- Email: [email protected]
Measurement of nasal nitric oxide
PAEDIATRIC RESPIRATORY REVIEWS (2007) 8, 269–272
PRACTICAL PROCEDURES: PULMONARY FUNCTION TESTING
Measurement of nasal nitric oxide Regula Corbelli1,* and Ju¨rg Hammer2 1
University Children’s Hospital, Geneva, Switzerland; 2Division of Intensive Care and Pulmonology, University Children’s Hospital, Basel, Switzerland KEYWORDS nasal nitric oxide; primary ciliary dyskinesia
Summary Nasal nitric oxide (nNO) is produced in high quantity in the upper airways. It is thought to be involved in host defence functions and regulation of mucociliary function, and to serve as a biochemical airborne transmitter. The measurement of nNO is easy and non-invasive. It has evolved as a screening test to exclude primary ciliary dyskinesia (PCD) in patients with suggestive symptoms, because nNO is extremely low in this condition. Nasal NO is also altered in other nasal, sinus and pulmonary pathologies, but is without diagnostic value outside of PCD. ß 2007 Elsevier Ltd. All rights reserved.
INTRODUCTION
alteration in nasal cavity volume. Swelling of the mucosa or secretions may block the passage of NO from the sinuses to the nasal cavity and affects its measurement.
Nitric oxide (NO) originating from the upper and lower airways has been studied and measured since the late 1980s. It is produced enzymatically from l-arginine by a family of constitutive and inducible NO synthases found in the respiratory epithelium, nerve fibres, seromucous glands and endothelial cells of capillaries and arterial vessels. The inducible isoform is upregulated by inflammation, including in allergy and infection. The main source of nasal NO (nNO) is the mucosa of the paranasal sinuses. Nasal NO concentrations are over 100-fold higher relative to those measured in lower airways, with highest levels up to several 1000 parts per billion in the paranasal sinuses. The physiological function of nNO remains only partially understood but it is thought to play a role in local host defence by its antimicrobial action, in the regulation of ciliary motility,1 and as an airborne messenger to the lungs, regulating bronchial tone and pulmonary vascular resistance.2 Nasal NO production and absorption is modified by alterations in nasal blood flow and/or volume and by * Corresponding author. University Children’s Hospital Geneva, Rue Willy-Donze´ 6, CH-1211 Geneva 14, Switzerland. Tel.: +41 22 372 98 92; Fax: +41 22 382 47 79. E-mail address: [email protected] (R. Corbelli). 1526-0542/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2007.07.007
MEASUREMENT OF NASAL NITRIC OXIDE Methods Measuring nNO means measuring NO concentration in the upper, supravelar airways, which include the nasal cavities, paranasal sinuses, middle ear and nasopharynx. Velum closure is required to exclude contamination with air rising from the lower respiratory tract. Nasal NO is usually measured by chemiluminescence based on the reaction of NO with O3, resulting in the emission of light. Alternatives include luminol-/H2O2-based chemiluminescence, tunable diode laser absorption spectrometry and laser magnetic resonance spectroscopy. The fractional concentration of nNO is expressed in parts per billion (ppb) and is termed nasal FENO. Nasal NO output equals nNO exhaled per time unit and is termed nasal V˙ NO . It is calculated by the product of NO concentration in nanolitres per litre and the expiratory/aspiratory flow rate in litres per minute corrected to BTPS (body temperature and pressure, saturated).
