Journal of Clinical Immunology

, Volume 39, Issue 2, pp 216–224 | Cite as

Nasal Nitric Oxide in Primary Immunodeficiency and Primary Ciliary Dyskinesia: Helping to Distinguish Between Clinically Similar Diseases

  • Zofia N. Zysman-Colman
  • Kimberley R. Kaspy
  • Reza Alizadehfar
  • Keith R. NyKamp
  • Maimoona A. Zariwala
  • Michael R. Knowles
  • Donald C. Vinh
  • Adam J. ShapiroEmail author
Original Article



Primary ciliary dyskinesia (PCD) is a rare disorder of the mucociliary clearance leading to recurrent upper and lower respiratory tract infections. PCD is difficult to clinically distinguish from other entities leading to recurrent oto-sino-pulmonary infections, including primary immunodeficiency (PID). Nasal nitric oxide (nNO) is a sensitive and specific diagnostic test for PCD, but it has not been thoroughly examined in PID. Past publications have suggested an overlap in nNO levels among subjects with PCD and PID. We sought to determine if nNO measurements among patients diagnosed with PID would fall significantly above the established PCD diagnostic cutoff value of 77 nL/min.


Children > 5 years old and adults with definitive PID or PCD diagnoses were recruited from outpatient subspecialty clinics. Participants underwent nNO testing by standardized protocol using a chemiluminescence analyzer and completed a questionnaire concerning their chronic oto-sino-pulmonary symptoms, including key clinical criteria specific to diagnosed PCD (neonatal respiratory distress at term birth, year-round cough or nasal congestion starting before 6 months of age, any organ laterality defect).


Participants included 32 patients with PID, 27 patients with PCD, and 19 healthy controls. Median nNO was 228.9.1 nL/min in the PID group, 19.7 nL/min in the PCD group, and 269.4 in the healthy controls (p < 0.0001). Subjects with PCD were significantly more likely to report key clinical criteria specific to PCD, but approximately 25% of PID subjects also reported at least 1 of these key clinical criteria (mainly year-round cough or nasal congestion).


While key clinical criteria associated with PCD often overlap with the symptoms reported in PID, nNO measurement by chemiluminescence technology allows for effective discrimination between PID and PCD.


Primary ciliary dyskinesia primary immunodeficiency nasal nitric oxide 



We would like to acknowledge Whitney Wolf (research technician) for specimen and DNA handling and processing and Invitae (San Francisco, California) for performing next-generation sequencing of known PCD genes. We also appreciate Shrikant Mane, Francesc Lopez-Giraldez, and Weilai Dong (Yale Center for Mendelian Genomics, [UM1 HG006504]) for providing whole exome sequencing and bioinformatics support.


Funds to support this project were received from the Montreal Children’s Hospital Foundation and the National Institute of Health (NIH) research grant nos. U54HL096458 and 5R01HL071798. The Genetic Disorders of Mucociliary Clearance (U54HL096458) is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Disease Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR). NCATS funded through a collaboration between NCATS and NHLBI.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.


The content of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

Supplementary material

10875_2019_613_MOESM1_ESM.docx (46 kb)
ESM 1 (DOCX 116 kb)


