Treatment Of Primary Ciliary Dyskinesia Research Articles

Primary ciliary dyskinesia: review of the draft clinical guidelines, 2022

Primary ciliary dyskinesia (PCD) is a rare hereditary disease from the group of ciliopathies, which is based on a defect in the cilia ultrastructure of the respiratory epithelium and similar structures (sperm flagella, villi of the fallopian tubes, ventricular ependyma, etc.), leading to motor function impairment. The prevalence of the disease varies significantly around the world and is not known reliably in the Russian Federation.The aim of the review was to analyze literature data on modern approaches to the diagnosis and treatment of PCD.Methodology. The data of 90 articles and the opinions of experts providing care to patients with PCD were used.Results. The classic manifestations of PCD depend on age. The leading manifestations of the disease in patients with PCD are recurrent inflammatory diseases of the upper and lower respiratory tract (bronchitis, pneumonia), with the formation of bronchiectasis, damage to the ENT organs (chronic rhinitis, rhinosinusitis, nasal polyposis, repeated otitis media, progressive hearing loss). Currently, there is no single method which could serve as a “gold” standard for diagnosing PCD. The diagnosis of PCD is based on the characteristic clinical picture in combination with the results of special tests (nitric oxide in exhaled air, DNA diagnostics, high-speed video microscopy, transmission electron microscopy). The genetic diagnostics has not been developed sufficiently in the global practice yet and is unavailable in our country. The approach to the treatment of a patient with PCD should be multidisciplinary due to multiple organ lesions. According to the European consensus, the goal of PCD therapy is to restore or maintain normal lung function. There have been no randomized trials of treatment for PCD, and therefore all treatment recommendations are based on very low-level evidence or extrapolated from cystic fibrosis guidelines. Recommendations on mucolytic, antibacterial and anti-inflammatory therapy of PCD are given with consideration for the international and domestic experience.Conclusion. The development of a new version of clinical guidelines containing up-to-date relevant information will improve the diagnosis and treatment of PCD in the Russian Federation.

Inhaled delivery of a lipid nanoparticle encapsulated messenger RNA encoding a ciliary protein for the treatment of primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a respiratory disease caused by dysfunction of the cilia with currently no approved treatments. This predominantly autosomal recessive disease is caused by mutations in any one of over 50 genes involved in cilia function; DNAI1 is one of the more frequently mutated genes, accounting for approximately 5–10% of diagnosed PCD cases. A codon-optimized mRNA encoding DNAI1 and encapsulated in a lipid nanoparticle (LNP) was administered to mice via aerosolized inhalation resulting in the expression human DNAI1 in the multiciliated cells of the pseudostratified columnar epithelia. The spatial localization of DNAI1 expression in the bronchioles indicate that delivery of the DNAI1 mRNA transpires the lower airways. In a PCD disease model, exposure to the LNP-encapsulated DNAI1 mRNA resulted in increased ciliary beat frequency using high speed videomicroscopy showing the potential for an mRNA therapeutic to correct cilia function in patients with PCD due to DNAI1 mutations.

A Novel Compound Heterozygous Mutation in the DNAH11 Gene Found in Neonatal Twins With Primary Ciliary Dyskinesis.

Background: Primary ciliary dyskinesia (PCD) is a rare genetically heterogeneous disorder of motile cilia. Common features of PCD include upper and lower respiratory tract disease, secretory otitis media, situs inversus and fertility problems. To date, although several PCD-associated genes have been identified, the genetic causes of most PCD cases remain elusive. Methods: In this case study, we analyzed the clinical and genetic data of one case of monochorionic diamniotic twins which were suspected of having PCD on the basis of clinical and radiological features including situs inversus, recurrent wet cough and sinusitis as well as varying degrees of respiratory distress. Whole-exome sequencing was performed to identify variants of the DNAH11 gene in the twins. Sanger sequencing and real-time quantitative polymerase chain reaction (RT-qPCR) were used for validation of DNAH11 variants both in the patient and the twins. Results: In the twins, we found a novel mutation at c.2436C > G (p.Y812 *) and a pathogenic deletion encompassing 2.0 Kb of 7P15.3 ([GRCh38] chr7: g.21,816,397-21,818,402). The deleted region included exons 64 and 65 of DNAH11. Sanger sequencing also revealed that the twins’ father was a carrier of heterozygous C.2436C > G and a heterozygous deletion was detected in the mother. No other clinically relevant genetic variants were identified. Conclusion: We describe a novel DNAH11 gene compound heterozygous mutation in newborn twins with PCD and recommend that PCD diagnosis should be considered in newborns presenting with respiratory distress and/or situs inversus. Early diagnosis and treatment of PCD will help control disease progression and improve the patient’s quality of life.