270
R. CORBELLI, AND J. HAMMER
The recommended and most validated method for measuring nasal NO is with the subject seated.3 A nasal olive with a central lumen is placed in the naris and air is aspired by a fixed and constant flow rate in the range of 0.25–3 L/min (transnasal flow rate) by a suction pump with air entrained via the other naris. A side port samples gas for NO analysis. With the targeted aspiration rate a steady plateau level of NO concentration will be obtained within 10(20)–30 s. Transnasal flow rate should be recorded because the fractional NO concentration is inversely related to transnasal flow rate. Slow oral exhalation against a resistance of at least 10 cmH2O is the preferred method to obtain velum closure, but any other reliable method such as breath holding is acceptable. Velum closure should always be confirmed by capnography to ensure that the measurement of nNO is not influenced by air from the lower airways. It has been suggested that the highest peak value should be recorded in infants and children unable to perform velum closure and to achieve a steady plateau level.4 This technique still awaits validation in a large infant population. Another method to measure nNO is by nasal exhalation (via one or both nasal cavities) into a tight face mask covering the nose. A dynamic flow resistor together with a visual computerized feedback display is necessary to achieve a fixed flow rate. This method has been used to measure nNO during humming.5
Normal values Normal values for nNO have been reported by several authors, mostly for small groups of healthy children.6–9 Values are difficult to compare as different measurement techniques and transnasal flow rates have been used in these studies (Table 1). The largest group of 289 healthy children has been examined by Struben et al using a transnasal flow rate of 0.7 L/min. Average values for
nNO in adults and children were between 200 and 800 ppb.10,11 They were found to be independent of sex, height, weight, body mass index or passive smoking. There was a positive correlation with age in children under 12 years of age and nNO was significantly lower in those with a history of adenoidectomy. Prediction equations were calculated from this large cohort as follows:
Age < 12 years: nNO (ppb) = 314.6 + 11.5 age (years) 57.5 adenoidectomy (yes = 1, no = 0) + 0.5 ambient NO (ppb) Age 12 years: nNO (ppb) = 452.6 2.9 (age 12) 16 adenoidectomy (yes = 1, no = 0) + 0.5 ambient NO (ppb) High nNO values in the range of 100–200 ppb have also been reported in newborns despite their poorly developed and only partially pneumatized paranasal sinuses.4
Factors influencing measurements During humming, nNO increases 5–15-fold compared with silent nasal exhalation.5 It is thought that humming increases NO influx from the paranasal sinuses to the nasal cavity. The effect diminishes after repeated humming manoeuvres. The increase of nNO during humming indicates patency of the ostiomeatal complex and does not occur in patients with obstructed sinuses or nasal polyps.17 Ambient NO affects the measurement of nNO disproportionally, especially if its concentration is higher than 20 ppb.10 Hence, ambient NO should always be recorded and a clean air source is preferable when ambient NO is high. It is recommended not to do any exercise for 1 h before the measurement, since this may diminish nNO concentration. Diurnal variations in nNO concentrations
Table 1 Normal values for nasal NO in paediatric patients Study
n
Age (years)a
Technique
Aspiration flow rate (L/min)
NO concentration (ppb)a
Struben et al. 10 Baraldi et al. 12 Balfour-Lynn et al. 13 Narang et al. 7 Do¨tsch et al. 14 Corbelli et al. 9 Karadag et al. 6 Lundberg et al. 15 Kharitonov et al. 16 Stehling et al. 17 Baraldi et al. 4
289 133 54 53 37 24 20 19 8 6 5
(6–17) (6–15) 12.2 (6–17) 10.7 (5.5–19) (4–18) 12.4 (4.5–24) 10.8 (5–15) 12.2 (6.1–15.6) Term newborns 2–24 days 0.3 (1–7 months)
Breath hold Tidal breathing Breath hold Breath hold Tidal breathing Breath hold Breath hold Tidal breathing Breath hold Tidal breathing Tidal breathing
0.7 0.7 0.25 0.25 0.7 1.2 0.25 0.7 0.3 ? 0.11
449 (SD 115) 216 (95% CI 204–228) 1024 (158–2502) 716 (398–1437) 101 (SD 49) 223.7 (90–950) 553 (116–1437) 239 (SD 20) 843 (SD 152) 171.2 (100–232) 295 (225–379)
a
Data represents mean or median with the range in parentheses except where stated otherwise.
