Primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) remains underdiagnosed, although its prevalence is greatly increasing, particularly in Canadian Indigenous populations. Key clinical features (neonatal respiratory distress, early-onset, year-round wet cough or sino-nasal congestion, or organ laterality defect(s)) should prompt referral for PCD diagnostic testing. Current PCD diagnostic testing in Canada includes nasal nitric oxide measurement with confirmation by genetic testing and/or ciliary transmission electron microscopy. Therapeutic goals in PCD include slowing disease progression, treating acute respiratory exacerbations, preventing complications, and improving quality of life until effective, personalized therapies become available. Primary ciliary dyskinesia (PCD) is an inherited disease of motile cilia, characterized by neonatal respiratory distress, chronic sino-oto-pulmonary infections, left-right organ laterality defects, and subfertility (1). The classic Kartagener Syndrome triad of situs inversus totalis, bronchiectasis, and chronic sinusitis frequently occurs in PCD yet is not always present, especially in children. This review highlights the multitude of symptoms that should prompt referral for PCD in pediatric practice, diagnostic tests for PCD confirmation, standard PCD therapies that pediatricians may encounter, and research into personalized treatments for patients with PCD. With genetic discovery over the past decade, the estimated prevalence of PCD has risen from 1:15,000-1,30,000 to 1:7600 people (2,3). Through founder variants or consanguinity, this prevalence may be even higher in specific populations, including Canadian Inuit and South Asian communities. In these groups, PCD prevalence may approach 1:1400 to 1:2200 patients (4,5), respectively, which is similar to the cystic fibrosis (CF) prevalence in White Canadians (6). In fact, the prevalence of PCD in Canadian Inuit represents the highest prevalence of any group worldwide and likely extends across the Arctic (7). PCD also occurs in Canadian First Nations through a likely genetic founder variant from Cree origins (8). Overall, PCD remains underdiagnosed with approximately 50,000 patients estimated across North America but less than 2000 definitively diagnosed per PCD Foundation estimates. Many of these people are misdiagnosed or followed as cases of idiopathic bronchiectasis, without receiving appropriate PCD care (9). Motile cilia are hair-like structures at the apical surface of cells lining the upper and lower respiratory tract. Approximately 200 cilia per epithelial cell sweep fluid, mucus, and inhaled particulates/organisms along the airway surface to be expectorated or swallowed. Motile cilia are also crucial in cerebrospinal fluid movement and gamete propulsion in males and females. Each cilia is composed of nine peripheral microtubule doublets encircling a central pair of microtubules (classic 9 + 2 configuration), outer and inner dynein arms, nexin-dynein regulatory complexes, and radial spokes (10,11) (Figure 1). Dyskinetic ciliary beating due to a genetic variant affecting proteins in any of these structures, or decreased ciliary numbers from variants in oligociliary genes, cause ineffective mucociliary clearance, leading to chronic inflammation, bacterial superinfection, irreversible airway dilatation/damage (bronchiectasis), and sometimes respiratory failure (12). Ultrastructure of a normal ciliary axoneme. Cross-section of a normal ciliary axoneme with 9 + 2 configurations, showing the various ultrastructural components that power ciliary beat (outer and inner dynein arms), drive normal axonemal formation along its length (nexin-dynein regulatory links), and provide best stability (radial spokes and central apparatus) The classic respiratory symptoms in PCD start in infancy, often immediately at birth, and typically do not wait to present in later childhood. The North American Genetic Diseases of Mucociliary Clearance Consortium (GDMCC) recognizes four key clinical symptoms that are highly sensitive and specific for PCD in children, including (1) neonatal respiratory distress requiring oxygen therapy or non-invasive ventilation for ≥24 h in a full-term newborn, (2) year-round wet cough starting within the first 6 months of life, (3) year-round sino-nasal congestion starting within the first 6 months of life, or (4) any organ laterality defect (situs inversus totalis or situs ambiguus) (13). The presence of any two of