The incidence of PCD ranges from , to , Since PCD causes deficiency or even stasis of the transport of secretions throughout the respiratory tract, it favors the growth of viruses and bacteria. As a result, patients have lifelong chronic and recurrent infections, typically suffering from bronchitis, pneumonia, hemoptysis, sinusitis, and infertility. Bronchiectasis and other chronic conditions infections can be the end result of the irreversible bronchial alterations, leading to chronic cor pulmonale and its consequences. Only half of the patients affected by PDC present all of the symptoms, a condition designated complete KS, compared with incomplete KS, typically defined as cases in which situs inversus does not occur. The diagnosis is made clinically and confirmed through transmission electron microscopy.
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It results in mucus accumulation and bacterial colonization of the respiratory tract which leads to chronic upper and lower airway infections, organ laterality defects, and fertility problems. We review the respiratory signs and symptoms of PCD, as well as the screening tests for and diagnostic investigation of the disease, together with details related to ciliary function, ciliary ultrastructure, and genetic studies.
In addition, we describe the difficulties in diagnosing PCD by means of transmission electron microscopy, as well as describing patient follow-up procedures. The prevalence of PCD ranges from , to ,, PCD occurring most frequently in families with consanguineous marriages. Evidence suggests that the diagnosis of PCD is often delayed, which is mainly due to a failure to recognize the disease and the need for sophisticated technical resources for PCD screening.
According to a European consensus statement, the diagnosis of PCD should be based on the presence of a phenotype consistent with the disease and confirmed by diagnostic tests performed at specialized centers. Ciliary biology Cilia are specialized hairlike structures covered by plasma membrane and extending from the cell surface. Cilia are classified as motile or nonmotile. During embryonic development gastrulation , cells in the ventral node contain a single motile cilium per cell.
This specialized motile cilium has nine pairs of peripheral microtubules with dynein arms but no central pair of microtubules; its rotational motion contributes to the development of organ laterality during embryogenesis.
In the absence of normal nodal ciliary function, organ placement is random. Nonmotile cilia play a role in the perception of extracellular physical and biochemical signals. Normal ciliary ultrastructure in ciliated airway epithelial cells An axial view of a cilium Figure 1 shows nine peripheral microtubule doublets. Each doublet consists of the A and B tubules.
The uniform space between the microtubule doublets is maintained by nexin, which keeps the adjacent microtubules together. In addition, there are the outer and inner dynein arms throughout the A tubule, a central pair of isolated microtubules connected and surrounded by a discontinuous central sheath of protein, and radial spokes, which connect the central microtubules to the peripheral microtubules. The outer and inner dynein arms have high, medium, and low molecular weight proteins.
The microtubules on the opposite side mediate ciliary bending a forward power stroke and a backward recovery stroke. In the airways, cilia can be found up to the 16th bronchial division. Ciliated respiratory epithelial cells are characterized by long cytoplasmic projections, with approximately cilia per cell.
Age-specific indicators include prenatal indicators situs abnormalities on ultrasound , neonatal indicators rhinorrhea at birth, neonatal respiratory distress with no apparent cause in full-term infants, abnormal situs, complex congenital heart disease-especially with laterality disorders-and a family history of PCD , childhood indicators chronic productive cough, atypical asthma unresponsive to treatment, idiopathic bronchiectasis, rhinosinusitis-the presence of nasal polyposis is rare-agenesis of one or more sinuses, severe otitis media with effusion, prolonged otorrhea after ventilation tube insertion, and having a family member diagnosed with PCD , and adulthood indicators childhood data plus male infertility due to immotile sperm, ectopic pregnancy, and subfertility due to static cilia in the fallopian tube.
Mucus accumulation in the Eustachian tube causes conductive hearing loss that varies with time. In cases of idiopathic bronchiectasis, PCD is a diagnosis of exclusion, given that other causes of bronchiectasis should be ruled out before screening for PCD.