Inhaled Delivery of a Lipid Nanoparticle Encapsulated Messenger RNA Encoding a Ciliary Protein for the Treatment of Primary Ciliary Dyskinesia

Inhaled Delivery of a Lipid Nanoparticle Encapsulated Messenger RNA Encoding a Ciliary Protein for the Treatment of Primary Ciliary Dyskinesia

New Diagnostic Methods and Treatment Recommendations in Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a rare and genetically heterogeneous disease and clinically characterized by neonatal respiratory distress, organ laterality defects, persistent rhinosinusitis, chronic bronchitis, and eventually bronchiectasis. Currently, there is no single “gold standard” diagnostic test for PCD. PICADAR (Primary Ciliary Dyskinesia Rule) score is a guide to decide for further evaluation of diagnostic tests in PCD. European Respiratory Society (ERS) and American Thoracic Society (ATS) recommend diagnostic tests, including nasal nitric oxide (nNO), high-speed video analysis (HSVMA), transmission electron microscopy (TEM) and genetic testing. Cryo-electron tomography and immunofluorescence methods are new techniques recently performed by specialized centers and needs to be improved. Age at diagnosis for PCD changes according to awareness of disease and available diagnostic tests in different centers. Regular follow-up and multidisciplinary approach is important in the management of PCD. The main aim of the treatment is to prevent pulmonary exacerbations and slow the progression of the disease since there are no treatment approaches to correct the underlying cilia structure and its functions in PCD. Although, there are not enough randomized controlled trials for the treatment of PCD, recent treatments are usually based on to improve the mucociliary clearance. Early diagnosis with multidisciplinary management and nutritional advice could improve growth and delay disease progression leading to bronchiectasis and lung function impairment in PCD

Knowledge of Rare Respiratory Diseases among Paediatricians and Medical School Students.

Alpha-1-antitrypsin deficiency (AATD) and primary ciliary dyskinesia (PCD) are underdiagnosed rare diseases showing a median diagnostic delay of five to ten years, which has negative effects on patient prognosis. Lack of awareness and education among healthcare professionals involved in the management of these patients have been suggested as possible causes. Our aim was to assess knowledge of these diseases among paediatricians and medical school students to determine which knowledge areas are most deficient. A survey was designed with questions testing fundamental aspects of the diagnosis and treatment of AATD and PCD. A score equal to or greater than 50% of the maximum score was set as the level necessary to ensure a good knowledge of both diseases. Our results indicate a profound lack of knowledge of rare respiratory diseases among paediatric professionals and medical students, suggesting that it is necessary to increase rare respiratory diseases training among all physicians responsible for suspecting and diagnosing them; this will allow early diagnosis and the setup of preventive measures and appropriate early-stage treatment. The first step in closing this knowledge gap could be to include relevant material in the medical syllabus.

Pathogenesis and treatment of primary ciliary dyskinesia

Bronchiectasis refers to irreversible enlargement and thickening of the wall of the terminal bronchi, including destruction of the bronchial wall muscles and elastic supporting tissues. It can be caused by infection, physiochemical, immunological or genetic and so on. The pathogenesis and treatment of hereditary bronchiectasis, especially primary ciliary dyskinesia (PCD), has attracted much attention in recent years. In this paper, the classification of bronchiectasis and the pathogenesis and treatment of PCD are discussed. The pathogenesis and treatment of hereditary bronchiectasis are described. Key words: Bronchiectasis/ET; Ciliary motility disorders/GE; Review

A Systematic Review of the Treatment of Chronic Rhinosinusitis in Adults with Primary Ciliary Dyskinesia

Background: Primary ciliary dyskinesia (PCD) may be an underlying factor in some cases of refractory chronic rhinosinusitis (CRS). However, clinical management of this condition is not well defined. This systematic review examines the available evidence for the diagnosis and management of CRS in adults with PCD. Methods: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pubmed, EMBASE, and Cochrane database were queried for studies pertinent to treatment of PCD in adults. Two investigators performed eligibility assessment for inclusion or exclusion in a standardized manner. Results: Of the 278 articles identified, six studies met the criteria for analysis. These studies had a predominately low level of evidence. Medical therapy included oral antibiotics and nasal saline rinses. Endoscopic sinus surgery (ESS) was described in three of six studies. Outcomes measures were limited and included non-validated questionnaires, subjective reporting of CRS symptoms, and decreased preciptins against pseudomonas following ESS. Recommendation for a standardized therapeutic strategy was not possible with the available literature. Conclusion: A paucity of evidence is available to guide the treatment of PCD in the adult population. Further prospective studies are needed to determine the optimal diagnostic and management strategy for this condition.

