[Congenital ciliary dyskinesia. Focus]. / Dyskinésie ciliaire congénitale. Mise au point.

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease, caused by specific primary structural and/or functional abnormalities of the motile cilia. Prevalence, about 1/15,000 to 1/30,000, is probably underestimated, as diagnosis might not be evocated in absence of Kartagener syndrome. Diagnosis is confirmed in presence of abnormal ciliary motility as well as ciliary ultrastructure. Disease-causing mutations in at least 16 genes have already been identified; analysis will be guided by the type of ultrastructural abnormalities. An early and adequate diagnosis and therapy can theoretically improve the prognosis of the disease.

[Primary ciliary dyskinesia: who and how to confirm the diagnosis?]. / Dyskinésie ciliaire congénitale: qui et comment explorer?

Primary ciliary dyskinesia (PCD) is a rare genetic disease associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease from early childhood, situs abnormalities and abnormal sperm motility. The diagnosis of PCD can be difficult and is based on the presence of the characteristic clinical phenotype, evidence of abnormal ciliary function and specific ultrastructural ciliary defects identified by transmission electron microscopy. Because prognosis of the disease is related to the age of diagnosis, we suggest in this article, elements that should early orientate diagnostic evaluation of patients suspected of having PCD.

A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia.

Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for the diagnosis of primary ciliary dyskinesia (PCD). We report our extensive experience of TEM analysis in a large series of patients in order to evaluate its feasibility and results. TEM analysis performed in 1,149 patients with suspected PCD was retrospectively reviewed. Biopsies (1,450) were obtained from nasal (44%) or bronchial (56%) mucosa in children (66.5%) and adults (33.5%). TEM analysis was feasible in 71.4% of patients and showed a main defect suggestive of PCD in 29.9%. TEM was more feasible in adults than in children, regardless of the biopsy site. Main defects suggestive of PCD were found in 76.9% of patients with sinopulmonary symptoms and in only 0.4% of patients with isolated upper and 0.4% with isolated lower respiratory tract infections. The defect pattern was similar in children and adults, involving dynein arms (81.2%) or central complex (CC) (18.8%). Situs inversus was never observed in PCD patients with CC defect. Kartagener syndrome with normal ciliary ultrastructure was not an exceptional condition (10.2% of PCD). In conclusion, TEM analysis is feasible in most patients and is particularly useful for PCD diagnosis in cases of sinopulmonary syndrome of unknown origin.

Long term effects of azithromycin in patients with cystic fibrosis: A double blind, placebo controlled trial.

BACKGROUND: Macrolides display immunomodulatory effects that may be beneficial in chronic inflammatory pulmonary diseases. The aim of the study was to document whether long term use of azithromycin may be associated with respiratory benefits in young patients with cystic fibrosis. METHODS: A multicentre, randomised, double blind, placebo controlled trial was conducted from October 2001 to June 2003. The criteria for enrollment were age older than 6 years and forced expiratory volume in 1 second (FEV1) of 40% or more. The active group received either 250 mg or 500 mg (body weight < or > or =40 kg) of oral azithromycin three times a week for 12 months. The primary end point was change in FEV1. RESULTS: Eighty two patients of mean (SD) age 11.0 (3.3) years and mean (SD) FEV1 85 (22)% predicted were randomised: 40 in the azithromycin group and 42 in the placebo group. Nineteen patients were infected with Pseudomonas aeruginosa. The relative change in FEV1 at month 12 did not differ significantly between the two groups. The number of pulmonary exacerbations (count ratio 0.50 (95% CI 0.32 to 0.79), p < 0.005), the time elapsed before the first pulmonary exacerbation (hazard ratio 0.37 (95% CI 0.22 to 0.63), p < 0.0001), and the number of additional courses of oral antibiotics were significantly reduced in the azithromycin group regardless of the infectious status (count ratio 0.55 (95% CI 0.36 to 0.85), p < 0.01). No severe adverse events were reported. CONCLUSION: Long term use of low dose azithromycin in young patients with cystic fibrosis has a beneficial effect on lung disease expression, even before infection with Pseudomonas aeruginosa.

RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare disease classically transmitted as an autosomal recessive trait and characterised by recurrent airway infections due to abnormal ciliary structure and function. To date, only two autosomal genes, DNAI1 and DNAH5 encoding axonemal dynein chains, have been shown to cause PCD with defective outer dynein arms. Here, we investigated one non-consanguineous family in which a woman with retinitis pigmentosa (RP) gave birth to two boys with a complex phenotype combining PCD, discovered in early childhood and characterised by partial dynein arm defects, and RP that occurred secondarily. The family history prompted us to search for an X linked gene that could account for both conditions. RESULTS: We found perfect segregation of the disease phenotype with RP3 associated markers (Xp21.1). Analysis of the retinitis pigmentosa GTPase regulator gene (RPGR) located at this locus revealed a mutation (631_IVS6+9del) in the two boys and their mother. As shown by study of RPGR transcripts expressed in nasal epithelial cells, this intragenic deletion, which leads to activation of a cryptic donor splice site, predicts a severely truncated protein. CONCLUSION: These data provide the first clear demonstration of X linked transmission of PCD. This unusual mode of inheritance of PCD in patients with particular phenotypic features (that is, partial dynein arm defects and association with RP), which should modify the current management of families affected by PCD or RP, unveils the importance of RPGR in the proper development of both respiratory ciliary structures and connecting cilia of photoreceptors.

Abnormal central complex is a marker of severity in the presence of partial ciliary defect.