The consensus among American and British researchers is that the PCD phenotype and nasal NO measurements are important; ciliary motion has been studied in greater detail by European researchers, 15,16 as has ciliated cell culture. However, American centers for the diagnosis of PCD have reported difficulties in standardizing the interpretation of ciliary motion and electron microscopy.
Therefore, at those centers, the diagnosis of PCD is based on the presence of a phenotype consistent with the disease and abnormal nasal NO values, associated with genetic testing to identify the mutations. It allows the visualization of the normal pattern of ciliary beating; that is, a forward power stroke followed by a slow, slightly sideways, backward recovery stroke.
Changes in the normal pattern of ciliary beating can be associated with specific genetic defects. However, in patients with Kartagener syndrome, sperm flagella and respiratory cilia vary across individuals and might not be equal in the same patient; this suggests that ciliary and flagellar axonemes 24,25 are controlled by common genes and different genes.
Definitive diagnosis In order to establish a definitive diagnosis of PCD, certain phenotypic characteristics at least three characteristics, typically five or more characteristics should be present: neonatal respiratory distress in full-term infants; laterality defects; chronic, year-round nasal congestion; chronic, year-round productive cough; recurrent lower respiratory tract infections; bronchiectasis; chronic otitis media with effusion for more than 6 months; chronic pansinusitis; male infertility; and a history of ciliary dyskinesia in a close relative.
At several centers worldwide, the use of nasal NO testing is recommended in order to confirm the diagnosis, 15 and the diagnostic tests should be repeated when the phenotype and low levels of nasal NO do not correlate with ciliary ultrastructure and beat frequency.
Secondary defects should be excluded when the results of nasal NO testing are normal and accompanied by ciliary motility defects or ciliary ultrastructural defects. A genetic test result is considered positive for PCD when there are two genes with trans mutations-in which the wild-type allele A and mutant allele b of one gene are located on one chromosome and the mutant allele a and wild-type allele B of another gene are located on the homologous chromosome-and no correcting mutations.
At the epithelial level, it has been suggested that there is reduced NO biosynthesis or increased NO metabolism caused by the accumulation of thick mucus or the presence of bacteria.
At the anatomical level, it has been suggested that NO is sequestered in blocked nasal sinuses or, alternatively, nasal NO biosynthesis or NO storage capacity is limited because of agenesis of the paranasal sinuses.
It consists of placing a particle of saccharin of 1 mm in diameter on the floor of the nasal cavity, approximately 1 cm into the inferior turbinate. The patient sits quietly with the head bent forward and must not sniff, sneeze, cough, eat, or drink for the duration of the test. The time in min to tasting saccharin in the pharynx is measured. The result of the test is considered abnormal when the time to tasting saccharin in the pharynx is greater than 60 min.
However, false positives can occur in 0. Nasal mucociliary transport can be slower in patients with septal deviation or rhinoscleroma. In a recent review, 6 the saccharin test was reported to be difficult to perform correctly and unreliable in children under 12 years of age. In addition, cases with extremely uncoordinated ciliary beating might be missed by the saccharin test. Pulmonary radioaerosol mucociliary clearance testing Current clinical experience is insufficient to recommend the use of pulmonary radioaerosol mucociliary clearance tests in clinical practice.
A family history of ciliopathy should raise the suspicion of PCD in patients or their relatives with characteristics suggestive of PCD. Ciliopathies constitute a group of diseases associated 12 with genetic mutations that result in changes in ciliary formation or function.
Given that cilia are components of many cell types, ciliary dysfunction can manifest as a constellation of clinical features such as retinal degeneration, kidney disease, and cerebral abnormalities. Molecular genetic studies conducted in recent years suggest a clear relationship between primary cilium development and function and various clinical conditions.
The variety of PCD-associated defects and the rarity of the disease make it difficult to standardize the interpretation of electron microscopy. Some of the material is separated for ciliary beat frequency and ciliary beat pattern analysis, and the remainder is sent for electron microscopy analysis.
