Discinesia ciliar primaria: criterios clínicos de indicación de estudio ultraestructural Primary ciliary dyskinesia (PCD) is a congenital disease characterized by impaired ciliary function, which involves .. Discinesia ciliar primaria y secundaria. A discinesia ciliar secundária ou adquirida pode ser causada por agressão aos cílios das vias aéreas, em decorrência de insultos variados por agentes físicos e . Key words: Kartagener Syndrome; Primary Ciliary Dyskinesia; Cilia; embryology; Situs Inversus de causalidad posible con la discinesia ciliar primaria y de otros diagnósticos asociados a disfunción ciliar secundaria como fibrosis quística.

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Primary ciliary dyskinesia PCD cilair a genetic disorder of ciliary structure or function. It results in mucus accumulation and bacterial colonization of the respiratory tract which leads to chronic upper and lower secundaira 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.

Primary ciliary dyskinesia PCD is a disease characterized by a change in ciliary beat frequency, ciliary beat pattern, or both and has a heterogeneous genetic basis, typically being an autosomal recessive disorder; the main consequence of ciliary dysfunction is a reduced efficiency of mucociliary clearance of the upper and lower airways, leading to chronic infections and inflammation. Few countries have records of the prevalence, diagnosis, and prognosis of Disxinesia, the data varying greatly across countries.

The prevalence of PCD ranges from 1: Evidence suggests that the diagnosis duscinesia PCD is often delayed, which is mainly due to a failure to recognize the disease and the need for sophisticated technical resources for Discinwsia screening. In Europe, there are reports of more than 1, PCD patients at centers in 26 countries. 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.

Cilia are specialized hairlike structures covered by plasma membrane and extending from the cell surface. Cilia are classified as motile or nonmotile. Motile cilia play a role in cell motility and extracellular fluid movement. During embryonic development gastrulationcells 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. 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. Motile ciliated airway epithelial cells are present in the nasal cavity, paranasal sinuses, middle ear, fallopian tube, cervix, vasa deferentiaand ependyma. 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.

The main function of ciliated airway epithelial cells is to mediate the propulsion of the mucus gel layer toward the head through coordinated movements.

The presence of general clinical indicators culiar all age groups and age-specific indicators should raise the clinical suspicion of PCD. Age-specific indicators include prenatal indicators situs abnormalities on ultrasoundneonatal indicators rhinorrhea ssecundaria 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 PCDchildhood 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 PCDand 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 cilisr time. According to a European consensus statement, diagnostic tests should be performed in the following groups: Patients should be referred to a specialized center 6 for clinical history taking and screening tests, as well as ciliary function tests ciliary beat frequency and ciliary beat pattern2 ciliary ultrastructural analysis, immunofluorescence, and genetic analysis.


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 diagnosis of PCD depends on appropriate training and resources. 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, 1516 as has ciliated cell culture.

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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. High-speed video imaging of the ciliary beat frequency and pattern contributes to the understanding of the effects of ciliary defects on mucus transport.

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.

Immunofluorescence assays of cilia collected by nasal brushing, performed with specific antibodies and based on established mutations, can aid in the genetic diagnosis of PCD.

Semen analysis is used in some centers in Brazil as an indirect indicator of PCD, given that sperm cells behave like modified cilia, with reduced motility. 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 2425 are controlled by common genes and different genes.

In order to establish a definitive diagnosis of PCD, certain phenotypic characteristics at least three characteristics, typically five or more characteristics should be present: 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 secunndaria gene are located on one chromosome and the mutant allele discinesoa and wild-type allele B of another gene disvinesia located on the homologous chromosome-and no correcting mutations. Screening tests are important in order to select which of the patients with signs and symptoms suggestive of PCD should undergo analysis of ciliary function and ultrastructure.

Exhaled nasal NO measurement is currently the most recommended screening test. 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, discibesia 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.

The saccharin test is a good test to assess nasal seucndaria transport, which is usually prolonged in individuals with PCD. 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 ciliae beating might be missed by the saccharin test.

Current clinical experience is insufficient to recommend the use of pulmonary radioaerosol mucociliary clearance tests in clinical practice. Genetic studies have identified mutations in several genes encoding ciliary structure and functional proteins; however, genetic tests are not readily available in clinical practice.

There is evidence that ciliary disorders are related to various developmental problems and clinical conditions, which are known as ciliopathies. 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.

Kartagener syndrome is a rare congenital malformation consisting of the triad of situs inversus, bronchiectasis, and sinusitis. Although several transmission electron microscopy facilities have been working on the standardization of diagnostic criteria to be used in ciliary ultrastructural analysis, no proposal has been universally accepted. The variety of PCD-associated defects and the rarity of the disease make it difficult to standardize the interpretation of cjliar microscopy.

There are multiple factors that limit the use of electron microscopy as a diagnostic test for PCD: For ciliated cell collection, nasal brushing has lower morbidity than does nasal biopsy, as well as being ciiar costly and easier to perform.

Diagnosis of primary ciliary dyskinesia

Some of the material is separated for ciliary beat frequency and ciliary beat pattern analysis, and the remainder is sent for electron microscopy analysis. For ciliated cell collection, patients are required to be free of acute respiratory infection for weeks in order to minimize the presence of changes caused by secondary dyskinesia.

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.

The peripheral microtubules can show disorganization and inner dynein arm defects, 3 as well as transposition defects the central pair being replaced by a peripheral microtubule. Quantification of outer and inner dynein arms is performed in some centers, the standards varying across centers. Partial absence of dynein as a primary defect is considered controversial and requires further studies for confirmation.

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.

Dynein arm defects are the most common defects in patients with PCD: In patients with PCD, ultrastructural changes include nexin link defects, 49 absence of the central pair of microtubules, and absence of the basal bodies and sheath alternatively, the basal bodies and sheath are present but have a reduced number of cilia.

Secondary or acquired ciliary dyskinesia can be caused by injury to ciliated airway epithelial cells by physical and chemical agents. Respiratory infections and the inflammatory immune response to the infections can affect ciliary function, inducing secondary ciliary dyskinesia.

Secondary discineisa include compound cilia fused membranes or multiple axonemes within a single membraneperipheral 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.

Ciliated cell cultures are performed only at specialized centers and are followed by transmission electron microscopy analysis, being recommended to differentiate between primary and secondary defects.

Culture duration is approximately 6 weeks. The absence of secondary defects after growth in culture media ciliogenesis contributes to the diagnosis of PCD. The presence of inner dynein arm defects 3 or ciliary disorientation alone requires new samples in order to confirm the diagnosis. The ciliary ultrastructure report should secundaris conclusive regarding the presence or absence of PCD-related defects. The results of all investigations should be expressed ckliar a definitive diagnosis Chart 3.

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.

The presence of bronchiectasis is related to age. Genetic defects in respiratory epithelial cilia cause a significant reduction in mucociliary transport, with retention of secretions, recurrent infections, and, consequently, bronchiectasis. Impaired alveolar gas exchange can occur in the long term, causing respiratory failure, pulmonary hypertension, and right heart failure.

Loss of lung function occurs as secumdaria result of undertreatment or delayed diagnosis. There is a relationship between age and loss of lung function, FEV 1 decreasing with age.

A mean FEV 1 drop ciloar 0.