MEASUREMENT OF NASAL NITRIC OXIDE
271
Table 2 Cut-off levels, sensitivity and specificity of nasal NO concentrations in discriminating between patients with PCD and nonPCD bronchiectasis Study
Aspiration flow rate (L/min)
Cut-off level (ppb)
Sensitivity (%)
Specificity (%)
Horvath et al. 24 Narang et al. 7 Corbelli et al. 9
0.25 0.25 1.2
187 250 105
93 97 94
95 90 88
have been reported18 with daytime awake NO output being greater than NO output at night during sleep.19 Nasal decongestants containing alpha-2 agonists also decrease nNO.
DIAGNOSTIC VALUE Primary ciliary dyskinesia (PCD) is the only disease for which nNO is known to have a clear diagnostic value. Nasal NO concentrations are extremely low in patients with PCD, usually lower than 2–10% of normal.20,21 Nasal NO concentrations also discriminate PCD patients from patients with any other type of bronchiectasis.6-9 Such low values were even reported in infants with proven PCD.4,22 NO plays a role in signal transduction associated with ciliary function, but the pathomechanism for the low nNO in PCD is unclear. It is unrelated to the type of ultrastructural ciliary defect.23 Patients with suggestive symptoms and very low nNO concentrations have to be considered for further, usually more invasive, diagnostic work-up. High nNO levels exclude PCD with a high sensitivity and specificity (Table 2). Cut-off values have to be established by each lab according to the method used. Although low nNO concentrations have been reported in other respiratory diseases, such as cystic fibrosis and nonPCD bronchiectasis,24 nNO has no diagnostic value in these conditions.25 The same applies for all disorders of the upper airways such as allergic rhinitis,26,27 or chronic sinusitis and nasal polyposis where nNO is also low due to blockage of the ostiomeatal complex.28,29
REFERENCES 1. Alberty J, Stoll W, Rudack C. The effect of endogenous nitric oxide on mechanical ciliostimulation of human nasal mucosa. Clin Exp Allergy 2006; 36: 1254–1259. 2. Lundberg JO, Settergren G, Gelinder S, Lundberg JM, Alving K, Weitzberg E. Inhalation of nasally derived nitric oxide modulates pulmonary function in humans. Acta Physiol Scand 1996; 158: 343– 347. 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: 912–930. 4. Baraldi E, Pasquale MF, Cangiotti AM, Zanconato S, Zacchello F. Nasal nitric oxide is low early in life: case study of two infants with primary ciliary dyskinesia. Eur Respir J 2004; 24: 881–883. 5. Weitzberg E, Lundberg JO. Humming greatly increases nasal nitric oxide. Am J Respir Crit Care Med 2002; 166: 144–145.
6. Karadag B, James AJ, Gultekin E, Wilson NM, Bush A. Nasal and lower airway level of nitric oxide in children with primary ciliary dyskinesia. Eur Respir J 1999; 13: 1402–1405. 7. Narang I, Ersu R, Wilson NM et al. Nitric oxide in chronic airway inflammation in children: diagnostic use and pathophysiological significance. Thorax 2002; 57: 586–589. 8. Daya H, Qian W, McClean P et al. Nasal nitric oxide in children: a novel measurement technique and normal values. Laryngoscope 2002; 112: 1831–1835. 9. Corbelli R, Bringolf-Isler B, Amacher A, Sasse B, Spycher M, Hammer J. Nasal nitric oxide measurements to screen children for primary ciliary dyskinesia. Chest 2004; 126: 1054–1059. 