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

Abstract

Purpose: 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.

Methods: 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).

Results: 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).

Conclusions: 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.

Keywords: Primary ciliary dyskinesia; nasal nitric oxide; primary immunodeficiency.

Fig 1

Initial nNO in primary immunodeficiency, PCD and healthy controls were compared using a Kruskal-Wallis test with post-hoc pairwise Mann-Whitney U tests. Horizontal lines represent the group median. Dashed line represents the PCD diagnostic cut-off of 77 nL/min. ****p < 0.0001. Only two PCD subjects (both with pathogenic variants in RSPH1) had initial or repeat nNO values above the PCD diagnostic cutoff of 77 nL/min (solid black horizontal line). This is consistent with previous observations that pathogenic variants in RSPH1 can sometimes result in nNO measurements above the diagnostic cutoff [29]. Two PID subjects initially had nNO measurements below the diagnostic cutoff of 77nL/min. Both of these subjects eventually had nNO measurements that rose above 77 nL/min, though one subject with RAG1 immunodeficiency had repeat nNO values fall below this cutoff.

Fig 2

CVID – Common variable immunodeficiency, hypogam – hypogammaglobulinemia, PAD-polysaccharide antibody deficiency, MBL – Mannose binding lectin deficiency, XLA – X-linked agammaglobulinemia, CD – complement deficiency

Fig 3

One PCD subject with RSPH1 and longitudinal measurements mutation had one of three values above the diagnostic cutoff of 77 nL/min. As noted, this is consistent with observations that RSPH1 mutations can occasionally generate nNO measurements above 77 nL/min.