Parameters for evaluating ciliary ultrastructure Ciliary orientation Ciliary disorientation is associated with PCD. In cases of ciliary disorientation, ciliary ultrastructure is normal and ciliary beat frequency is normal or near normal, but ciliary motion is inefficient because of ciliary beat disorientation; that is, it does not correctly propel the mucus.
Normal ciliary ultrastructure and PCD Extremely reduced nasal NO levels and abnormal ciliary function ciliary beat frequency, ciliary beat pattern, or both with normal ciliary ultrastructure require genetic testing for a mutation consistent with the disease i.
Respiratory infections and the inflammatory immune response to the infections can affect ciliary function, inducing secondary ciliary dyskinesia. Secondary lesions include compound cilia fused membranes or multiple axonemes within a single membrane , peripheral and central microtubular abnormalities, swelling of the membranes, shortened dynein arms, ciliary membrane blebs, and absence of the ciliary membrane.
Patients with normal ciliary ultrastructure and abnormal ciliary function require ciliary orientation studies. Culture duration is approximately 6 weeks. The ciliary ultrastructure report should be conclusive regarding the presence or absence of PCD-related defects. The results of all investigations should be expressed as a definitive diagnosis Chart 3. Radiology In patients with PCD, a HRCT scan of the chest Figure 3 shows middle and lower lobe involvement-the middle and lower lobes being more affected than the upper lobes in PCD patients when compared with cystic fibrosis patients in whom the upper lobes are more affected than the middle and lower lobes -with subsegmental atelectasis, peribronchial thickening, mucus plugging, evidence of air trapping, ground-glass opacities, 25 areas of consolidation, and well-defined bronchiectasis.
Impaired alveolar gas exchange can occur in the long term, causing respiratory failure, pulmonary hypertension, and right heart failure. There is a relationship between age and loss of lung function, FEV1 decreasing with age. A mean FEV1 drop of 0. Therapy is aimed at improving mucociliary clearance, treating infections, and improving or stabilizing lung function, preventing chronic lung injury. The recommendations are based on expert opinion, being inferred from the available evidence for cystic fibrosis, although there are differences between the two diseases in terms of their pathophysiology.
Regular visits to referral centers are to take place every months in children and every months in adults, as needed. Respiratory monitoring The two pillars upon which respiratory treatment stands are antibiotic therapy and chest physiotherapy. Chest physiotherapy should be performed twice a day for 20 min, increasing during exacerbations. Antibiotic therapy should be initiated at the first sign of any increase in respiratory symptoms or deterioration of lung function, lasting two weeks in general.
Antibiotics should be given on the basis of culture sensitivity testing. Intravenous treatment should be used if symptoms do not respond to oral antibiotics. In adults, colonization with Pseudomonas aeruginosa is not rare and might require more aggressive intravenous therapy and long-term use of inhaled antibiotics.
Hypertonic saline can be effective in improving mucociliary clearance; however, to date, there have been no controlled clinical trials to support its use.
The high genetic variability of the disease determines differences in progression among patients. Pulmonary impairment is more severe in patients diagnosed in adulthood than in those diagnosed in adolescence.
A minority of patients might progress to severe lung disease with respiratory failure requiring lung transplantation. Ciliated cell cultures can aid in the diagnosis of PCD. Normal ciliary ultrastructure does not rule out PCD. The results of all investigations should be expressed as a definitive diagnosis. Acknowledgments We would like to thank Dr. Samia Rached for the CT image. References 1. Factors influencing age at diagnosis of primary ciliary dyskinesia in European children.
Eur Respir J. Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Primary ciliary dyskinesia: evaluation using cilia beat frequency assessment via spectral analysis of digital microscopy images.
J Appl Physiol J Pneumol. Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children. When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol. Genet Med. Disorders of ciliary motility. Am J Med Sci. Regulation of mucociliary clearance in health and disease. Cilia Dysfunction in Lung Disease. Annu Rev Physiol.
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