10. Struben VM, Wieringa MH, Mantingh CJ et al. Nasal NO: normal values in children age 6 through to 17 years. Eur Respir J 2005; 26: 453– 457. 11. Struben VM, Wieringa MH, Mantingh CJ, Bruinsma SM, de Jongste JC, Feenstra L. Silent and humming nasal NO measurements in adults aged 18–70 years. Eur J Clin Invest 2005; 35: 653–657. 12. Baraldi E, Azzolin NM, Cracco A, Zacchello F. Reference values of exhaled nitric oxide for healthy children 6–15 years old. Pediatr Pulmonol 1999; 27: 54–58. 13. Balfour-Lynn IM, Laverty A, Dinwiddie R. Reduced upper airway nitric oxide in cystic fibrosis. Arch Dis Child 1996; 75: 319–322. 14. Do¨tsch J, Demirakca S, Terbrack HG, Huls G, Rascher W, Kuhl PG. Airway nitric oxide in asthmatic children and patients with cystic fibrosis. Eur Respir J 1996; 9: 2537–2540. 15. Lundberg JON, Nordvall SL, Weitzberg E, Kollberg H, Alving K. Exhaled nitric oxide in paediatric asthma and cystic fibrosis. Arch Dis Child 1996; 75: 323–326. 16. Kharitonov SA, Walker L, Barnes PJ. Repeatability of standardised nasal nitric oxide measurements in healthy and asthmatic adults and children. Respir Med 2005; 99: 1105–1114. 17. Maniscalco M, Sofia M, Weitzberg E et al. Humming-induced release of nasal nitric oxide for assessment of sinus obstruction in allergic rhinitis: pilot study. Eur J Clin Invest 2004; 34: 555–560. 18. Stark H, Purokivi M, Kiviranta J, Randell J, Tukiainen H. Short-term and seasonal variations of exhaled and nasal NO in healthy subjects. Respir Med 2007; 101: 265–271. 19. O’Hearn DJ, Giraud GD, Sippel JM, Edwards C, Chan B, Holden WE. Exhaled nasal nitric oxide output is reduced in humans at night during the sleep period. Respir Physiol Neurobiol 2007; 156: 94–101. 20. Lundberg JO, Weitzberg E, Nordvall SL, Kuylenstierna R, Lundberg JM, Alving K. Primarily nasal origin of exhaled nitric oxide and absence in Kartagener’s syndrome. Eur Respir J 1994; 7: 1501–1504. 21. Silkoff PE. Nasal nitric oxide: clue to a diagnosis of ciliary dyskinesia. Chest 2004; 126: 1013–1014. 22. Stehling F, Roll C, Ratjen F, Grasemann H. Nasal nitric oxide to diagnose primary ciliary dyskinesia in newborns. Arch Dis Child Fetal Neonatal Ed 2006; 91: F233. 23. Noone PG, Leigh MW, Sannuti A et al. Primary ciliary dyskinesia. Diagnostic and phenotypic features. Am J Respir Crit Care Med 2004; 169: 459–467. 24. Horvath I, Loukides S, Wodehouse T et al. Comparison of exhaled and nasal nitric oxide and exhaled carbon monoxide levels in bronchiectatic patients with and without primary ciliary dyskinesia. Thorax 2003; 58: 68–72.
272
25. Struben VMD, Sewbalak WV, Wieringa MH et al. Nasal nitric oxide in cystic fibrosis with and without humming. Eur J Clin Invest 2007; 37: 140–144. 26. Kharitonov SA, Rajakulasingam K, O’Connor B, Durham SR, Barnes PJ. Nasal nitric oxide is increased in patients with asthma and allergic rhinitis and may be modulated by nasal glucocorticoids. J Allergy Clin Immunol 1997; 99: 58–64.
R. CORBELLI, AND J. HAMMER
27. Struben VMD, Wieringa MH, Feenstra L, de Jongste JC. Nasal nitric oxide and nasal allergy. Allergy 2006; 61: 665–670. 28. Colantonio D, Brouillette L, Parikh A, Scadding GK. Paradoxical low nasal nitric oxide in nasal polyposis. Clin Exp Allergy 2002; 32: 698–701. [29]. Ragab SM, Lund VJ, Saleh HA, Scadding G. Nasal nitric oxide in objective evaluation of chronic rhinosinusitis therapy. Allergy 2006; 61: 717–724.