these key clinical symptoms confers a sensitivity of 80% for having PCD, while the presence of all four key symptoms is 99% specific for the disease (13). The PICADAR clinical scoring instrument is also highly predictive of PCD in children but relies heavily upon organ laterality defects and may be less accurate in cases of PCD with normal organ arrangement (14). Specific combinations of symptoms, including situs inversus totalis with neonatal respiratory distress in a term infant, strongly suggest PCD (15) (Table 1). In children with unexplained, chronic respiratory issues but no apparent laterality defects on chest radiography, abdominal and cardiac imaging demonstrating an organ laterality defect can greatly increase the suspicion of PCD (17). Key clinical symptoms of primary ciliary dyskinesia (PCD) in newborns, children, and adults* ○ Situs inversus totalis and neonatal respiratory distress‡ ○ Situs ambiguus and neonatal respiratory distress‡ without cardiac defect ○ Situs ambiguus and neonatal respiratory distress‡ out of proportion to cardiac defect ○ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h and lobar atelectasis on chest radiography ○ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h and family history of PCD, chronic sino-oto-pulmonary disease, or unexplained bronchiectasis ○ At least 2 of 4 key clinical symptoms: ▪ Year-round wet cough with onset before 6 months of age or ▪ Year-round nasal congestion with onset before 6 months of age or ▪ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h or ▪ An organ laterality defect Unexplained bronchiectasis** with chronic sino-oto-pulmonary disease since early childhood or family history of PCD ○ Unexplained bronchiectasis** and at least 1 of 6 key clinical symptoms: ▪ Chronic rhino-sinusitis or ▪ Ongoing otitis/effusion in adolescence/adulthood or ▪ An organ laterality defect or ▪ Male or female infertility ▪ Chronic sino-oto-pulmonary symptoms since early childhood or ▪ Family history of PCD ○ Situs inversus totalis and neonatal respiratory distress‡ ○ Situs ambiguus and neonatal respiratory distress‡ without cardiac defect ○ Situs ambiguus and neonatal respiratory distress‡ out of proportion to cardiac defect ○ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h and lobar atelectasis on chest radiography ○ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h and family history of PCD, chronic sino-oto-pulmonary disease, or unexplained bronchiectasis ○ At least 2 of 4 key clinical symptoms: ▪ Year-round wet cough with onset before 6 months of age or ▪ Year-round nasal congestion with onset before 6 months of age or ▪ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h or ▪ An organ laterality defect Unexplained bronchiectasis** with chronic sino-oto-pulmonary disease since early childhood or family history of PCD ○ Unexplained bronchiectasis** and at least 1 of 6 key clinical symptoms: ▪ Chronic rhino-sinusitis or ▪ Ongoing otitis/effusion in adolescence/adulthood or ▪ An organ laterality defect or ▪ Male or female infertility ▪ Chronic sino-oto-pulmonary symptoms since early childhood or ▪ Family history of PCD *Version adapted from Wee et al., Primary Ciliary Dyskinesia, Pediatrics (2024) (15); †Prenatal cerebral ventriculomegaly, presumably from ependymal ciliary dysfunction in brain ventricles, has been described in newborns with PCD. However, this finding has not been verified as predictive of PCD diagnosis versus controls (16); ‡In PCD, the neonatal respiratory distress often occurs 12 to 24 h after birth and is accompanied by shifting, lobar atelectasis on chest radiography; **Bronchiectasis in PCD is more prominent in the middle/lower lobes Key clinical symptoms of primary ciliary dyskinesia (PCD) in newborns, children, and adults* ○ Situs inversus totalis and neonatal respiratory distress‡ ○ Situs ambiguus and neonatal respiratory distress‡ without cardiac defect ○ Situs ambiguus and neonatal respiratory distress‡ out of proportion to cardiac defect ○ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h and lobar atelectasis on chest radiography ○ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h and family history of PCD, chronic sino-oto-pulmonary disease, or unexplained bronchiectasis ○ At least 2 of 4 key clinical symptoms: ▪ Year-round wet cough with onset before 6 months of age or ▪ Year-round nasal congestion with onset before 6 months of age or ▪ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h or ▪ An organ laterality