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 will discuss 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, hair like organelles that are anatomically and functionally oriented and cluster to pairway 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. Motile cilia are also present elsewhere in the human body.

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, which occur in 50% of people with PCD, and unexplained neonatal respiratory distress in full-term babies that begins the first day of life, reported in approximately 60% of children with PCD. 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 (62%) 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. Nasal polyposis has been reported to occur infrequently in children with PCD but occurs in up to 34% to 56% of adults with PCD, suggesting that they are a later manifestation of disease. Chronic rhinosinusitis, defined as 12 consecutive weeks of sinonasal inflammation, is a nearly universal complication in adult patients.

Middle ear disease presents another otolaryngologic challenge. Based on results from a North American collaborative, 88% of children with PCD have recurrent otitis media in the first 2 years of life, with half experiencing sequelae, such as conductive hearing loss. 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.

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 small series of patients with PCD.

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.

Transmission electron microscopy, evaluating for axonemal ultrastructural defects in epithelial cells collected from the nasal or endobronchial mucosa, has long been considered the conventional diagnostic approach, despite its limitations. Nasal specimens are often more feasible than endobronchial scrape biopsies and are adequate for ultrastructural analyses, with high success rates when performed by trained personnel. The lack of ultrastructural defects does not exclude the diagnosis, because people with PCD can have normal or near-normal axonemal structure.

Recently, immunofluorescent staining of specific markers has been used to identify axonemal defects and may overcome some limitations of electron microscopy. When combined with clinical criteria, nasal nitric oxide (nNO) measurement has become an effective screening tool in patients 5 years and older and can reduce the number of unnecessary and costly evaluation of patients unlikely to have the disease.

When compared with transmission electron microscopy and genetic testing, nNO levels 77 nL/min or below are sensitive and specific for PCD in cooperative children and adults, but people who have variants in some PCD-associated genes can have nondiagnostic nNO values. Affected individuals with higher nNO levels account for less than 5% of known PCD cases. Thus, reduced nNO concentrations alone are never sufficient to make the diagnosis of PCD. Conversely, people with cystic fibrosis or primary immunodeficiencies, conditions that have clinical features that overlap with PCD, can have reduced nNO levels. These observations reinforce the need to thoroughly evaluate patients suspected of PCD and not necessarily rely on a single diagnostic test.

Genetic Testing for PCD

Primary ciliary dyskinesia is a genetically heterogeneous disease, as suggested by its varied ultrastructural and functional phenotypes. It has been described in many ethnic groups without racial or gender predilection. In most cases, PCD is transmitted by an autosomal recessive pattern of inheritance, but autosomal dominant and X-linked inheritance patterns have been reported.

The genetics of PCD has yielded unexpected insights into the disease. A growing number of disease-associated genes and pathogenic variants have been identified, which encode axonemal, cytoplasmic, and regulatory proteins involved in the assembly, structure, and function of motile cilia.

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 respiratoryexacerbations. The choice of antimicrobials is guided by results of routine surveillance sputum cultures. Treatments with inhaled antimicrobials, nebulized hypertonic saline, or mucolytics have not been adequately studied thus far to determine their effectiveness.

The management of recurrent acute otitis media with myringotomy tubes in patients with PCD follows the American Academy of Otolaryngology–Head and Neck Surgery standard guidelines, but treatment of COME has been debated.

Some studies have reported that PET placement is associated with improved hearing thresholds in children with COME and chronic conductive hearing loss, but others have not found this association. 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. Access to hearing amplification can vary significantly by region and is not always available to patients, which influences practice patterns. Many patients with PCD will undergo PET placement, and 63% will undergo repeated insertions. Repeated PET placement and recurrent otorrhea place patients at greater risk for persistent tympanic membrane perforation, a common complication in patients with PCD. Because tube otorrhea is so prevalent, it is important for patients and families to fully understand this risk and share in decision-making.

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. If persistent otorrhea is present, various management options should be discussed.

Guidelines published by the PCD Foundation61recommend 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. At this time, not enough is understood about long-term hearing outcomes or the potential to develop hearing loss. Authors also advocate for routine audiograms, with more frequent assessment as needed.

Sinonasal disease is ubiquitous in children with PCD and the most common complaint in adult patients. 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. Because of their safety profiles, nasal saline irrigationsare often recommended for patients with PCD. Topical corticosteroids are frequently prescribed to reduce sinonasal inflammation, although there are no prospective studies to support this practice.

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. As we better understand the genetic and pathophysiologic bases of clinical PCD, our approach toward diagnostic testing for PCD has radically changed. 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; Maithilee Menezes; Thomas W. Ferkol; JAMA Otolaryngol Head Neck Surg. 2021;147(8):753-759.

doi:10.1001/jamaoto.2021.0934