"Advances in the Diagnosis and Treatment of Primary Ciliary Dyskinesia"- A Review

The understanding of the genetics, pathophysiology, and clinical features of PCD has greatly advanced during the past decade. In this review, Katherine Dunsky and team discussed how these discoveries have led to a revolution in diagnostic testing and may identify novel molecular therapeutic targets, with a focus on the otolaryngologic manifestations of PCD.

Structure and Function of Cilia

Generally classified by microtubular structure and function, there are 3 types of cilia in the body. Nodal cilia are motile monocilia that are transiently expressed during development, and their function is necessary to establish left-right sidedness. Primary (sensory) cilia are usually solitary, nonmotile organelles that are present on the surface of most nondividing cells; these structures sense the extracellular environment. Additionally, they regulate development pathways, and defects can lead to growing number of complex, clinically varied conditions, collectively known as ciliopathies.

The third type, motile cilia, are critical to mucosal defenses in the upper and lower respiratory tracts. Ciliated epithelial cells have roughly 200 uniform motile cilia, hairlike organelles that are anatomically and functionally oriented and cluster atop airway cells, beating rhythmically and sweeping fluid, mucus, and trapped particulates along the epithelial surface. Any disturbance in their movement can cause upper or lower airway disease.

In a healthy epithelium, cilia are aligned in parallel orientation of the central pair of tubules, part of the central apparatus, with adjacent cilia, and ciliary motility is maintained in the same direction along the airway. Normal beat frequency of human motile cilia typically ranges from 8 to 14 Hz but can respond to various external stimuli. Several signaling mechanisms are also known to regulate ciliary beat frequency, including intracellular calcium, cyclic adenosine monophosphate, extracellular adenosine triphosphate, and nitric oxide.

Clinical Features of PCD

PCD is a clinically heterogenous disease. The earliest presenting signs are left-right laterality defects, such as situs inversus totalis, situs ambiguus, and heterotaxy and unexplained neonatal respiratory distress in full-term babies that begins the first day of life. Characteristically, these infants require supplemental oxygen and even mechanical ventilator support for 2 or more days. Chest imaging often reveals upper or middle lobe atelectasis. Certainly, the combination of unexplained neonatal respiratory distress with laterality defects in a term neonate should prompt diagnostic evaluation for PCD.

Most children present in the first year of life with respiratory tract involvement. Many children present with year-round, wet or productive cough, beginning in early infancy, owing to mucostasis and impaired mucociliary clearance. Treatment with antibiotics may reduce cough frequency or productivity, but the cough characteristically does not fully resolve. The severity and progression of lower airway disease can be variable, but bronchiectasis is common, even in infants and toddlers. Defined as irreversible airway dilatation, bronchiectasis is the pathophysiological consequence of chronic infection and inflammation that often leads to worsening airway obstruction and recurrent exacerbations.

More than 80% of patients with PCD have nonseasonal, daily nasal congestion with copious, watery nasal discharge that begins before 6 months of age and persists into childhood. As with cough, antibiotics may reduce nasal symptoms but they rarely fully resolve.

In children, nasal discharge and obstructive symptoms can be overlooked and attributed to viral illness or allergies, resulting in delays in diagnosis. Nasal polyposis is seen in children with PCD, although less often than cystic fibrosis. Chronic rhinosinusitis, defined as 12 consecutive weeks of sinonasal inflammation, is a nearly universal complication in adult patients.

Similar to the lower airways, the most common pathogens isolated from the paranasal sinuses include Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa.

In adults with PCD, rhinorrhea is frequently reported, and nearly all will have mucosaledema, purulent secretions, or nasal polyps on endoscopy. Abnormalities are often found on imaging studies, and chronic sinonasal inflammation has been theorized to lead to hypoplasia or aplasia of the paranasal sinuses, particularly the frontal and sphenoid sinuses.

Middle ear disease presents another otolaryngologic challenge. Chronic otitis media with effusion (COME), defined as persistent middle ear effusion with at least a 3-month duration, is often reported in children but appears to decline with age, coupled with improved air conduction thresholds. Even so, middle ear symptoms persist in many adults with PCD. Otorrhea is common in PCD. Nearly half of patients who have undergone pressure equalization tube (PET) placement experience at least 1 episode of otorrhea.

Both conductive hearing loss and sensorineural hearing loss occur at increased frequency in patients with PCD, a particular concern in children owing to the critical role of hearing in speech and language development. While conductive hearing loss tends to improve with age, sensorineural hearing loss has recently been identified in children and adults in as many as one-third of patients. Finally, both subclinical vestibular dysfunction and olfactory dysfunction have also been reported.

In addition to laterality defects, people with PCD can have other nonrespiratory manifestations. Male and female subfertility are common, owing to sperm dysmotility and ciliary dysfunction in the fallopian tubes, respectively. Studies have suggested associations between genotype and fertility. Finally, neonatal hydrocephalus is a rare clinical manifestation in classic PCD but may be seen in other motile ciliopathies.