  1. 1.
    Leigh MW, O’Callaghan C, Knowles MR. The challenges of diagnosing primary ciliary dyskinesia. Proc Am Thorac Soc. 2011;8(5):434–7. Scholar
  2. 2.
    Shapiro AJ, Zariwala MA, Ferkol T, Davis SD, Sagel SD, Dell SD, et al. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review. Pediatr Pulmonol. 2016;51(2):115–32. Scholar
  3. 3.
    Leigh MW, Ferkol TW, Davis SD, Lee HS, Rosenfeld M, Dell SD, et al. Clinical features and associated likelihood of primary ciliary dyskinesia in children and adolescents. Ann Am Thorac Soc. 2016;13(8):1305–13. Scholar
  4. 4.
    Kouis P, Yiallouros PK, Middleton N, Evans JS, Kyriacou K, Papatheodorou SI. Prevalence of primary ciliary dyskinesia in consecutive referrals of suspect cases and the transmission electron microscopy detection rate: a systematic review and meta-analysis. Pediatr Res. 2017;81(3):398–405. Scholar
  5. 5.
    Zariwala MA, Knowles MR, Leigh MW. Primary Ciliary Dyskinesia. In: MP A, HH A, RA P, editors. GeneReviews. Seattle: University of Wahington; 2007 [updated 2015 Sept 3].Google Scholar
  6. 6.
    Lundberg J, Weitzberg E, Nordvall S, Kuylenstierna R, Lundberg J, Alving K. Primarily nasal origin of exhaled nitric oxide and absence in Kartagener’s syndrome. Eur Respir J. 1994;7(8):1501–4.CrossRefGoogle Scholar
  7. 7.
    Collins SA, Gove K, Walker W, Lucas JS. Nasal nitric oxide screening for primary ciliary dyskinesia: systematic review and meta-analysis. Eur Respir J. 2014;44(6):1589–99.CrossRefGoogle Scholar
  8. 8.
    American Thoracic S, European RS. 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. Scholar
  9. 9.
    Shapiro AJ, Josephson M, Rosenfeld M, Yilmaz O, Davis SD, Polineni D, et al. Accuracy of nasal nitric oxide measurement as a diagnostic test for primary ciliary dyskinesia. A systematic review and meta-analysis. Ann Am Thorac Soc. 2017;14(7):1184–96. Scholar
  10. 10.
    Shapiro AJ, Davis SD, Polineni D, Manion M, Rosenfeld M, Dell SD, et al. Diagnosis of primary ciliary dyskinesia. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2018;197(12):e24–39. Scholar
  11. 11.
    Horvàth I, Loukides S, Wodenhouse T, Csiszér E, Cole P, Kharitonov S, et al. Comparison of exhaled and nasal nitric oxide and exhaled carbon monoxide in patients with and without primary ciliary dyskinesia. Thorax. 2003;58:68–72.CrossRefGoogle Scholar
  12. 12.
    Boon M, Meyts I, Proesmans M, Vermeulen FL, Jorissen M, De Boeck K. Diagnostic accuracy of nitric oxide measurements to detect primary ciliary dyskinesia. Eur J Clin Investig. 2014;44(5):477–85. Scholar
  13. 13.
    Leigh MW, Hazucha MJ, Chawla KK, Baker BR, Shapiro AJ, Brown DE, et al. Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia. Ann Am Thorac Soc. 2013;10(6):574–81. Scholar
  14. 14.
    Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Clin Immunol. 1999;93(3):190–7. Scholar
  15. 15.
    Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43. Scholar
  16. 16.
    Knowles MR, Ostrowski LE, Leigh MW, Sears PR, Davis SD, Wolf WE, et al. Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med. 2014;189(6):707–17. Scholar
  17. 17.
    Marthin JK, Philipsen MC, Rosthoj S, Nielsen KG. Infant nasal nitric oxide over time: natural evolution and impact of respiratory tract infection. Eur Respir J. 2018;51(6):1702503. Scholar
  18. 18.
    Nakano H, Ide H, Imada M, Osanai S, Takahashi T, Kikuchi K, et al. Reduced nasal nitric oxide in diffuse panbronchiolitis. Am J Respir Crit Care Med. 2000;162(6):2218–20. Scholar
  19. 19.
    Suojalehto H, Vehmas T, Lindström I, Kennedy DW, Kilpeläinen M, Plosila T, et al. Nasal nitric oxide is dependent on sinus obstruction in allergic rhinitis. Laryngoscope. 2014;124(6):E213–8.CrossRefGoogle Scholar
  20. 20.
    Struben VMD, Wieringa MH, Feenstra L, De Jongste JC. Nasal nitric oxide and nasal allergy. Allergy. 2006;61(6):665–70. Scholar
  21. 21.
    Yoshida K, Takabayashi T, Imoto Y, Sakashita M, Narita N, Fujieda S. Reduced nasal nitric oxide levels in patients with eosinophilic chronic rhinosinusitis. Allergol Int 2018. doi:
  22. 22.
    Lee JM, McKnight CL, Aves T, Yip J, Grewal AS, Gupta S. Nasal nitric oxide as a marker of sinus mucosal health in patients with nasal polyposis. Int Forum Allergy Rhinol. 2015;5(10):894–9. Scholar