defect Unexplained bronchiectasis** with chronic sino-oto-pulmonary disease since early childhood or family history of PCD ○ Unexplained bronchiectasis** and at least 1 of 6 key clinical symptoms: ▪ Chronic rhino-sinusitis or ▪ Ongoing otitis/effusion in adolescence/adulthood or ▪ An organ laterality defect or ▪ Male or female infertility ▪ Chronic sino-oto-pulmonary symptoms since early childhood or ▪ Family history of PCD ○ Situs inversus totalis and neonatal respiratory distress‡ ○ Situs ambiguus and neonatal respiratory distress‡ without cardiac defect ○ Situs ambiguus and neonatal respiratory distress‡ out of proportion to cardiac defect ○ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h and lobar atelectasis on chest radiography ○ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h and family history of PCD, chronic sino-oto-pulmonary disease, or unexplained bronchiectasis ○ At least 2 of 4 key clinical symptoms: ▪ Year-round wet cough with onset before 6 months of age or ▪ Year-round nasal congestion with onset before 6 months of age or ▪ Neonatal respiratory distress‡ at term birth, requiring supplemental oxygen or positive pressure support for ≥24 h or ▪ An organ laterality defect Unexplained bronchiectasis** with chronic sino-oto-pulmonary disease since early childhood or family history of PCD ○ Unexplained bronchiectasis** and at least 1 of 6 key clinical symptoms: ▪ Chronic rhino-sinusitis or ▪ Ongoing otitis/effusion in adolescence/adulthood or ▪ An organ laterality defect or ▪ Male or female infertility ▪ Chronic sino-oto-pulmonary symptoms since early childhood or ▪ Family history of PCD *Version adapted from Wee et al., Primary Ciliary Dyskinesia, Pediatrics (2024) (15); †Prenatal cerebral ventriculomegaly, presumably from ependymal ciliary dysfunction in brain ventricles, has been described in newborns with PCD. However, this finding has not been verified as predictive of PCD diagnosis versus controls (16); ‡In PCD, the neonatal respiratory distress often occurs 12 to 24 h after birth and is accompanied by shifting, lobar atelectasis on chest radiography; **Bronchiectasis in PCD is more prominent in the middle/lower lobes Neonatal respiratory distress is present in up to 80% of neonates with PCD (18). Compared to other causes of neonatal respiratory distress, the onset of PCD tends to be delayed, often presenting at 12 to 24 h of life or later. Up to 70% of newborns also show lobar atelectasis of the upper or middle lobes on chest radiography, which often appears days after the onset of distress and may be prolonged, especially in premature neonates with PCD (16,18). On average, term babies with PCD and neonatal respiratory distress require 2 weeks of respiratory support, and home supplemental oxygen may be needed (18). Prenatal cerebral ventriculomegaly is reported in limited cases of PCD (16), and hydrocephalus may rarely arise in some cases with variants in specific genes (19–21). At birth or soon thereafter, year-round nasal congestion appears with eventual chronic sinusitis. This issue very often occurs on a daily basis and never fully resolves, even after antibiotic therapy (22). Nasal polyps may occur with age but are less common compared to patients with CF (23). Year-round wet cough, similarly occurring on a daily basis without complete resolution, also appears in early infancy. Chronic sputum production is common. Recurrent lower respiratory tract infections are also common, leading to decreased pulmonary function and the development of bronchiectasis that typically affects the lower and middle lobes. Poor clinical outcomes, including more advanced bronchiectasis, faster decline in pulmonary function, and poor physical growth are associated with specific PCD genotypes (CCDC39, CCDC40) (24,25). Conversely, patients with variants in DNAH11 show relative preservation of lung function and a lower prevalence of neonatal respiratory distress (26). Outside of the respiratory tract, ciliary dysfunction in eustachian tubes leads to recurrent otitis media and/or persistent middle ear effusions in the vast majority of children with PCD (27). These issues commonly result in conductive hearing loss and/or speech delay (28,29). Repeat placement of middle ear ventilation tubes in childhood and even into adulthood is often required to treat effusions. Organ laterality defects, caused by dysfunction of nodal cilia in developing embryos, occur in approximately 50% of PCD cases. Laterality defects may