Study protocol, rationale and recruitment in a European multi-centre randomized controlled trial to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in primary ciliary dyskinesia

BackgroundClinical management of primary ciliary dyskinesia (PCD) respiratory disease is currently based on improving mucociliary clearance and controlling respiratory infections, through the administration of antibiotics. Treatment practices in PCD are largely extrapolated from more common chronic respiratory disorders, particularly cystic fibrosis, but no randomized controlled trials (RCT) have ever evaluated efficacy and safety of any pharmacotherapeutics used in the treatment of PCD. Maintenance therapy, with the macrolide antibiotic azithromycin, is currently widely used in chronic respiratory diseases including PCD. In addition to its antibacterial properties, azithromycin is considered to have beneficial anti-inflammatory and anti-quorum-sensing properties.The aim of this study is to determine the efficacy of azithromycin maintenance therapy for 6 months on respiratory exacerbations in PCD. The secondary objectives are to evaluate the efficacy of azithromycin on lung function, ventilation inhomogeneity, hearing impairment, and symptoms (respiratory, sinus, ears and hearing) measured on a PCD-specific health-related quality of life instrument, and to assess the safety of azithromycin maintenance therapy in PCD.MethodsThe BESTCILIA trial is a European multi-centre, double-blind, randomized, placebo-controlled, parallel group study. The intervention is tablets of azithromycin 250/500 mg according to body weight or placebo administered three times a week for 6 months. Subjects with a confirmed diagnosis of PCD, age 7–50 years, are eligible for inclusion. Chronic pulmonary infections with Gram-negative bacteria or any recent occurrence of non-tuberculous mycobacteria are exclusion criteria. The planned number of subjects to be included is 125. The trial has been approved by the Research Ethics Committees of the participating institutions.DiscussionWe present a study protocol of an ongoing RCT, evaluating for the first time, the efficacy and safety of a pharmacotherapeutic treatment for patients with PCD. The RCT evaluates azithromycin maintenance therapy, a drug already commonly prescribed in other chronic respiratory disorders. Furthermore, the trial will utilize the Lung clearance index and new, PCD-specific quality of life instruments as outcome measures for PCD. Recruitment is hampered by frequent occurrence of Pseudomonas aeruginosa infection, exacerbations at enrolment, and the patients’ perception of disease severity and necessity of additional management and treatment during trial participation.Trial registrationEudraCT 2013-004664-58 (date of registration: 2014-04-08).

Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review: Diagnosis and Management of PCD

Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review: Diagnosis and Management of PCD

Clinical analysis of patients with primary ciliary dyskinesia in mainland China.

Primary ciliary dyskinesia (PCD) is a rare, genetic disorder featured with dysfunctional motility of cilia. Clinical presentations of PCD include situs inversus, repeated respiratory tract infections, otitis media, sinusitis and infertility. This study aims to provide clinical strategies on diagnosis and treatment of PCD. Clinical data of seven patients diagnosed as PCD in Zhongshan Hospital, Fudan University were analyzed. We also extracted data from other cases in mainland China from the China Academic Journals Full-Text Database by the end of 2012. A total of 127 cases of PCD were summarized and analyzed in this study. Seven patients in Zhongshan Hospital, Fudan University were finally confirmed to have PCD. All of them had clinical history of recurrent respiratory infection. Imaging analysis showed varying degrees of bronchiectasis. Pulmonary function tests in four patients showed combined obstructive and restrictive patterns. Three cases were confirmed to have PCD by electron microscopy. We then further extracted information from literature for those 127 PCD patients in mainland China. All of them had chronic respiratory infection. Seven cases were complicated with recurrent otitis media and 15 cases were complicated with infertility. A total of 119 patients were diagnosed with situs inversus totalis (94%). Among those 127 patients, only 9 patients' diagnosis was confirmed by electron microscopy. Four patients received sinus resection, and one patient received pulmonary lobectomy due to recurrent hemoptysis. One patient died of massive hemoptysis. Being a rare disease and easily confused with uncomplicated bronchiectasis, PCD diagnosis warrants particular attention. Recurrent respiratory infection, especially situs inversus could be the most important indicator of this disease.

Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia that leads to oto-sino-pulmonary diseases and organ laterality defects in approximately 50% of cases. The estimated incidence of PCD is approximately 1 per 15,000 births, but the prevalence of PCD is difficult to determine, primarily because of limitations in diagnostic methods that focus on testing ciliary ultrastructure and function. Diagnostic capabilities have recently benefitted from (1) documentation of low nasal nitric oxide production in PCD and (2) discovery of biallelic mutations in multiple PCD-causing genes. The use of these complementary diagnostic approaches shows that at least 30% of patients with PCD have normal ciliary ultrastructure. More accurate identification of patients with PCD has also allowed definition of a strong clinical phenotype, which includes neonatal respiratory distress in >80% of cases, daily nasal congestion and wet cough starting soon after birth, and early development of recurrent/chronic middle-ear and sinus disease. Recent studies, using advanced imaging and pulmonary physiologic assessments, clearly demonstrate early onset of lung disease in PCD, with abnormal air flow mechanics by age 6-8 years that is similar to cystic fibrosis, and age-dependent onset of bronchiectasis. The treatment of PCD is not standardized, and there are no validated PCD-specific therapies. Most patients with PCD receive suboptimal management, which should include airway clearance, regular surveillance of pulmonary function and respiratory microbiology, and use of antibiotics targeted to pathogens. The PCD Foundation is developing a network of clinical centers, which should improve diagnosis and management of PCD.

Ciliary function and the treatment of primary ciliary dyskinesia

Ciliary function and the treatment of primary ciliary dyskinesia

Conditional Deletion of Dnaic1 in a Murine Model of Primary Ciliary Dyskinesia Causes Chronic Rhinosinusitis

Studies of primary ciliary dyskinesia (PCD) have been hampered by the lack of a suitable animal model because disruption of essential ciliary genes in mice results in a high incidence of lethal hydrocephalus. To develop a viable mouse model for long-term studies of PCD, we have generated a transgenic mouse line in which two conserved exons of the mouse intermediate dynein chain gene, Dnaic1, are flanked by loxP sites (Dnaic1(flox/flox)). Dnaic1 is the murine homolog of human DNAI1, which is mutated in approximately 10% of human PCD cases. These mice have been crossed with mice expressing a tamoxifen-inducible Cre recombinase (CreER). Treatment of adult Dnaic1(flox/flox)/CreER(+/-) mice with tamoxifen results in an almost complete deletion of Dnaic1 with no evidence of hydrocephalus. Treated animals have reduced levels of full-length Dnaic1 mRNA, and electron micrographs of cilia demonstrate a loss of outer dynein arm structures. In treated Dnaic1(flox/flox)/CreER(+/-) animals, mucociliary clearance (MCC) was reduced over time. After approximately 3 months, no MCC was observed in the nasopharynx, whereas in the trachea, MCC was observed for up to 6 months, likely reflecting a difference in the turnover of ciliated cells in these tissues. All treated animals developed severe rhinosinusitis, demonstrating the importance of MCC to the health of the upper airways. However, no evidence of lung disease was observed up to 11 months after Dnaic1 deletion, suggesting that other mechanisms are able to compensate for the lack of MCC in the lower airways of mice. This model will be useful for the study of the pathogenesis and treatment of PCD.

Primary ciliary dyskinesia: Myths and realities

Primary ciliary dyskinesia (PCD) is an inherited disease affecting the structure and function of the cilia lining the respiratory tract. Because functioning cilia are paramount in mucociliary clearance mechanisms, PCD results in recurrent ear, nose and lung infections, as well as neonatal respiratory distress. Kartagener’s syndrome, a triad of situs inversus totalis, recurrent sinusitis and bronchiectasis was first described in 1933, and is now recognized as only one of the classical phenotypes of PCD (Figure 1). Infertility occurs in the majority of males with PCD. Hydrocephalus, complex heart disease, polysplenia and biliary atresia are uncommon associations. Figure 1) High resolution computed tomography scan of the chest of an eight-year-old boy with Kartagener’s syndrome (primary ciliary dyskinesia with situs inversus totalis) showing extensive bronchiectasis at a young age PCD is a rare disease with an estimated incidence of approximately 1:15,000; thus, it often does not get attention in a medical school curriculum and is not the focus of much research. As a result, it is often underdiagnosed and undertreated. There are many myths about the presentation and treatment of PCD that are only becoming evident with newer multicentre collaborative research efforts that have allowed larger numbers of patients to be studied together. The present brief commentary will touch on some of the myths and realities of PCD that have recently become evident.

