Primary Ciliary Dyskinesia and Newborn Respiratory Distress
Section snippets
Ciliary Structure and Function
The respiratory epithelium in the nasopharynx, middle ear, paranasal sinuses, and conducting airways (including trachea, bronchi, and bronchioles) is lined by a ciliated, pseudostratified columnar epithelium that is essential for mucociliary clearance. Each mature ciliated epithelial cell has approximately 200 uniform cilia (5 to 6 μm in length and 0.2 μm diameter) that are functionally and anatomically oriented in the same direction. With a beating frequency of 5 to 20 Hz, cilia play a central
Role of Cilia in Pulmonary Defense
The human lung is exposed daily to inhaled pathogens and airborne irritants. Innate host defenses are critical in acute pulmonary injury and infection. Complex, local defenses have evolved to protect the airway, including mucociliary clearance. By this mechanism, inhaled particles are entrapped in mucus on the airway surface, then cleared by the coordinated action of cilia that sweeps mucus toward the pharynx. The volume and composition of airway surface liquid (ASL) influence the efficiency of
Primary Ciliary Dyskinesia
PCD is a human genetic disease associated with abnormal ciliary structure and function.6, 7, 8, 9, 10, 16, 17, 18, 19, 20 This genetically heterogeneous disorder involves multiple genes and usually is expressed in an autosomal recessive pattern with an estimated incidence of 1 in 15,000 to 30,000 births.21, 22 Ciliary dysfunction causes impaired mucociliary clearance, which results in the retention of inhaled particles, including bacteria, in the lung, paranasal sinuses, and middle ear (Table 1
Primary Ciliary Dyskinesia and Neonatal Respiratory Distress
Respiratory distress syndrome in newborn babies is the most common respiratory cause of death and morbidity in children in the first year of life,43 occurring at a rate of 25.1 cases per 100,000 births, based on 2001 data.44 Regardless of the cause, infants with respiratory distress present with similar clinical findings: tachypnea, increased work of breathing, and retractions. As respiratory distress progresses, gas exchange abnormalities develop, ultimately resulting in respiratory failure
Diagnosis of Primary Ciliary Dyskinesia
The diagnosis of PCD requires a high index of suspicion, and currently patients must have a compatible clinical phenotype and specific ultrastructural defects of the cilia detected by transmission electron microscopy.6, 10, 20 Expertise in evaluating ciliary ultrastructure is important to distinguish the primary (genetic) defects from acquired detects that result from exposure to different environmental and infectious agents.6, 71, 72 Absent (or shortened) dynein arms occur in up to 90% of
Genetics of Primary Ciliary Dyskinesia
As predicted from the complexity of ciliary structure and function, PCD is a genetically heterogeneous disorder that, in most cases, is autosomal recessive.81, 82 However, our understanding of the link between ultrastructural changes of cilia and the underlying genetic defect of PCD has lagged, which is in part related to the fact that mutations in any one of the 250 proteins that constitute a cilium could potentially cause PCD. For instance, the absence of a dynein arm may reflect a defect in
Management of Primary Ciliary Dyskinesia
Unfortunately, no specific therapeutic modalities are available to correct the ciliary dysfunction. Consequently, treatment focuses on facilitating the clearance of retained mucus secretions from the respiratory tract as well as aggressive therapy of bacterial infections.36 It is generally accepted that early diagnosis and institution of these therapies can limit early damage to these organs and slow the progression of disease. Unfortunately, little evidence exists showing the efficacy of
Prognosis
In contrast to cystic fibrosis, many individuals with PCD have experienced a normal or near-normal lifespan. However, the rate of lung disease progression is variable, and bronchiectasis may progress to severe pulmonary disability and eventually respiratory failure. Earlier diagnosis and institution of therapy could improve the overall health and prognosis for these patients.
Summary
PCD is a genetic disorder that results in dysfunction of motile cilia, resulting in chronic infections of the upper and lower respiratory tracts, male infertility, and situs inversus totalis in half of affected individuals. It has become increasingly clear that transient respiratory distress and hypoxemia in newborn period is highly prevalent in the PCD population, which suggests that cilia function may be important in transition from the fluid-filled fetal lung to air-filled neonatal lung.
Acknowledgments
Drs. Leigh and Ferkol are both members of the National Instuitutes of Health (NIH) Genetic Disorders of Mucociliary Clearance Consortium, and their work on primary ciliary dyskinesia is supported by NIH Grant Awards RR019480 (ML and TF) and HL079024 (TF). Dr. Ferkol is currently a member of a Speakers Bureau sponsored by Chiron Corporation.
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Cited by (51)
Pulmonary interstitial glycogenosis – A systematic analysis of new cases
2018, Respiratory MedicineCitation Excerpt :In our cohort one child (Patient K) presented with heterotaxy syndrome which was later confirmed to be related to primary ciliary dyskinesia (PCD) by genetic testing. 75–85% of all PCD patients suffer from RDS after birth and the exact causes are not yet identified [32–35]. We speculate that this could be related to the presence of PIG as it is known that respiratory cilia play a relevant role in organ development and maturation [36] and PIG may be related to lung dys-maturity, as indicated above.
Flexural Rigidity and Shear Stiffness of Flagella Estimated from Induced Bends and Counterbends
2016, Biophysical JournalCitation Excerpt :Motile cilia and flagella play a wide range of important roles in developmental and physiological processes, such as determination of left-right asymmetry, cerebrospinal fluid flow, mucociliary clearance, sperm swimming, and egg transport in fallopian tubes (1). Ciliary dysfunction is known or suspected in a number of genetic and acquired disorders (ciliopathies) including primary ciliary dyskinesia (2,3), chronic obstructive pulmonary disease (4), asthma (5), and otitis media (2). However, the complexity of the coupling between structure-function and mechanics-biochemistry in ciliary bending has precluded the mechanistic understanding required for rational development of diagnosis and treatment of ciliary dysfunction.
When to suspect primary ciliary dyskinesia in children
2016, Paediatric Respiratory ReviewsCitation Excerpt :Chest radiographs [CXRs] commonly demonstrate upper and middle lobar collapse, which is sometimes diagnosed as neonatal pneumonia. Bedside nurses often report nasal congestion or cough (sometimes even productive) in these children, which is quite unusual for a neonate, but almost pathognomic for an infant with PCD [1,4,7,10,11,19,22,23]. In term newborns with respiratory distress, the presence of lobar collapse, SIT, or a persisting oxygen need for >2 days predicts PCD in an affected neonate with 87% sensitivity and 96% specificity.6 [19] When neonatal respiratory distress is present in a baby with SIT or SA without cyanotic cardiac defects, there is a very high likelihood of PCD, and proper PCD investigations should be conducted as soon as possible [19].
Diagnostic Methods in Primary Ciliary Dyskinesia
2016, Paediatric Respiratory ReviewsEstablishing normative nasal nitric oxide values in infants
2015, Respiratory MedicinePrimary Ciliary Dyskinesia: Clinical Criteria Indicating Ultrastructural Studies
2013, Archivos de Bronconeumologia