range from classic situs inversus totalis (mirror image reversal of all organs) to situs ambiguus (left-right patterning defects falling on a spectrum between normal and complete reversal) in 12% to 20% of patients (17,30). Patients with situs ambiguus may display collections of organ defects (e.g., left or right isomerism), single organ defects (e.g., isolated dextrocardia or isolated asplenia/polysplenia), or complex congenital cardiovascular defects (heterotaxy) (31) (Table 2). Children with complex cardiovascular or splenic defects seem to have worse long-term respiratory and nutritional outcomes (32). Possible organ laterality defects with situs ambiguus in PCD Isolated dextrocardia Simple congenital heart defects (ASD, VSD, etc.) Complex congenital heart defects (heterotaxy) Atrial isomerism Common atrium Atrioventricular discordance Ventriculoarterial discordance Situs inversus abdominalis Midline liver Dextrogastria Polysplenia or asplenia (right- or left-sided) Intestinal malrotation Horseshoe kidney Annular pancreas Duodenal atresia Fused adrenal glands Extrahepatic biliary atresia Right aortic arch Bilateral or left superior vena cava Interrupted inferior vena cava Levotransposition or dextrotransposition of the great vessels Anomalous pulmonary venous return Left pulmonary isomerism Right pulmonary isomerism Pulmonary situs inversus Isolated dextrocardia Simple congenital heart defects (ASD, VSD, etc.) Complex congenital heart defects (heterotaxy) Atrial isomerism Common atrium Atrioventricular discordance Ventriculoarterial discordance Situs inversus abdominalis Midline liver Dextrogastria Polysplenia or asplenia (right- or left-sided) Intestinal malrotation Horseshoe kidney Annular pancreas Duodenal atresia Fused adrenal glands Extrahepatic biliary atresia Right aortic arch Bilateral or left superior vena cava Interrupted inferior vena cava Levotransposition or dextrotransposition of the great vessels Anomalous pulmonary venous return Left pulmonary isomerism Right pulmonary isomerism Pulmonary situs inversus ASD atrial septal defect; VSD ventricular septal defect Possible organ laterality defects with situs ambiguus in PCD Isolated dextrocardia Simple congenital heart defects (ASD, VSD, etc.) Complex congenital heart defects (heterotaxy) Atrial isomerism Common atrium Atrioventricular discordance Ventriculoarterial discordance Situs inversus abdominalis Midline liver Dextrogastria Polysplenia or asplenia (right- or left-sided) Intestinal malrotation Horseshoe kidney Annular pancreas Duodenal atresia Fused adrenal glands Extrahepatic biliary atresia Right aortic arch Bilateral or left superior vena cava Interrupted inferior vena cava Levotransposition or dextrotransposition of the great vessels Anomalous pulmonary venous return Left pulmonary isomerism Right pulmonary isomerism Pulmonary situs inversus Isolated dextrocardia Simple congenital heart defects (ASD, VSD, etc.) Complex congenital heart defects (heterotaxy) Atrial isomerism Common atrium Atrioventricular discordance Ventriculoarterial discordance Situs inversus abdominalis Midline liver Dextrogastria Polysplenia or asplenia (right- or left-sided) Intestinal malrotation Horseshoe kidney Annular pancreas Duodenal atresia Fused adrenal glands Extrahepatic biliary atresia Right aortic arch Bilateral or left superior vena cava Interrupted inferior vena cava Levotransposition or dextrotransposition of the great vessels Anomalous pulmonary venous return Left pulmonary isomerism Right pulmonary isomerism Pulmonary situs inversus ASD atrial septal defect; VSD ventricular septal defect Rare syndromic forms of PCD also exist, including X-linked retinitis pigmentosa due to variants in RPGR (33,34), X-linked oro-facial-digital syndrome through OFD1 variants, autosomal recessive lissencephaly with the TP73 gene, and Cri-du-Chat syndrome through hemizygous inheritance of a single variant in DNAH5 plus the characteristic 5p deletion, which includes the same allele, on the opposite chromosome (35). Diagnosis of PCD was difficult before genetic discovery defined many of the underlying genes. As there is no single test that can detect all cases of PCD, patients often require several tests for a diagnosis, including genetic testing, ciliary ultrastructural analysis on transmission electron microscopy (TEM), and nasal nitric oxide (nNO) measurement. None of these tests can rule out PCD. Additional testing limited to research laboratories includes high-speed videomicroscopy