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Importance of nitric oxide in regulation of ciliary activity and secretion of the mucin was discussed. Advantage of measurement of nasal nitric oxide concentration in course of maxillary sinuses diseases was emphasized.
BACKGROUND: Primary ciliary dyskinesia is characterized by a congenital alteration of the ciliary ultrastructure and function. As a consequence, their respiratory tract sweeping action is lost and recurrent respiratory infections ensue. AIM: To analyze a clinical series of patients with primary ciliary dyskinesia, their clinical and laboratory features. PATIENTS AND METHODS: A retrospective review of patients with primary ciliary dyskinesia seen a University Hospital, between 1994 and 1998. Bronchial biopsies were obtained with 3.6 mm diameter Olympus fibrobronchoscope, using a cayman type forceps. Ultrastructural alterations of respiratory tract ciliated cells were recorded. RESULTS: Six patients (four male) aged 9 months to 13 years old were reviewed. Three patients had situs inversus. All had repeated bouts of obstructive bronchitis and pneumonia, five had sinusitis, four atelectasis, three recurrent otitis and three had bronchiectasis. Cystic fibrosis and immunological alterations were ruled out in five children. Ultrastructural analysis revealed absence of dynein arms in three cases, absence of the internal dynein arm in one, additional peripheral microtubules and absence of dynein arms in one case. CONCLUSIONS: Primary ciliary dyskinesia must be considered in the differential diagnosis of recurrent respiratory infections. Ultrastructural analysis of ciliary structure can be done in bronchial biopsies obtained through bronchoscopy.
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In the ciliary dyskinesia (immotile cilia syndrome) shows the partial or total lacking of cilia's elements. The ciliary dyskinesia may be developed congenital or acquired. The authors report on the experience with 72 biopsies from bronchial mucosa of 68 children, submitted with the question of immotile cilia syndrome. On micrographs (M: 64,000x) of the specimens processed by routine electron microscopical method the number of outer and inner dynein arm, A and B peripheral tubules, central tubules and central sheet were determined to normal 9 + 2 structure. 50-100 ciliaris per case were examined. Total or partial lacking of dynein and non-dynein elements were expressed for the total number of ciliaris compartments. Considering any earlier quantitative examination with this expression there was ease to characterised the quantitative behaviour of the components of ciliaris. Seven Kartagener's syndrome cases was the positive control for determined the quantitative differences between the primer and secondary ciliary changes. In the primary ciliary defects where the situs inversus were presented the total lacking of outer or/and inner dynein arms, where the situs inversus were not presented only the total lacking of inner dynein arms could be found. In secondary ciliary defects the partial lacking of the dynein arms and tubular components were presented. The used method is suitable to characterise the primary or secondary ciliary defects of bronchial mucosa.
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BACKGROUND: Primary ciliary dyskinesia (PCD) is an inherited disease characterized by specific ultrastructural defects of cilia and sperms. The impairment of mucociliary clearance (MCC) results in chronic respiratory infections and subsequently in bronchiectasis. MAIN PURPOSE: The evaluate rational decisions in early diagnosis of PCD. METHODS: Samples of nasal mucosa or tissue of tonsilla pharyngea after adenotomy were studied by transmission electron microscopy (TEM) in 47 patients aged 1-15 years, suffering from recurrent or chronic respiratory infections. RESULTS: Congenital ultrastructural ciliary defects specific for PCD--the lack of dynein arms, radial spokes defects and microtubular transposition--were observed in 13 patients. TEM investigation is an expansive, time consuming method not available in routine practice. Therefore we have evaluated a diagnostic procedure which uses available examination methods focused on the diagnoses of PCD. TEM of respiratory cilia is indicated in patients with situs viscerum solitus if chronic respiratory disease develops and after more frequent causes--asthma, cystic fibrosis, congenital anomalies of respiratory system and immunodeficiency had been excluded. CONCLUSIONS: The correct and early diagnosis is important for effective therapy in order to improve MCC. This approach can prevent the development of bronchiectasis during childhood.
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Nitric oxide (NO) has witnessed an explosion of interest of scientists all over the world during the last decade. This small gaseous molecule is produced in many systems such as the nervous system, cardiovascular system, the upper and lower airways. In all of these it contributes to a number of (patho)physiological processes. Concerning the airways, NO concentrations in the upper respiratory tract are much higher (i.e. ranging from 200 to 2000 parts per billion (ppb)) than NO levels in the lower respiratory tract (i.e. ranging from 4 to 160 ppb). NO is most frequently measured using a chemiluminescence method, based on a reaction of NO with O3 resulting in the emission of light. In the airways NO exerts many functions in host defense, ciliary activity, inflammation and it is also an aerocrine messenger between the upper and lower airways. Nasal NO concentrations are influenced by age, physical exercise, smoking and certain drugs. Nasal NO is conveniently measured in all ages and can be used for screening of disease or monitoring the effects of treatment. Pathological conditions, as in allergic rhinitis, sinusitis, nasal polyps, cystic fibrosis and primary ciliary dyskinesia, result in altered nasal NO concentrations. The clinical relevance for measurement of nasal NO in different conditions, however, remains to be established.
