Introduction:
Nasal nitric oxide levels are significantly reduced in primary ciliary dyskinesia (PCD), and assessing this nasal gas is recommended for diagnosing PCD in cooperative patients aged five years and older. However, accurate measurement requires specific protocols using chemiluminescence analyzers to minimize the influence of various internal and external factors on the results. Repeat testing on different occasions is necessary to confirm persistently low values consistent with PCD. When conducted according to standardized protocols, nNO values provide valuable insights into patients suspected of having PCD.
What Is Primary Ciliary Dyskinesia?
Primary ciliary dyskinesia (PCD) is a genetically diverse disorder, primarily inherited in an autosomal recessive manner, affecting the function of motile cilia. This condition leads to impaired mucus clearance from the upper and lower airways. The compromised mucus clearance predisposes individuals to recurrent ear, sinus, and lung infections from an early age. Infants with PCD often require prolonged intensive care for respiratory distress shortly after birth, and many young children experience significant speech and hearing impairments due to chronic middle ear infections with fluid buildup.
Frequent lower respiratory infections, commonly diagnosed as recurrent pneumonia or bronchitis, are also typical in individuals with PCD. Most adolescents and adults with PCD develop chronic sinusitis and bronchiectasis, which can progress to respiratory failure in severe cases. Key clinical indicators in children that aid in distinguishing PCD from other chronic respiratory conditions include neonatal respiratory distress necessitating at least 24 hours of oxygen or positive airway pressure support despite being born at term, persistent year-round nasal congestion, and wet cough beginning before six months of age, and the presence of an organ laterality defect such as situs inversus totalis or situs ambigous.
What Is the Role of Nitric Oxide in the Body?
Nitric oxide (NO) is a vital signaling molecule produced across the human body, regulating various physiological and cellular functions in various organs. In the respiratory tract, normal NO concentrations in the nasal passages surpass those in the lower airways by 10 to 100 times. While exhaled NO has long been utilized as a marker for lower airway inflammation, NO originating from the sinonasal system has emerged more recently as a potential indicator of respiratory ailments.
Nitric oxide is generated by various cell types within the lungs and plays a pivotal role in regulating pulmonary vasomotor tone through several established mechanisms. It stimulates soluble guanylyl cyclase, leading to increased cyclic GMP levels in lung smooth muscle cells, which in turn modulate K+ and Ca2+ channel gating, contributing to nitric oxide-mediated vasodilation. Additionally, nitric oxide may regulate pulmonary vasodilation by directly activating K+ (potassium) channels or modulating the expression and activity of angiotensin II receptors.
Inhalation of nitric oxide has been demonstrated to acutely ameliorate hypoxemia associated with pulmonary hypertension in both human and animal studies, likely due to its vasodilatory effects. It improves oxygenation and reduces the need for extracorporeal membrane oxygenation in term and near-term infants with persistent pulmonary hypertension, yet long-term benefits remain uncertain. In other conditions, such as prematurity and acute respiratory distress syndrome, short-term benefits of high-dose inhaled nitric oxide have not conclusively outweighed potential toxicities, including surfactant dysfunction and lung macrophage priming.
Conversely, protective effects of nitric oxide have been observed in various pathological states, including hyperoxic and ischemia/reperfusion injury, as it can counteract oxidative damage induced by reactive intermediates like superoxide anions and hydroxyl radicals. However, the optimal dose and timing of nitric oxide administration in clinical settings require elucidation through further trials before definitive recommendations can be made regarding its optimal use in patients.
Can Nasal Nitric Oxide Measurement Test Help in Diagnosing Primary Ciliary Dyskinesia?
Nasal nitric oxide (nNO) levels are significantly diminished in individuals with primary ciliary dyskinesia (PCD), often less than one-tenth of the values observed in healthy controls. While most studies consistently show higher nNO levels in disease control subjects compared to PCD patients, overlap exists in conditions like cystic fibrosis (CF), diffuse panbronchiolitis, and acute viral respiratory infections. Therefore, ruling out CF through sweat testing or genetic analysis is crucial before nNO testing, as up to one-third of CF patients have nNO levels below 77 nl/min. Patients with conditions such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, immunodeficiency, non-CF bronchiectasis, and chronic sinusitis without nasal polyposis typically exhibit higher nNO levels than those with PCD.
Numerous studies indicate that nasal nitric oxide (nNO) levels are significantly lower in individuals with primary ciliary dyskinesia (PCD) compared to healthy counterparts, forming the basis for its adoption as a diagnostic tool for PCD in recent clinical guidelines from the American Thoracic Society (ATS). Meta-analyses and prospective cohort studies corroborate nNO testing as a safe, noninvasive, feasible, and accurate diagnostic method for PCD. However, conducting nNO testing for PCD diagnosis necessitates specialized equipment, trained personnel, and standardized protocols, posing challenges in accessibility for patients under suspicion of having PCD.
While some studies show a distinct nNO difference between infants with PCD and healthy infants (less than one to two years old), external factors such as high ambient NO concentrations can influence these values, leading to overlapping ranges.
As a result, testing is recommended for children under one to two years old when larger validation studies are conducted. In children aged two to five, nNO values may not reliably distinguish between healthy individuals and those potentially affected by PCD. As children age and their nasal sinus cavities develop, nNO levels typically increase, reaching near-adult values after 5 years, with further minor increases until age 12.
Clinical trials involving children aged five years and older and adults referred for suspected PCD have shown high diagnostic accuracy of nNO measurement compared to transmission electron microscopy and/or PCD genetic testing. Utilizing a standardized protocol with chemiluminescence NO analyzer and mouth resistor, nNO values below 77 nl/min are highly sensitive and specific for diagnosing PCD in individuals with appropriate clinical features. Patients undergoing nNO testing must have a high pretest probability of PCD based on key clinical indicators. Repeat testing on separate occasions, at least two weeks apart, is recommended to confirm persistently low values, ruling out transient factors like viral infections.
Serially repeated nNO measurements over months or years are crucial in cases where low nNO is the sole confirmatory PCD diagnostic test. In most patients with PCD, nNO values remain consistently low over time, and any normalization of nNO levels outside the diagnostic range should prompt further investigation for alternative respiratory conditions.
Conclusion:
A precise diagnosis of primary ciliary dyskinesia (PCD) is crucial to ensure patients receive appropriate specialized care before irreversible lung function decline occurs. Early identification also facilitates genetic counseling, tailored ear and rhino-sinus condition management, and screening for PCD-related issues such as cardiac problems. The correlation between markedly low levels of nasal nitric oxide (nNO) and PCD has been acknowledged for over 15 years, with nNO measurement increasingly employed as a screening tool for PCD.