PRACTICAL PROCEDURES: PULMONARY FUNCTION TESTING
Measurement of nasal nitric oxide Regula Corbelli1,* and Ju¨rg Hammer2 1
University Children’s Hospital, Geneva, Switzerland; 2Division of Intensive Care and Pulmonology, University Children’s Hospital, Basel, Switzerland KEYWORDS nasal nitric oxide; primary ciliary dyskinesia
Summary Nasal nitric oxide (nNO) is produced in high quantity in the upper airways. It is thought to be involved in host defence functions and regulation of mucociliary function, and to serve as a biochemical airborne transmitter. The measurement of nNO is easy and non-invasive. It has evolved as a screening test to exclude primary ciliary dyskinesia (PCD) in patients with suggestive symptoms, because nNO is extremely low in this condition. Nasal NO is also altered in other nasal, sinus and pulmonary pathologies, but is without diagnostic value outside of PCD. ß 2007 Elsevier Ltd. All rights reserved.
INTRODUCTION
alteration in nasal cavity volume. Swelling of the mucosa or secretions may block the passage of NO from the sinuses to the nasal cavity and affects its measurement.
Nitric oxide (NO) originating from the upper and lower airways has been studied and measured since the late 1980s. It is produced enzymatically from l-arginine by a family of constitutive and inducible NO synthases found in the respiratory epithelium, nerve fibres, seromucous glands and endothelial cells of capillaries and arterial vessels. The inducible isoform is upregulated by inflammation, including in allergy and infection. The main source of nasal NO (nNO) is the mucosa of the paranasal sinuses. Nasal NO concentrations are over 100-fold higher relative to those measured in lower airways, with highest levels up to several 1000 parts per billion in the paranasal sinuses. The physiological function of nNO remains only partially understood but it is thought to play a role in local host defence by its antimicrobial action, in the regulation of ciliary motility,1 and as an airborne messenger to the lungs, regulating bronchial tone and pulmonary vascular resistance.2 Nasal NO production and absorption is modified by alterations in nasal blood flow and/or volume and by * Corresponding author. University Children’s Hospital Geneva, Rue Willy-Donze´ 6, CH-1211 Geneva 14, Switzerland. Tel.: +41 22 372 98 92; Fax: +41 22 382 47 79. E-mail address: [email protected] (R. Corbelli). 1526-0542/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2007.07.007
MEASUREMENT OF NASAL NITRIC OXIDE Methods Measuring nNO means measuring NO concentration in the upper, supravelar airways, which include the nasal cavities, paranasal sinuses, middle ear and nasopharynx. Velum closure is required to exclude contamination with air rising from the lower respiratory tract. Nasal NO is usually measured by chemiluminescence based on the reaction of NO with O3, resulting in the emission of light. Alternatives include luminol-/H2O2-based chemiluminescence, tunable diode laser absorption spectrometry and laser magnetic resonance spectroscopy. The fractional concentration of nNO is expressed in parts per billion (ppb) and is termed nasal FENO. Nasal NO output equals nNO exhaled per time unit and is termed nasal V˙ NO . It is calculated by the product of NO concentration in nanolitres per litre and the expiratory/aspiratory flow rate in litres per minute corrected to BTPS (body temperature and pressure, saturated).
