Association of Neonatal Hospital Length of Stay with Lung Function in Primary Ciliary Dyskinesia

Wee, Wallace; Leigh, Margaret W.; Davis, Stephanie D.; Rosenfeld, Margaret; Sullivan, Kelli; Sawras, Michael; Ferkol, Thomas; Knowles, Michael R.; Milla, Carlos; Sagel, Scott D.; Zariwala, Maimoona A.; Pullenayegum, Eleanor; Dell, Sharon D.

doi:10.1513/annalsats.202202-116oc

Cited by 9 publications

(4 citation statements)

References 21 publications

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“…Up to 80% of infants with PCD develop neonatal respiratory distress, typically within the first 12-48 hr following birth, due to lobar collapse/atelectasis which can require supplemental oxygen and prolonged hospitalization (10, 52–54). Therefore, we studied PCD piglets within the first days of birth to investigate for features of neonatal respiratory distress.…”

Section: Resultsmentioning

confidence: 99%

Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia

Abou Alaiwa,

Hilkin,

Price

et al. 2024

Preprint

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Mutations in more than 50 different genes cause primary ciliary dyskinesia (PCD) by disrupting the activity of motile cilia that facilitate mucociliary transport (MCT). Knowledge of PCD has come from studies identifying disease-causing mutations, characterizing structural cilia abnormalities, finding genotype-phenotype relationships, and studying the cell biology of cilia. Despite these important findings, we still lack effective treatments and people with PCD have significant pulmonary impairment. As with many other diseases, a better understanding of pathogenic mechanisms may lead to effective treatments. To pursue disease mechanisms, we used CRISPR-Cas9 to develop a PCD pig with a disrupted DNAI1 gene. PCD pig airway cilia lacked the outer dynein arm and had impaired beating. MCT was impaired under both baseline conditions and after cholinergic stimulation in PCD pigs. Neonatal PCD pigs developed neonatal respiratory distress with evidence of atelectasis, air trapping, and airway mucus obstruction. Despite airway mucus accumulation, lung bacterial counts were similar between neonatal wild-type and PCD pigs. Sinonasal disease was present in all neonatal PCD pigs. Older PCD pigs developed worsening airway mucus obstruction, inflammation, and bacterial infection. This pig model closely mimics the disease phenotype seen in people with PCD and can be used to better understand the pathophysiology of PCD airway disease.

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Section: Resultsmentioning

confidence: 99%

Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia

Abou Alaiwa,

Hilkin,

Price

et al. 2024

Preprint

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“…Finally, long-term follow up suggests that infants with a genetic diagnosis of PCD have respiratory symptoms consistent with PCD and benefit from respiratory therapy for airway clearance. PCD was shown to be associated with prolonged length of stay and decreased lung function on follow up in neonates without CHD [34]. These clinical implications emphasize, again, the importance of early diagnosis through genetic testing and understanding of the genetic diagnosis of ciliary dysfunction for infants with H-CHD.…”

Section: U N C O R R E C T E D a U T H O R P R O O Fmentioning

confidence: 92%

Ciliopathy gene variants and perioperative respiratory outcomes in infants with heterotaxy syndrome and congenital heart disease

Marquez

Carlozzi

Miller

et al. 2023

TRD

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BACKGROUND: Ciliary dysfunction underlies the pathogenesis of both heterotaxy syndrome and primary ciliary dyskinesia (PCD), often with overlapping genetic variants. OBJECTIVE: This case series aims to describe genetic testing and postoperative outcomes for infants with heterotaxy-associated congenital heart disease (H-CHD) with pathogenic variants in genes associated with ciliary structure or function. METHODS: Infants who underwent surgery for H-CHD between 2017 and 2022 were included in this single-center review. The results of genetic testing, microarray or sequencing-based tests, were reviewed. Baseline clinical data and postoperative outcomes are summarized for individuals with variants in ciliary genes. RESULTS: Of 32 infants who underwent surgery, 12 had sequencing-based testing. A genetic variant associated with ciliopathy was reported in 10 of 12 infants (83%), 3 (25%) were diagnostic of PCD and 2 (17%) were considered possibly diagnostic. Infants with variants in ciliary genes had high prevalence of postoperative respiratory complications, however a relationship between genetic test results and respiratory complications could not be proven. All infants with a genetic diagnosis of PCD showed clinical symptoms of PCD on follow-up. CONCLUSIONS: Sequencing-based testing has high detection rate for PCD in infants with H-CHD and may be valuable given their increased risk of respiratory complications after surgery.

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“…DNAH11 and RSPH1 have both been noted to have lower frequencies of NRD [ 74 , 171 ]. Conversely, patients with IDA+MTD defects (consisting of patients with CCDC39 and CCDC40 variants) were found to have longer neonatal lengths of stays compared to other ultrastructure groups [ 183 ].…”

Section: Genotype–phenotype Relationships In Pcdmentioning

confidence: 99%

Primary Ciliary Dyskinesia: A Clinical Review

Despotes,

Zariwala,

Davis

et al. 2024

Cells

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Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous, motile ciliopathy, characterized by neonatal respiratory distress, recurrent upper and lower respiratory tract infections, subfertility, and laterality defects. Diagnosis relies on a combination of tests for confirmation, including nasal nitric oxide (nNO) measurements, high-speed videomicroscopy analysis (HSVMA), immunofluorescent staining, axonemal ultrastructure analysis via transmission electron microscopy (TEM), and genetic testing. Notably, there is no single gold standard confirmatory or exclusionary test. Currently, 54 causative genes involved in cilia assembly, structure, and function have been linked to PCD; this rare disease has a spectrum of clinical manifestations and emerging genotype–phenotype relationships. In this review, we provide an overview of the structure and function of motile cilia, the emerging genetics and pathophysiology of this rare disease, as well as clinical features associated with motile ciliopathies, novel diagnostic tools, and updates on genotype–phenotype relationships in PCD.

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Association of Neonatal Hospital Length of Stay with Lung Function in Primary Ciliary Dyskinesia

Cited by 9 publications

References 21 publications

Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia

Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia

Ciliopathy gene variants and perioperative respiratory outcomes in infants with heterotaxy syndrome and congenital heart disease

Primary Ciliary Dyskinesia: A Clinical Review

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