Dyskinesia

Primary abnormalities of ciliary structure and function termed primary ciliary dyskinesia (PCD), are often diagnosed late in adult and pediatric patients presenting with respiratory tract manifestations such as bronchiectasis, sinusitis, or with infertility. Accurate diagnosis requires the suspicion of clinicians, and referral to a specialist center with expertise in assessing ciliary ultrastructure by electron microscopy, and performing ciliary function studies. While no cure is available, once diagnosed, careful attention can be directed to minimizing morbidity through measures such as bronchial clearance and prompt treatment of infection. (1)

Nitric oxide (NO) was discovered in the late 1980s to be an essential biological mediator in diverse species and systems. (2) This molecule is synthesized by a family of constitutive and inducible NO synthases. The nasal cavity and paranasal sinuses excrete concentrations of NO that can reach several parts per million, orders of magnitude higher than the lower airway. (3) This exuberant synthesis of NO is sufficient for an important antibacterial and antiviral effect, perhaps ensuring sinus sterility in health. Of relevance here, NO also has been reported to modulate ciliary function. Inhalation via the nose, which conditions the inspirate with endogenous NO, has been reported to have discernible effects on ventilation-perfusion matching in the lung. This may represent an important physiologic mechanism controlling matching of ventilation to pulmonary blood flow, and supports parental advice to "breathe through your nose"! The measurement of nasal NO is described in an American Thoracic Society statement on exhaled and nasal NO measurement from 1999. (4)

In this issue of CHEST (see page 1054), Corbelli et al measured nasal and exhaled NO in children with PCD proven by ciliary ultrastructure on electron microscopy and compared these to children with other lung conditions and healthy control subjects. Mean values for nasal NO in ?CD were 13.7 parts per billion (ppb) [95% confidence limit, 6.8 to 27.8], compared to 132.7 ppb (95% confidence limit, 76.5 to 230.2) in non-PCD respiratory patients and 223.7 ppb (95% confidence limit, 175.5 to 285.2) for control subjects. Others have also reported similar findings as discussed by the authors. There are few tests that show such a profound contrast between health and disease. Exhaled NO did not differentiate between the three groups, although the numbers were smaller. A nasal NO < 105 ppb had a sensitivity of 94% and a specificity of 89% for proven PCD. A low nasal NO has also been reported in cystic fibrosis, non-?CD bronchiectasis, sinusitis, and panbronchiolitis, so a firm diagnosis requires examination of ciliary ultrastructure.

Aside from a marker of PCD, NO production may be involved in ciliary motility. Thus, the administration of NO donors (5) and the precursor of NO, the amino acid L-arginine, have been reported to increase ciliary beat frequency, while inhibitors of NO synthase reduce ciliary beat frequency. (6) Both inducible and constitutive NO synthase isoforms may be expressed in ciliated nasal epithelial cells. (6) The low nasal NO could also be linked to a susceptibility to upper airway infection.

So where do we go from here? Nasal NO should be available in specialist centers, and should be measured with simple and foolproof standardized techniques. (4,7) Larger studies should examine the utility for the diagnosis of PCD in patients with sinusitis and bronchiectasis by publishing ranges in health and disease. Careful controlled studies should examine whether therapeutic intervention to increase the levels of upper airway NO modulate ciliary function and if this improves clinical outcomes. Companies should endeavor to provide simple and cost-effective instruments to measure nasal NO and obtain regulatory medical device clearance with reimbursement codes. Awareness of PCD is being increased through the PCD Foundation (http://www.pcdfoundation.org). Registries of PCD patients will allow clinical trials to be performed and therapeutic agents to be validated for this rare but important set of conditions. Pharmaceutical companies may become interested if nasal NO augmentation, not only helps patients with PCD but also those with other abnormalities of ciliary function whether primary or secondary.

REFERENCES

(1) Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia diagnosis and standards of care. Eur Respir J 1998; 12:982-988

(2) Koshland DE Jr. The molecule of the year. Science 1992; 258:1861

(3) Lundberg JO, Farkas-Szallasi T, Weitzberg E, et al. High nitric oxide production in human paranasal sinuses. Nat Med 1995; 1:370-373

(4) Recommendations for standardized procedures for the on line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children 1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 1999; 160: 2104-2117

(5) 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

(6) Kim JW, Min YG, Rhee CS, et al. Regulation of mucociliary motility by nitric oxide and expression of nitric oxide synthase in the human sinus epithelial cells. Laryngoscope 2001; 111:246-250

(7) Silkoff PE, Chatkin J, Qian W, et al. Nasal nitric oxide: a comparison of measurement techniques. Am J Rhinol 1999; 13:169-178

Philip E. Silkoff, MD, FCCP

Wilmington, DE

Dr. Silkoff is Medical Director, AstraZeneca Pharmaceuticals, Wilmington, DE.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Philip Silkoff, MD, FCCP, Medical Director, AstraZeneca Pharmaceuticals, DCC-2, 1800 Concord Pike, Wilmington, DE 19850-6437; e-mail: philip.silkoff@astrazeneca.com

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