The architecture of the cilium seemingly is very simple but the appearance is deceptive; its 'engine' actually is quite complex. There is a circle of nine microtubular doublets around two central singlet microtubules, with dynein arms and spokes extending from the doublets, and nexin links joining them. The inner microtubules are partly surrounded by a central sheath. Many uncertainties remain, for instance the role of the spokes, the nexin links and of the various categories of inner dynein arms. The complexity as seen today is largely the result of new methodologies being introduced, such as the deep-etch technique or image processing using various computer programs. The inborn disease named immotile-cilia syndrome is characterized by the cilia being defective. It is a highly heterogeneous disease in that more than a dozen subgroups characterized by different ciliary defects have been recognized.
In this article a review is presented of the morphology and function of respiratory cilia and emphasis is placed on the importance of mucociliary clearance as the most important defense mechanism of the upper and lower airways. Physical factors and pharmacological substances which can influence ciliary activity and mucociliary transport are mentioned. Finally, a description is given of changes, mostly reversible, of the mucociliary transport system in infections and IgE-mediated allergy and of the, irreversible changes in congenital diseases like cystic fibrosis and primary ciliary dyskinesia, with some remarks as to the therapeutical consequences of these disturbances.
Mucociliary transport is a major defense mechanism of the airways. Mucociliary clearance is functionally and ultrastructurally organized at different levels from individual cilia to the ciliated tapestry. The correlations among ciliary beat frequency (CBF), secondary abnormalities (SCD), ciliary (dis)orientation (COR), coordinated ciliary activity and ciliary immotility were investigated based on the findings in over 700 non-PCD biopsies taken in the context of diagnostic investigations for respiratory problems. CBF decreased with increasing percentages of SCD, from 7.6 +/- 1.8 Hz (0-5% SCD) to 4.9 +/- 3.3 Hz (> 25% SCD). COR increased with increasing percentages of SCD, from 15 +/- 7 degrees for < 5% SCD to 28 +/- 8 degrees (> 25% SCD). SCD also correlated with ciliary (im)motility, but not with ciliary coordination. No correlation was found between COR and CBF. However, increased COR (28 +/- 8 degrees) was found in samples with only immotile cilia, compared to those with ciliary activity (19 +/- 9 degrees). Similar findings were demonstrated between COR and coordinated activity, particularly between immotile cilia (28 +/- 8 degrees) and those with coordinated ciliary activity (19 +/- 9 degrees). CBF values from samples with no coordinated activity (5.5 +/- 2.9 Hz) were significantly different from those with coordinated ciliary activity (7.4 +/- 1.6 Hz). In conclusion, mucociliary transport is a well organized, complex process with many interactions between parameters at various levels of functional and structural organization. SCD seems to play a crucial role. The correlations among the different parameters can help us further understand the functional and ultrastructural mechanisms needed for efficient mucociliary clearance.
Primary ciliary dyskinesia (PCD) is an inherited condition characterised by functional and/or structural congenital abnormalities of cilia. Presentation is often in the neonatal period, but there are age-related differences in presentation, and diagnosis is often delayed. The usual clinical picture is of recurrent upper and lower respiratory symptoms (rhinitis, glue ear, recurrent cough and sputum production), with mirror image arrangement in 50% of the children. Around 50% males have immotile sperm, but male infertility is not invariable. There are known associations between PCD and complex congenital heart disease, severe oesophageal disease, and more rarely, hydrocephalus and biliary atresia. Diagnosis is with a combination of the saccharine test, nasal nitric oxide, ciliary beat frequency and electron microscopy. Patients should be followed up by specialists familiar with the different ways of managing the upper and lower airway complications.
Dynein arms and spokes are crucial components of cilia. Reference values for the dynein arms and spokes were calculated based on biopsies from non-PCD patients as well as after ciliogenesis in culture. The mean values in the biopsies (n = 251) were 8.4 +/- 0.5, 2.9 +/- 0.7 and 4.7 +/- 1.0 for the outer dynein arms, inner dynein arms and spokes respectively. After ciliogenesis in culture (n = 462) identical values were found: 8.7 +/- 0.4, 3.0 +/- 0.4 and 5.5 +/- 0.6. The lower limits of normality can be set at 7.0 and 1.2 for the outer and inner dynein arms respectively. The dynein arms and spokes were not influenced by the percentage of secondary abnormalities. In conclusion, dynein arms and spokes are readily identified after ciliogenesis in culture. These parameters are independent of secondary ciliary dyskinesia.
