and consumables rather than the practicality or accuracy of the test • The project cited positive feedback for the FeNO machine with very good patient compliance • All sites agreed that the device was easy to use and training was not lengthy (less than for spirometry) • Moreover, fewer patients were unable to complete FeNO measurement than spirometry Full guideline pages 149–151 127
- 115. 16.6 Recommendationsand link to evidence Other considerations Details of the feasibility project are available in appendix Q. The aim of the feasibility project was to assess the impact and feasibility of adopting the diagnostic tests (e.g. FeNO and spirometry) recommended, into primary care. General concerns Firstly it was recognised that children may not be able to perform some of the tests. An additional recommendation has now been made which informs the clinician what to do should this problem arise. The GC agreed that objective testing was imperative before a diagnosis of asthma could be made however, before objective testing is possible, symptoms should be treated and monitored. Secondly the feasibility report identified that in the current format the diagnostic algorithms could be difficult to follow in some places. Therefore the GC agreed a new format should be designed that would simplify the algorithm and make them easier to interpret. Concerns specific to FeNO From the feasibility project results, the main barrier to implementation was cited as the cost of the device and consumables rather than the practicality or accuracy of the test. The project cited positive feedback for the FeNO machine with very good patient compliance. All sites agreed that the device was easy to use and training was not lengthy (less than for spirometry). Moreover, fewer patients were unable to complete FeNO measurement than spirometry (5 vs 9). Moving forward, the GC considered that the use of diagnostic hubs could help alleviate the issue of cost as the cost of the machine would only need to be incurred once. Likewise there are economies of scale that arise through bulk purchasing of the consumables. It was considered that this would reduce costs and improve the practicality of implementing the algorithm. A recommendation was developed, aimed at clinical commissioners, to consider establishing asthma diagnostic hubs to achieve economies of scale in implementing the diagnostic algorithms (see section 21.2). Following completion of the feasibility project in October 2016, results of the updated searches in 2017 are available in appendix R. One study was identified which the GC agreed did not suggest a change in the recommendations was warranted.
- 116. Phased implementation (1) NICE is recommending objective testing with spirometry and FeNO for most people with suspected asthma; a significant enhancement to current practice, which will take the NHS some time to implement, with additional infrastructure and training needed in primary care New models of care, being developed locally, could offer the opportunity to implement these recommendations.This may involve establishing diagnostic hubs to make testing efficient and affordable.They will be able to draw on the positive experience of NICE’s primary care pilot sites, which trialled the use of FeNO Full guideline pages 14 and 15 129