270
R. CORBELLI, AND J. HAMMER
The recommended and most validated method for measuring nasal NO is with the subject seated.3 A nasal olive with a central lumen is placed in the naris and air is aspired by a fixed and constant flow rate in the range of 0.25–3 L/min (transnasal flow rate) by a suction pump with air entrained via the other naris. A side port samples gas for NO analysis. With the targeted aspiration rate a steady plateau level of NO concentration will be obtained within 10(20)–30 s. Transnasal flow rate should be recorded because the fractional NO concentration is inversely related to transnasal flow rate. Slow oral exhalation against a resistance of at least 10 cmH2O is the preferred method to obtain velum closure, but any other reliable method such as breath holding is acceptable. Velum closure should always be confirmed by capnography to ensure that the measurement of nNO is not influenced by air from the lower airways. It has been suggested that the highest peak value should be recorded in infants and children unable to perform velum closure and to achieve a steady plateau level.4 This technique still awaits validation in a large infant population. Another method to measure nNO is by nasal exhalation (via one or both nasal cavities) into a tight face mask covering the nose. A dynamic flow resistor together with a visual computerized feedback display is necessary to achieve a fixed flow rate. This method has been used to measure nNO during humming.5
Normal values Normal values for nNO have been reported by several authors, mostly for small groups of healthy children.6–9 Values are difficult to compare as different measurement techniques and transnasal flow rates have been used in these studies (Table 1). The largest group of 289 healthy children has been examined by Struben et al using a transnasal flow rate of 0.7 L/min. Average values for
nNO in adults and children were between 200 and 800 ppb.10,11 They were found to be independent of sex, height, weight, body mass index or passive smoking. There was a positive correlation with age in children under 12 years of age and nNO was significantly lower in those with a history of adenoidectomy. Prediction equations were calculated from this large cohort as follows:
Age < 12 years: nNO (ppb) = 314.6 + 11.5 age (years) 57.5 adenoidectomy (yes = 1, no = 0) + 0.5 ambient NO (ppb) Age 12 years: nNO (ppb) = 452.6 2.9 (age 12) 16 adenoidectomy (yes = 1, no = 0) + 0.5 ambient NO (ppb) High nNO values in the range of 100–200 ppb have also been reported in newborns despite their poorly developed and only partially pneumatized paranasal sinuses.4
Factors influencing measurements During humming, nNO increases 5–15-fold compared with silent nasal exhalation.5 It is thought that humming increases NO influx from the paranasal sinuses to the nasal cavity. The effect diminishes after repeated humming manoeuvres. The increase of nNO during humming indicates patency of the ostiomeatal complex and does not occur in patients with obstructed sinuses or nasal polyps.17 Ambient NO affects the measurement of nNO disproportionally, especially if its concentration is higher than 20 ppb.10 Hence, ambient NO should always be recorded and a clean air source is preferable when ambient NO is high. It is recommended not to do any exercise for 1 h before the measurement, since this may diminish nNO concentration. Diurnal variations in nNO concentrations
Table 1 Normal values for nasal NO in paediatric patients Study
n
Age (years)a
Technique
Aspiration flow rate (L/min)
NO concentration (ppb)a
Struben et al. 10 Baraldi et al. 12 Balfour-Lynn et al. 13 Narang et al. 7 Do¨tsch et al. 14 Corbelli et al. 9 Karadag et al. 6 Lundberg et al. 15 Kharitonov et al. 16 Stehling et al. 17 Baraldi et al. 4
289 133 54 53 37 24 20 19 8 6 5
(6–17) (6–15) 12.2 (6–17) 10.7 (5.5–19) (4–18) 12.4 (4.5–24) 10.8 (5–15) 12.2 (6.1–15.6) Term newborns 2–24 days 0.3 (1–7 months)
Breath hold Tidal breathing Breath hold Breath hold Tidal breathing Breath hold Breath hold Tidal breathing Breath hold Tidal breathing Tidal breathing
0.7 0.7 0.25 0.25 0.7 1.2 0.25 0.7 0.3 ? 0.11
449 (SD 115) 216 (95% CI 204–228) 1024 (158–2502) 716 (398–1437) 101 (SD 49) 223.7 (90–950) 553 (116–1437) 239 (SD 20) 843 (SD 152) 171.2 (100–232) 295 (225–379)
a
Data represents mean or median with the range in parentheses except where stated otherwise.