Ultrastructural secondary ciliary dyskinesia (SCD) was measured using transmission electron microscopy in 301 biopsies and 439 samples after ciliogenesis in the sequential monolayer-suspension culture. Biopsies were taken in the context of exclusion of primary ciliary dyskinesia. SCD was frequently found in the biopsies: only 30% of the samples were normal (SCD < 5%), the mean percentage of SCD abnormalities was 11.9 +/- 12.9%. In 1/8 of the samples severe SCD (> 25%) was present. The most frequently encountered SCD abnormality was the membrane bleb, followed by the various peripheral microtubular abnormalities. With increasing total SCD the absence of the central pair became more important. After ciliogenesis in culture SCD was virtually absent: 1.0 +/- 1.8% for all 439 samples, 96% of the samples were within limits of normality (SCD < 5%). Moderate (15-25%) and severe SCD (> 25%) were never found. In more than 50% of the samples not one abnormality was found. There was no relation between the SCD in the biopsy and that after ciliogenesis. The absence of SCD after ciliogenesis is a major advantage for the diagnosis of PCD, specifically in cases with central pair abnormalities, peripheral microtubular pair abnormalities and those without a primary ultrastructural abnormality.
During the period 1990-1999 84 PCD patients were identified and characterized. The expression of inherited abnormalities in primary ciliary dyskinesia after ciliogenesis was investigated in 41 patients with dynein deficiency, 6 patients with absence of the central pair of microtubules and 24 PCD patients with normal ultrastructure. In patients with dynein deficiency, the outer dynein arms counts were 1.9 +/- 1.0 in the biopsies and 1.6 +/- 0.7 after ciliogenesis. Secondary abnormalities were found in 15.8 +/- 20.4% of the transverse sections of cilia and only in 1.0 +/- 1.3% after ciliogenesis. Ciliary orientation was 28 +/- 11 degrees and 24 +/- 10 degrees respectively in biopsies and cultures. In patients with absence of the central pair this was found in 15 +/- 16% in biopsies and 21 +/- 19% after ciliogenesis. The values for the outer dynein arm were 8.4 +/- 0.3 and 8.7 +/- 0.2 and for the secondary abnormalities were 11.7 +/- 7.3% and 0.5 +/- 1.3% in the biopsies, respectively after ciliogenesis. In patients with normal ultrastructure the scores for the dynein arms were similar. Secondary abnormalities were found in 12.2 +/- 11.7% in the biopsies and 0.6 +/- 0.9% after ciliogenesis while ciliary orientation was respectively 21 +/- 7 degrees and 25 +/- 8 degrees. In conclusion, inherited abnormalities in primary ciliary dyskinesia are expressed after ciliogenesis, while secondary abnormalities are virtually absent, thereby facilitating the ultrastructural diagnosis.
The sequential monolayer-suspension culture technique has been used in over 800 samples during the period from January 1, 1990 till December 31, 1999. Patients were referred from all over Belgium. The culture technique was successful in 75% of the samples. In 85% of the patients a final conclusion regarding the exclusion/diagnosis of primary ciliary dyskinesia was made. In a total of 84 patients (10.3%) the final diagnosis was primary ciliary dyskinesia. Eighteen percent of the samples were considered normal, in 24% secondary ciliary dyskinesia was diagnosed.
Adequate surface protection of the upper airway tract depends on intimate co-operation between natural non specific defence mechanisms such as ciliary function and acquired adaptative immunity. The latter is mediated by specific antibodies mainly belonging to secretory immunoglobulin A (SIgA) and to lesser extent secretory IgM (SigM) as well as by serum derived and locally produced IgG. Immunoglobulin's deficiency may exist in a significant percentage of patients with chronic or recurrent infections of the upper respiratory tract. So an immunologic screening should be extended to patients who have persistent sinus infection, despite normal mucocilary and ventilation patterns, inadequate response to antimicrobial therapy, culture of unusual pathogens from the upper respiratory tract or history of infection at other side, mainly bronchopulmonary. The therapeutic aspects include immunoglobulin replacement or mucosal immunogens whose efficacy is related with both an unspecific and a specific way. In the future, cytokines will probably become the strongest therapy of the immunoglobulin's deficiency.
Abnormalities of the local defense mechanisms of the upper airways are very common, but severe (inherited) diseases are rare. The most important ones are humoral immune deficiencies, cystic fibrosis and primary ciliary dyskinesia. In differentiating these diseases the clinical picture is essential, giving clues to each of the diseases. Additional investigations are indicated whenever common diseases such as allergy, gastro-esofageal reflux and adenoid hypertrophy cannot explain the problems. With a battery of tests including immunoglobulin measurements, sweat test and ciliary investigations in the majority of cases the explanation can be found.