  23. 23.
    Chawla K, Hazucha M, Dell SD, Ferkol T, Sagel SD, Rosenfeld M et al. A multi-center, longitudinal study of nasal nitric oxide in children with primary ciliary dyskinesia. Am J Respir Crit Care Med 2010;181. doi:
  24. 24.
    Narang I, Ersu R, Wilson NM, Bush A. Nitric oxide in chronic airway inflammation in children: diagnostic use and pathophysiological significance. Thorax. 2002;57(7):586–9. Scholar
  25. 25.
    Deschamp AR, Schornick L, Clem C, Hazucha M, Shapiro AJ, Davis SD. A comparison of nasal nitric oxide measurement modes. Pediatr Pulmonol. 2017;52(11):1381–2. Scholar
  26. 26.
    Kainulainen L, Vuorinen T, Rantakokko-Jalava K, Österback R, Ruuskanen O. Recurrent and persistent respiratory tract viral infections in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol. 2010;126(1):120–6. Scholar
  27. 27.
    Hall CB, Powell KR, MacDonald NE, Gala CL, Menegus ME, Suffin SC, et al. Respiratory syncytial viral infection in children with compromised immune function. N Engl J Med. 1986;315(2):77–81. Scholar
  28. 28.
    Klimov AI, Rocha E, Hayden FG, Shult PA, Roumillat LF, Cox NJ. Prolonged shedding of amantadine-resistant influenza a viruses by immunodeficient patients: detection by polymerase chain reaction-restriction analysis. J Infect Dis. 1995;172(5):1352–5.CrossRefGoogle Scholar
  29. 29.
    Weinstock DM, Gubareva LV, Zuccotti G. Prolonged shedding of multidrug-resistant influenza a virus in an immunocompromised patient. N Engl J Med. 2003;348(9):867–8. Scholar
  30. 30.
    Shapiro AJ, Leigh MW. Value of transmission electron microscopy for primary ciliary dyskinesia diagnosis in the era of molecular medicine: genetic defects with normal and non-diagnostic ciliary ultrastructure. Ultrastruct Pathol. 2017;41(6):373–85. Scholar
  31. 31.
    Thomas SR, Kharitonov SA, Scott SF, Hodson ME, Barnes PJ. Nasal and exhaled nitric oxide is reduced in adult patients with cystic fibrosis and does not correlate with cystic fibrosis genotype. CHEST J. 2000;117:1085–9.CrossRefGoogle Scholar
  32. 32.
    Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, et al. High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation. 2012;125(18):2232–42. Scholar
  33. 33.
    Skorpinski EW, Kung SJ, Yousef E, McGeady SJ. Diagnosis of common variable immunodeficiency in a patient with primary ciliary dyskinesia. Pediatrics. 2007;119(5):e1203–5. Scholar
  34. 34.
    Boon M, De Boeck K, Jorissen M, Meyts I. Primary ciliary dyskinesia and humoral immunodeficiency--is there a missing link? Respir Med. 2014;108(6):931–4. Scholar
  35. 35.
    Colantonio D, Brouillette L, Parikh A, Scadding GK. Paradoxical low nasal nitric oxide in nasal polyposis. Clin Exp Allergy. 2002;32(5):698–701. Scholar
  36. 36.
    Ragab SM, Lund VJ, Saleh HA, Scadding G. Nasal nitric oxide in objective evaluation of chronic rhinosinusitis therapy. Allergy. 2006;61(6):717–24. Scholar
  37. 37.
    Phillips PS, Sacks R, Marcells GN, Cohen NA, Harvey RJ. Nasal nitric oxide and sinonasal disease: a systematic review of published evidence. Otolaryngol Head Neck Surg. 2011;144(2):159–69.CrossRefGoogle Scholar
  38. 38.
    Baraldi E, Azzolin NM, Carra S, Dario C, Marchesini L, Zacchello F. Effect of topical steroids on nasal nitric oxide production in children with perennial allergic rhinitis: a pilot study. Respir Med. 1998;92(3):558–61. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Zofia N. Zysman-Colman
    • 1
  • Kimberley R. Kaspy
    • 2
  • Reza Alizadehfar
    • 2
    • 3
  • Keith R. NyKamp
    • 4
  • Maimoona A. Zariwala
    • 5
  • Michael R. Knowles
    • 6
  • Donald C. Vinh
    • 3
  • Adam J. Shapiro
    • 2
    • 3
    Email author
  1. 1.CHU Sainte-JustineMontrealCanada
  2. 2.Montreal Children’s HospitalMcGill University Health CenterMontrealCanada
  3. 3.McGill University Health Center Research InstituteMontrealCanada
  4. 4.InvitaeSan FransciscoUSA
  5. 5.Department of Pathology and Laboratory Medicine, Marsico Lung InstituteUniversity of North Carolina School of MedicineChapel HillUSA
  6. 6.Department of Medicine, Marsico Lung InstituteUniversity of North Carolina School of MedicineChapel HillUSA

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