Current and Future Treatments in Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.

Development of bacterial resistance during treatment with topical gentamicin for chronic rhinosinusitis in patients with cystic fibrosis and primary ciliary dyskinesis. Retrospective case series.

BACKGROUND: The management of chronic rhinosinusitis (CRS) in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) is still a challenge. At our institution we have used gentamycin nasal spray, extemporaneously produced, for prophylactic treatment of moderate-to-severe CRS. The aim of this study was to investigate the gentamycin susceptibility of bacteria in sputum samples in CF and PCD patients treated for CRS. METHODOLOGY: Patients with CF and PCD who were prescribed gentamycin nasal spray for CRS and had sputum bacterial cultures taken pre-treatment and followed-up at least once after ≥6 months were retrospectively included. Microbiological data were descriptively analysed in terms of bacterial species and resistance to gentamycin. RESULTS: A case series of 17 CF and 12 PCD patients passed the inclusion criteria. Of those cases, three (18%) CF patients and one (8%) PCD patient developed resistance to gentamycin during treatment with gentamycin nasal spray. In all four cases, the resistant bacterial isolates were <i>P. aeruginosa</i>. Additionally, two CF patients already had <i>P. aeruginosa </i> isolates resistant to gentamycin in the pre-treatment culture. In further two CF patients, the multi-resistant <i>Burgdorferi cepacia </i>complex, including gentamycin resistance, was identified. <i>P. aeruginosa </i> and <i>S. aureus </i> in CF and <i>P. aeruginosa</i> and <i>H. influenza </i> in PCD were the predominant bacterial species. CONCLUSIONS: The study showed that there was moderate incidence of gentamycin resistance in CF and PCD patients at our institution. However, further prospective studies are needed to confirm the outcomes.

Exacerbations and Pseudomonas aeruginosa colonization are associated with altered lung structure and function in primary ciliary dyskinesia.

BACKGROUND: Recurrent bacterial infections of the respiratory tract are one of the major clinical features of the primary ciliary dyskinesia (PCD), a rare genetic disease due to malfunctioning of motile cilia. Chronic infections and persistent inflammation of the respiratory system result in progressive lung disease. Aim of the study was to highlight the main factors associated with clinical, functional and anatomical deterioration in PCD patients. METHODS: We retrospectively analyzed data from 58 patients with PCD, 37 adults and 21 children. The demographic and clinical data, forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC), sputum microbiology and imaging results (chest CT scores-modified Bhalla) were recorded. Patients were stratified according to the number of exacerbations (< 2/year vs ≥ 2/year) and chronic Pseudomonas aeruginosa (PA) colonization. The possible correlations between lung function and chest CT scores were assessed; we also evaluated the correlation between these parameters and the severity scores for bronchiectasis (BSI, FACED and e-FACED). RESULTS: Chest CT scores showed a significant correlation with FEV1 (p = 0.0002), age (p <  0.0001), BMI (p = 0.0002) and number of lung lobes involved (p <  0.0001). PA colonization had an overall prevalence of 32.6%: no significant difference in FEV1 between PA colonized and non-colonized patients was found (p = 0.70), while chest CT score was significantly worse in chronic PA colonized patients (p = 0.009). Patients with a high number of exacerbation (≥ 2/year) were older (p = 0.01), had lower FEV1 (p = 0.03), greater number of lobes involved (p < 0.001) and worse CT score than patients with low number of exacerbations (p = 0.001); they also had higher prevalence of PA chronic bronchial infection (33.3% versus 13.6%, p = 0.10). Multivariable linear regression analyses adjusted for gender, age and BMI showed positive associations between PA colonization and number of exacerbations with severity of disease (number of lobes involved, CT score, BSI, FACED, and e-FACED). CONCLUSIONS: In our PCD population the number of exacerbations (≥ 2/year) and PA colonization were the two most relevant factors associated with severity of disease.

Targeting Pseudomonas aeruginosa in the Sputum of Primary Ciliary Dyskinesia Patients with a Combinatorial Strategy Having Antibacterial and Anti-Virulence Potential.

In primary ciliary dyskinesia (PCD) patients, Pseudomonas aeruginosa is a major opportunistic pathogen, frequently involved in chronic infections of the lower airways. Infections by this bacterial species correlates with a worsening clinical prognosis and recalcitrance to currently available therapeutics. The antimicrobial peptide, lin-SB056-1, in combination with the cation chelator ethylenediaminetetraacetic acid (EDTA), was previously demonstrated to be bactericidal against P. aeruginosa in an artificial sputum medium. The purpose of this study was to validate the anti-P. aeruginosa activity of such a combination in PCD sputum and to evaluate the in vitro anti-virulence effects of EDTA. In combination with EDTA, lin-SB056-1 was able to significantly reduce the load of endogenous P. aeruginosa ex vivo in the sputum of PCD patients. In addition, EDTA markedly reduced the production of relevant bacterial virulence factors (e.g., pyocyanin, proteases, LasA) in vitro by two representative mucoid strains of P. aeruginosa isolated from the sputum of PCD patients. These results indicate that the lin-SB056-1/EDTA combination may exert a dual antimicrobial and anti-virulence action against P. aeruginosa, suggesting a therapeutic potential against chronic airway infections sustained by this bacterium.

Prevalence of chronic rhinosinusitis in bronchiectasis patients suspected of ciliary dyskinesia.

BACKGROUND: Mucociliary clearance is a main defense mechanism of the airway and is impaired in ciliary dyskinesia. The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia. METHODS: Bronchiectasis patients referred to a rhinology clinic for nasal brush biopsy (NBB) were included in this study. NBB was performed using a curettage technique whereby ciliated epithelial cells were obtained from the surface of the inferior nasal turbinate. Results of transmission electron microscopy findings, primary ciliary dyskinesia (PCD) gene (35 genes) analyses (Invitae), and sinus computed tomography (CT) scans were reviewed. RESULTS: Twenty-three patients (age, 54 ± 2.9 years) were referred for NBB between 2015 and 2018. Thirteen patients (56.5%) met the criteria for diagnosis of CRS. Nineteen patients had ciliary ultrastructural defects. The most common finding was compound cilia (n = 11, 47.8%). Five patients (21.7%) had central microtubule defects (CMD) with higher forced expiratory volume in 1 second (FEV1 ) at the time of referral than those without CMD (CMD+ , 91 ± 3.7%; CMD- , 73.5 ± 5.7%; p = 0.023). Of 15 subjects with a PCD gene panel, 67% (9 of 15) carried at least 1 gene associated with PCD. Only 1 patient reached diagnosis of PCD. Approximately 50% of non-PCD carriers had a smoking history (p < 0.05). Lund-Mackay scores did not significantly differ between PCD and non-PCD carriers (p = 0.72). CONCLUSION: Nearly half of bronchiectasis patients referred for NBB had concurrent CRS. The presence of ciliary abnormalities was not amplified in bronchiectasis patients with CRS compared to those without CRS. Extrinsic factors may be related to ciliary structural abnormalities in non-PCD gene carriers.

Effect of Klebsiella ozaenae on ciliary activity in vitro: implications in the pathogenesis of atrophic rhinitis.

Klebsiella ozaenae is a gram-negative rod that has been isolated with relative frequency from patients with atrophic rhinitis. The relationship of this bacterium to the pathogenesis of atrophic rhinitis is not understood, and whether this bacterium is simply an opportunistic colonizer of the injured nose or the etiologic agent of the disease is unclear. This study was designed to investigate a potential role for bacterially produced cilioinhibition as a mechanism for the pathogenesis of atrophic rhinitis.