Supportive and Diagnostic Tests for PCD

Diagnosis of PCD has long been challenging because of limitations of diagnostic tests, but newer tools have emerged during the past decade. Nevertheless, clinicians should only perform testing in patients who have a clinical phenotype consistent with the disease

A study analyzing the clinical features of more than 500 children and adolescents with chronic respiratory symptoms identified 4 clinical features predictive of PCD: (1) unexplained neonatal respiratory distress in full-term infants; (2) left-right laterality defects; (3) persistent rhinitis that begins before 6 months of age; and (4) daily wet or productive cough that also starts before 6 months of age.

Indeed, the presence of 2 criteria-defined clinical features is considered sufficient for referral to North American PCD centers for specialized testing. In some cases, a single feature may still warrant diagnostic testing. Without these manifestations, patients are unlikely to have the disease, and further testing may not be indicated. Another validated, predictive tool (PICADAR) was created to estimate the probability of a positive diagnosis, which includes these features as well as historical elements.

Current Screening and Diagnostic Tests for Primary Ciliary Dyskinesia (PCD) in Patients Who Have a Compatible Clinical Phenotype

• Nasal nitric oxide: Nasal nitric oxide levels are reproducibly reduced in PCD. In patients 5 y or older, high sensitivity and specificity.
• High-speed video microscopy: Provides functional assessment of cilia beat patterns and frequency.
• Transmission electron microscopy: Historical criterion standard and can be diagnostic in 70% of cases.
• Genetic testing (>30 genes): Diagnostic in >70% of cases, including people with normal or nondiagnostic ultrastructural analyses.

Management of PCD

At this time, no treatment has been shown to correct or restore cilia function in patients with PCD. Management of PCD is similar to that used in other suppurative lung diseases, such as cystic fibrosis, relying on airway clearance techniques and systemic antibiotics to mobilize secretions and reduce the bacterial burden of the lower respiratory tract, especially during acute respiratory exacerbations.

The choice of antimicrobials is guided by results of routine surveillance sputum cultures. A recent multicenter clinical trial examined the efficacy of thrice-weekly azithromycin as an anti-inflammatory agent in select PCD subpopulations. While pulmonary function and quality-of-life measures were not different between placebo and treatment groups, macrolide therapy resulted in modest reduction in frequency of respiratory exacerbations.

PET placement is associated with improved hearing thresholds in children with COME and chronic conductive hearing loss. Moreover, persistent tube otorrhea has led some to recommend against PET placement in patients with PCD, maintaining that medical management with frequent assessments and hearing amplification, when needed, is sufficient.

It is imperative for treating otolaryngologists to monitor not only middle ear status, but also overall hearing. Chronic otitis media with effusion with or without otorrhea may also be associated with hearing loss. For those involved in the care of pediatric patients, awareness of issues related to hearing and hearing loss is important to mediate speech and language acquisition, as well as learning and academic success.

Guidelines published by the PCD Foundation recommend annual evaluations with an otolaryngologist beginning in childhood and regular assessments in adults to monitor for progression of middle ear disease. Furthermore, the guidelines recommend an initial audiological evaluation to assess for hearing loss and follow-up assessments as needed.

The current treatment for sinonasal disease has been based on management of chronic rhinosinusitis, consisting of a combination of medical and surgical therapies. Saline irrigations are recommended for the management of chronic rhinosinusitis as they have been shown to be associated with improved mucus clearance and potentially reduced burden of antigens and bacterial biofilms. Topical corticosteroids are frequently prescribed to reduce sinonasal inflammation.

Oral antibiotics are frequently used in the management of upper and lower respiratory tract infections during exacerbations. In some cases, prolonged suppressive antibiotic therapies are used.

Some people with PCD require surgical interventions, although there are no set guidelines regarding when surgical intervention is indicated. Adenoidectomy, nasal polypectomy, and functional endoscopic sinus surgery are often performed in children or adults, usually reserved for cases of failed medical therapy.

In summary, PCD is a rare, genetic disorder characterized by impaired ciliary function leading to chronic sinopulmonary disease, persistent middle ear effusions, laterality defects, and infertility. A growing number of PCD-associated genes and pathogenic variants have been identified, and these findings have yielded newer and unexpected insights into the processes involved in the assembly, structure, and function of a cilium.

Four clinical features have been found to be characteristic of PCD: unexplained neonatal respiratory distress, organ laterality defects present at birth, and year-round chronic cough and nasal congestion beginning in early infancy. Two or more of these features should prompt clinicians to consider the diagnosis.

"Owing to the high incidence of middle ear and sinonasal disease, otolaryngologists are often among the first clinicians to see children with PCD, often before a diagnosis is made, and should be familiar with recent advances in diagnostics. For people older than 5 years who have at least 2 criteria-specific clinical features, nNO measurements are recommended as a screen for PCD, and if positive, genetic testing and ultrastructural analyses are currently the preferred diagnostic tests. This knowledge has not yet led to advances in care. We are still lacking effective disease specific treatments and have many opportunities to improve care and define best practice."

Source: Katherine Dunsky, MD; Maithilee Menezes, MD; Thomas W. Ferkol, JAMA Otolaryngology–Head & Neck Surgery August 2021 Volume 147, Number 8

doi:10.1001/jamaoto.2021.0934