BACKGROUND: Ciliary ultrastructural defects with total lack of dynein arms (DA) cause abnormal mucociliary function leading to the chronic infections observed in primary ciliary dyskinesia. The role of partial ciliary ultrastructural defects, especially those involving the central complex, and their relationship with respiratory symptoms have been less thoroughly investigated. OBJECTIVE: In a pediatric population with partial ciliary defects, we determined the relationship(s) between ultrastructural findings, ciliary motility, and clinical and functional features, and evaluated the outcome of this population. DESIGN: We analyzed the clinical presentation and pulmonary function of 43 children with chronic bronchitis and partial ultrastructural defects (from 15% to 90%) of their respiratory cilia demonstrated on bronchial biopsies. The study population was divided into 3 groups according to ciliary ultrastructure: the main ultrastructural defect concerned the central complex in 23 patients (CC group), peripheral microtubules in 8 patients (PMT group), and DA in 12 patients (DA group). RESULTS: The percentage of ciliary defects was lower in the PMT group than in the CC and DA groups. Patients in the PMT group had less severe disease with frequent normal ciliary motility. Patients in the CC group had initially a higher incidence of respiratory tract infections, extensive bronchiectasis frequently requiring surgery, and arguments in favor of a congenital origin (high proportion of sibling form). Partial absence of DA, although of congenital origin, was associated with a good prognosis. In all groups, follow-up showed that the functional prognosis remained good with appropriate treatment. CONCLUSIONS: In children with chronic respiratory infections, presence of situs inversus, sibling form, obstructive pulmonary syndrome, or bronchiectasis required ultrastructural analysis, regardless of ciliary motility. Detection of CC abnormalities is a marker of severity and required intensive therapy and close follow-up.

[Diagnosis and management of cystic fibrosis in children]. / Diagnostic et prise en charge de la mucoviscidose chez l'enfant.

Cystic fibrosis is a genetic disease occurring more frequently in Caucasians. The cystic fibrosis gene, cloned in 1999, codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Dysfunction of this protein leads to the clinical manifestations of cystic fibrosis, mainly lung disease and exocrine pancreas disorders. The pathophysiology of the respiratory component is quite complex, basically related to major and excessive inflammatory processes and to early microbial colonization. Respiratory physical therapy is a key element to management of the respiratory disorder. Antibiotic treatments should be adapted to the bacterial ecology, mainly using antistaphylococcal and antihaemophilus drugs initially, then directed against Pseudomonas aeruginosa. Other drugs including inhaled antiinflammatory drugs are currently in the evaluation stage. In addition, nutritional care and correction of pancreas insufficiency are necessary. The diagnosis of this disease must be made early although systematic neonatal screening is not proposed. Early diagnosis is necessary for improved care and prognosis. Currently, median survival is 29 years. This survival time should probably improve with better understanding of the pathophysiological mechanisms and new therapeutic perspectives.

[Pathophysiology of acute thoracic syndrome]. / Physiopathologie du syndrome thoracique aigu.

Pulmonary complications are the leading cause of morbidity and mortality in sickle cell disease patients. Acute chest syndrome (ACS), in which chest pain and dyspnea, occurs in combination with a recent chest radiograph abnormality, raises both diagnostic and therapeutic challenges. The pathogenesis of ACS involves alterations in blood rheology, increased coagulability, and, above all, increased adhesion of sickle cells to the vascular endothelium and nitric oxide-mediated dysregulation of vascular reactivity. Sickle cell disease thus impacts all the cells in the vascular environment. Recently gained insights into pathophysiology offer hope that new treatments for preventing and treating acute and chronic pulmonary complications will soon become available.

[Mucoviscidosis: therapeutic strategies are multiplying]. / Mucoviscidose: les stratégies thérapeutiques se multiplient.

Since the cloning of the defective gene in cystic fibrosis, much has been learned on the function of CFTR and on the mechanisms regulating its expression. Based on the current understanding of the processes involved in lung disease progression, a number of approaches have been developed using gene therapy and pharmacological agents. Several of these agents have been reported to restitute a function to CFTR with specific mutations. Other molecules act on channels other than CFTR, and may be effective by bypassing CFTR itself. In the present review the various therapeutical strategies currently investigated are discussed.

Chronic interstitial lung disease in children: response to high-dose intravenous methylprednisolone pulses.

The prognosis for children with chronic interstitial lung disease is poor and the mortality rate is high, especially in infants. This explains the many therapeutical protocols which have been proposed and investigated by several authors. In the present work, we evaluated the response of three infants with idiopathic pulmonary fibrosis to high-dose intravenous prednisolone pulses. The patients were referred to the department at the age of 4, 17, and 3 months, respectively. The diagnosis was confirmed by open lung biopsy and intravenous pulse methyl prednisolone therapy was started with the following protocol: 300 mg/m2 methylprednisolone daily for 3 days, repeated every 4 to 6 weeks. Because of the extreme severity of the respiratory distress at the time of diagnosis, the intravenous pulse treatments were initially complemented by oral prednisone. Clinical improvement was noticed within 6 months with progressive correction of hypoxemia. After follow-up for 3.5 to 4 years, with a total number of pulses of 37, 26, and 32, respectively, the children are symptom-free and do not require oxygen supplementation. During this period, no side effects and no adrenal insufficiency could be documented. Based on current knowledge of steroid action, it can be speculated that the response to intermittent high-dose intravenous methylprednisolone may explain the ability of this mode of hormone administration to maintain an adequate level of glucocorticoid receptor expression. More information and trials through multicenter collaborations are needed to assess therapeutical protocols of repeated high-dose intravenous steroid treatment.