Discinesia ciliar primária: quando o pediatra deve suspeitar e como diagnosticar?

OBJETIVO: Revisar a discinesia ciliar primária (DCP) quanto aos seus aspectos ultra-estruturais, discriminar os defeitos ciliares primários dos secundários, descrever o quadro clínico, os testes laboratoriais de triagem e de diagnóstico disponíveis, bem como seu manejo clínico. FONTE DE DADOS: Pesquisa nas bases de dados Medline, Lilacs e SciELO, no período de 1980 a 2007. SÍNTESE DOS DADOS: A DCP é uma doença autossômica recessiva que compromete a estrutura e/ou a função ciliar e, conseqüentemente, o transporte mucociliar. As manifestações clínicas envolvem o trato respiratório superior e inferior, com infecções recorrentes do ouvido médio, seios paranasais e pulmonares, que podem evoluir para bronquiectasias. Outras manifestações incluem situs inversus totalis e infertilidade masculina. O diagnóstico deve ser suspeitado pelos pediatras em várias situações: recém-nascidos de termo com desconforto respiratório sem causa aparente; neonatos portadores de dextrocardia; lactentes com tosse persistente e/ou infecções otorrinolaringológicas de repetição, excluindo-se as imunodeficiências e a fibrose cística; crianças com asma atípica e as com bronquiectasias sem causa definida. Os testes de triagem diagnóstica são os da sacarina e do óxido nítrico nasal. As avaliações do defeito ultra-estrutural e funcional exigem análise por microscopia eletrônica e da freqüência e formato da onda de batimento ciliar. CONCLUSÕES: A DCP, apesar da baixa prevalência, é pouco diagnosticada pelas dificuldades de estabelecer o diagnóstico definitivo do defeito ciliar devido à complexidade da investigação laboratorial e pela falta de reconhecimento da doença pelos médicos. A suspeita clínica e o diagnóstico precoce são fundamentais para reduzir a morbidade e prevenir o desenvolvimento de complicações.

Genetic Defects in Ciliary Structure and Function

Cilia, hair-like structures extending from the cell membrane, perform diverse biological functions. Primary (genetic) defects in the structure and function of sensory and motile cilia result in multiple ciliopathies. The most prominent genetic abnormality involving motile cilia (and the respiratory tract) is primary ciliary dyskinesia (PCD). PCD is a rare, usually autosomal recessive, genetically heterogeneous disorder characterized by sino-pulmonary disease, laterality defects, and male infertility. Ciliary ultrastructural defects are identified in approximately 90% of PCD patients and involve the outer dynein arms, inner dynein arms, or both. Diagnosing PCD is challenging and requires a compatible clinical phenotype together with tests such as ciliary ultrastructural analysis, immunofluorescent staining, ciliary beat assessment, and/or nasal nitric oxide measurements. Recent mutational analysis demonstrated that 38% of PCD patients carry mutations of the dynein genes DNAI1 and DNAH5. Increased understanding of the pathogenesis will aid in better diagnosis and treatment of PCD.

Primary Ciliary Dyskinesia

Primary ciliary dyskinesia is a genetic disorder causing dysfunctional motility of cilia and impaired mucociliary clearance, resulting in a myriad of clinical manifestations including recurrent sinopulmonary disease, laterality defects and infertility. The heterogenous clinical presentation of primary ciliary dyskinesia and the limitations of transmission electron microscopy to assess ultrastructural defects within the cilium often delay diagnosis. Recent advances in the understanding of the basic biology and function of the cilium have led to potential diagnostic alternatives, including ciliary beat analysis and nasal nitric oxide measurements. Moreover, the identification of disease-causing mutations could lead to the development of comprehensive genetic testing that may overcome many of the current diagnostic limitations. Although the clinical manifestations of primary ciliary dyskinesia have been recognised for over a century, there are few studies examining treatments and standards of care have yet to be established. Multicentre collaborative efforts have been established in North America and Europe, which should help to develop standardised approaches to the diagnosis and treatment of primary ciliary dyskinesia.