MEASUREMENT OF NASAL NITRIC OXIDE
271
Table 2 Cut-off levels, sensitivity and specificity of nasal NO concentrations in discriminating between patients with PCD and nonPCD bronchiectasis Study
Aspiration flow rate (L/min)
Cut-off level (ppb)
Sensitivity (%)
Specificity (%)
Horvath et al. 24 Narang et al. 7 Corbelli et al. 9
0.25 0.25 1.2
187 250 105
93 97 94
95 90 88
have been reported18 with daytime awake NO output being greater than NO output at night during sleep.19 Nasal decongestants containing alpha-2 agonists also decrease nNO.
DIAGNOSTIC VALUE Primary ciliary dyskinesia (PCD) is the only disease for which nNO is known to have a clear diagnostic value. Nasal NO concentrations are extremely low in patients with PCD, usually lower than 2–10% of normal.20,21 Nasal NO concentrations also discriminate PCD patients from patients with any other type of bronchiectasis.6-9 Such low values were even reported in infants with proven PCD.4,22 NO plays a role in signal transduction associated with ciliary function, but the pathomechanism for the low nNO in PCD is unclear. It is unrelated to the type of ultrastructural ciliary defect.23 Patients with suggestive symptoms and very low nNO concentrations have to be considered for further, usually more invasive, diagnostic work-up. High nNO levels exclude PCD with a high sensitivity and specificity (Table 2). Cut-off values have to be established by each lab according to the method used. Although low nNO concentrations have been reported in other respiratory diseases, such as cystic fibrosis and nonPCD bronchiectasis,24 nNO has no diagnostic value in these conditions.25 The same applies for all disorders of the upper airways such as allergic rhinitis,26,27 or chronic sinusitis and nasal polyposis where nNO is also low due to blockage of the ostiomeatal complex.28,29
REFERENCES 1. Alberty J, Stoll W, Rudack C. The effect of endogenous nitric oxide on mechanical ciliostimulation of human nasal mucosa. Clin Exp Allergy 2006; 36: 1254–1259. 2. Lundberg JO, Settergren G, Gelinder S, Lundberg JM, Alving K, Weitzberg E. Inhalation of nasally derived nitric oxide modulates pulmonary function in humans. Acta Physiol Scand 1996; 158: 343– 347. 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: 912–930. 4. Baraldi E, Pasquale MF, Cangiotti AM, Zanconato S, Zacchello F. Nasal nitric oxide is low early in life: case study of two infants with primary ciliary dyskinesia. Eur Respir J 2004; 24: 881–883. 5. Weitzberg E, Lundberg JO. Humming greatly increases nasal nitric oxide. Am J Respir Crit Care Med 2002; 166: 144–145.
6. Karadag B, James AJ, Gultekin E, Wilson NM, Bush A. Nasal and lower airway level of nitric oxide in children with primary ciliary dyskinesia. Eur Respir J 1999; 13: 1402–1405. 7. Narang I, Ersu R, Wilson NM et al. Nitric oxide in chronic airway inflammation in children: diagnostic use and pathophysiological significance. Thorax 2002; 57: 586–589. 8. Daya H, Qian W, McClean P et al. Nasal nitric oxide in children: a novel measurement technique and normal values. Laryngoscope 2002; 112: 1831–1835. 9. Corbelli R, Bringolf-Isler B, Amacher A, Sasse B, Spycher M, Hammer J. Nasal nitric oxide measurements to screen children for primary ciliary dyskinesia. Chest 2004; 126: 1054–1059. 