analysis of ciliary beat pattern and ciliary protein immunofluorescence. Clinical practice guidelines suggest referral for possible PCD in patients with an appropriate PCD clinical phenotype, including at least two key clinical PCD symptoms (36) (Figure 2). In patients ≥5 years old who can cooperate, nNO measurement by exhalation against resistance at a PCD Foundation accredited centre is the preferred initial PCD investigation in North America. For unexplained reasons, nNO values measured by chemiluminescence devices, with approved protocols, are greatly reduced in patients with PCD. Repeatedly low nNO values (<77 nL/min) are highly sensitive and specific for PCD (38,39). Up to 10% of patients with PCD may have nNO values above the 77 nL/min cutoff, so normal nNO levels do not rule out PCD (40). Some patients with CF, rare combined immunodeficiencies, or acute viral respiratory infections may also have reduced nNO values (40–43). Thus, CF testing should be negative when using nNO testing to investigate PCD, and patients must be free from viral infection for at least 2 weeks before testing. Children <5 years old can undergo nNO testing using a tidal breathing technique, but cutoff values are not robustly validated with this technique (39). American Thoracic Society suggested algorithm for evaluating patients with suspected primary ciliary with of the American Thoracic American Thoracic The American of and is an of the American Thoracic nNO values are or nNO testing is genetic testing is preferred for diagnostic variants in genes cause PCD (Table genetic genes, and genetic testing 70% to 80% of PCD cases may with or genes are inherited in an autosomal recessive with a X-linked genes and a single autosomal that Thus, variants in a single PCD gene, or a single variant in an X-linked or autosomal gene, are definitively diagnostic of PCD. Ultrastructure defects and PCD genotypes with nasal nitric oxide levels and with organ laterality *Version adapted from Wee et al., Primary Ciliary Dyskinesia, Pediatrics (2024) (15); genes result in oligociliary defects with to a cilia per epithelial which to have normal on and genes are associated with central and radial However, these defects be diagnosed on as the majority of often normal or Ultrastructure defects and PCD genotypes with nasal nitric oxide levels and with organ laterality *Version adapted from Wee et al., Primary Ciliary Dyskinesia, Pediatrics (2024) (15); genes result in oligociliary defects with to a cilia per epithelial which to have normal on and genes are associated with central and radial However, these defects be diagnosed on as the majority of often normal or genetic testing is ciliary analysis with transmission electron microscopy should be on respiratory epithelial cells for ultrastructural However, analysis is difficult to of a Canadian and may be normal or in of PCD cases In 20% to of PCD and genetic testing may be with low nNO values as the positive PCD In these therapy for PCD is but must for other including CF and is no therapy to the underlying ciliary dysfunction in PCD. Thus, include slowing disease progression, treating acute respiratory exacerbations, preventing complications, and improving quality of Many PCD therapies are from the of CF and per PCD Foundation which is on a of and airway is the of PCD including chest resistance pressure or cardiovascular to daily Many PCD to to with inhaled not pulmonary function in clinical have a limited on quality of life inhaled including in PCD but respiratory outcomes in patients with bronchiectasis Patients with PCD a wet cough at this cough for several or when other respiratory symptoms present (e.g., in sputum quality or chest patients for a respiratory therapy with in sputum plus the of airway is appropriate for exacerbations, including supplemental oxygen or a in pulmonary function, require and with of daily airway antibiotic therapy is to 2 to weeks in PCD the majority of patients receiving antibiotic therapy of respiratory function after 1 of Chronic therapy is in PCD, and acute respiratory by 50% over a there is a of antibiotic resistance with this not occur 6 months of is often in patients with PCD and an of respiratory to or per therapies are for children with PCD, due to the presence of chronic rhino-sinusitis and otitis media with Children should be followed by an at least to two per for conductive hearing loss and/or persistent ear effusions. 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