10. Struben VM, Wieringa MH, Mantingh CJ et al. Nasal NO: normal values in children age 6 through to 17 years. Eur Respir J 2005; 26: 453– 457. 11. Struben VM, Wieringa MH, Mantingh CJ, Bruinsma SM, de Jongste JC, Feenstra L. Silent and humming nasal NO measurements in adults aged 18–70 years. Eur J Clin Invest 2005; 35: 653–657. 12. Baraldi E, Azzolin NM, Cracco A, Zacchello F. Reference values of exhaled nitric oxide for healthy children 6–15 years old. Pediatr Pulmonol 1999; 27: 54–58. 13. Balfour-Lynn IM, Laverty A, Dinwiddie R. Reduced upper airway nitric oxide in cystic fibrosis. Arch Dis Child 1996; 75: 319–322. 14. Do¨tsch J, Demirakca S, Terbrack HG, Huls G, Rascher W, Kuhl PG. Airway nitric oxide in asthmatic children and patients with cystic fibrosis. Eur Respir J 1996; 9: 2537–2540. 15. Lundberg JON, Nordvall SL, Weitzberg E, Kollberg H, Alving K. Exhaled nitric oxide in paediatric asthma and cystic fibrosis. Arch Dis Child 1996; 75: 323–326. 16. Kharitonov SA, Walker L, Barnes PJ. Repeatability of standardised nasal nitric oxide measurements in healthy and asthmatic adults and children. Respir Med 2005; 99: 1105–1114. 17. Maniscalco M, Sofia M, Weitzberg E et al. Humming-induced release of nasal nitric oxide for assessment of sinus obstruction in allergic rhinitis: pilot study. Eur J Clin Invest 2004; 34: 555–560. 18. Stark H, Purokivi M, Kiviranta J, Randell J, Tukiainen H. Short-term and seasonal variations of exhaled and nasal NO in healthy subjects. Respir Med 2007; 101: 265–271. 19. O’Hearn DJ, Giraud GD, Sippel JM, Edwards C, Chan B, Holden WE. Exhaled nasal nitric oxide output is reduced in humans at night during the sleep period. Respir Physiol Neurobiol 2007; 156: 94–101. 20. Lundberg JO, Weitzberg E, Nordvall SL, Kuylenstierna R, Lundberg JM, Alving K. Primarily nasal origin of exhaled nitric oxide and absence in Kartagener’s syndrome. Eur Respir J 1994; 7: 1501–1504. 21. Silkoff PE. Nasal nitric oxide: clue to a diagnosis of ciliary dyskinesia. Chest 2004; 126: 1013–1014. 22. Stehling F, Roll C, Ratjen F, Grasemann H. Nasal nitric oxide to diagnose primary ciliary dyskinesia in newborns. Arch Dis Child Fetal Neonatal Ed 2006; 91: F233. 23. Noone PG, Leigh MW, Sannuti A et al. Primary ciliary dyskinesia. Diagnostic and phenotypic features. Am J Respir Crit Care Med 2004; 169: 459–467. 24. Horvath I, Loukides S, Wodehouse T et al. Comparison of exhaled and nasal nitric oxide and exhaled carbon monoxide levels in bronchiectatic patients with and without primary ciliary dyskinesia. Thorax 2003; 58: 68–72.
272
25. Struben VMD, Sewbalak WV, Wieringa MH et al. Nasal nitric oxide in cystic fibrosis with and without humming. Eur J Clin Invest 2007; 37: 140–144. 26. Kharitonov SA, Rajakulasingam K, O’Connor B, Durham SR, Barnes PJ. Nasal nitric oxide is increased in patients with asthma and allergic rhinitis and may be modulated by nasal glucocorticoids. J Allergy Clin Immunol 1997; 99: 58–64.
R. CORBELLI, AND J. HAMMER
27. Struben VMD, Wieringa MH, Feenstra L, de Jongste JC. Nasal nitric oxide and nasal allergy. Allergy 2006; 61: 665–670. 28. Colantonio D, Brouillette L, Parikh A, Scadding GK. Paradoxical low nasal nitric oxide in nasal polyposis. Clin Exp Allergy 2002; 32: 698–701. [29]. Ragab SM, Lund VJ, Saleh HA, Scadding G. Nasal nitric oxide in objective evaluation of chronic rhinosinusitis therapy. Allergy 2006; 61: 717–724.