Advancing Primary Ciliary Dyskinesia Diagnosis through High-Speed Video Microscopy Analysis.

Primary ciliary dyskinesia (PCD) is an inherited disorder that impairs motile cilia, essential for respiratory health, with a reported prevalence of 1 in 16,309 within Hispanic populations. Despite 70% of Puerto Rican patients having the RSPH4A [c.921+3_921+6del (intronic)] founder mutation, the characterization of the ciliary dysfunction remains unidentified due to the unavailability of advanced diagnostic modalities like High-Speed Video Microscopy Analysis (HSVA). Our study implemented HSVA for the first time on the island as a tool to better diagnose and characterize the RSPH4A [c.921+3_921+6del (intronic)] founder mutation in Puerto Rican patients. By applying HSVA, we analyzed the ciliary beat frequency (CBF) and pattern (CBP) in native Puerto Rican patients with PCD. Our results showed decreased CBF and a rotational CBP linked to the RSPH4A founder mutation in Puerto Ricans, presenting a novel diagnostic marker that could be implemented as an axillary test into the PCD diagnosis algorithm in Puerto Rico. The integration of HSVA technology in Puerto Rico substantially enhances the PCD evaluation and diagnosis framework, facilitating prompt detection and early intervention for improved disease management. This initiative, demonstrating the potential of HSVA as an adjunctive test within the PCD diagnostic algorithm, could serve as a blueprint for analogous developments throughout Latin America.

Cystic Lung Changes, Bronchiectasis, and a Heterozygous-Primary Ciliary Dyskinesia-Associated Variant in the DNAH5 Gene: A Diagnostic Challenge.

BACKGROUND Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease that can present at different ages with different phenotypes. Missed and delayed diagnoses are fairly common. Many variants in the DNAH5 gene have been described that confirm the diagnosis of PCD. Advances in medicine, especially in molecular genetics, have led to increasingly early discoveries of such cases, especially in those with nonclassical presentations. CASE REPORT This report describes a patient with bronchiectasis, lung cysts, finger clubbing, and failure to thrive who was misdiagnosed for several years as having asthma. Many differentials were suspected and worked up, including a suspicion of PCD. Genetic tests with whole-exome sequencing (WES) and whole-genome sequencing (WGS) detected a heterozygous, likely pathogenic, variant in the DNAH5 gene associated with PCD. CONCLUSIONS Despite a thorough workup done for this case, including a genetic workup, a PCD diagnosis was not established. We plan to reanalyze the WGS in the future, and with advent of technology and better coverage of genes, a genetic answer for this challenging case may resolve this diagnostic quandary in the future.

The genetic framework of primary ciliary dyskinesia assessed by soft computing analysis.

BACKGROUND: International guidelines disagree on how best to diagnose primary ciliary dyskinesia (PCD), not least because many tests rely on pattern recognition. We hypothesized that quantitative distribution of ciliary ultrastructural and motion abnormalities would detect most frequent PCD-causing groups of genes by soft computing analysis. METHODS: Archived data on transmission electron microscopy and high-speed video analysis from 212 PCD patients were re-examined to quantitate distribution of ultrastructural (10 parameters) and functional ciliary features (4 beat pattern and 2 frequency parameters). The correlation between ultrastructural and motion features was evaluated by blinded clustering analysis of the first two principal components, obtained from ultrastructural variables for each patient. Soft computing was applied to ultrastructure to predict ciliary beat frequency (CBF) and motion patterns by a regression model. Another model classified the patients into the five most frequent PCD-causing gene groups, from their ultrastructure, CBF and beat patterns. RESULTS: The patients were subdivided into six clusters with similar values to homologous ultrastructural phenotype, motion patterns, and CBF, except for clusters 1 and 4, attributable to normal ultrastructure. The regression model confirmed the ability to predict functional ciliary features from ultrastructural parameters. The genetic classification model identified most of the different groups of genes, starting from all quantitative parameters. CONCLUSIONS: Applying soft computing methodologies to PCD diagnostic tests optimizes their value by moving from pattern recognition to quantification. The approach may also be useful to evaluate atypical PCD, and novel genetic abnormalities of unclear disease-producing potential in the future.

Fertility care among people with primary ciliary dyskinesia.

INTRODUCTION: Fertility care is important for people living with primary ciliary dyskinesia (PCD) who are at increased risk of fertility problems. We investigated fertility care in an international participatory study. METHODS: Participants of the COVID-PCD study completed an online questionnaire addressing fertility issues. We used logistic regression to study factors associated with fertility specialist visits. RESULTS: Among 384 respondents (response rate 53%), 266 were adults (median age 44 years, interquartile range [IQR]: 33-54, 68% female), 16 adolescents, and 102 parents of children with PCD. Only half of adult participants (128; 48%) received care from fertility specialists at a median age of 30 years (IQR: 27-33)-a median of 10 years after PCD diagnosis. Only 12% were referred to fertility specialists by their PCD physician. Fertility specialist visits were reported more often by adults with pregnancy attempts (odds ratio [OR]: 9.1, 95% confidence interval [CI]: 3.8-23.6) and among people who reported fertility as important for them (OR: 5.9, 95% CI: 2.6-14.6) and less often by females (OR: 0.4, 95% CI: 0.2-0.8). Only 56% of participants who talked with healthcare professionals about fertility were satisfied with information they received. They expressed needs for more comprehensive fertility information and reported dissatisfaction with physician knowledge about PCD and fertility. CONCLUSION: People with PCD are inconsistently referred to fertility specialists. We recommend care from fertility specialists become standard in routine PCD care, and that PCD physicians provide initial fertility information either at diagnosis or no later than transition to adult care.

Device comparison study to measure nasal nitric oxide in relation to primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic respiratory disease characterized by chronic cough, recurrent respiratory infections, and rhinosinusitis. The measurement of nasal nitric oxide (nNO) against resistance has been suggested as a sensitive screening method. However, current recommendations argue for the use of expensive, chemiluminescence devices to measure nNO. This study aimed to compare nNO measurement using three different devices in distinguishing PCD patients from healthy controls and cystic fibrosis (CF) patients and to evaluate their diagnostic precision. The study included 16 controls, 16 PCD patients, and 12 CF patients matched for age and sex. nNO measurements were performed using a chemiluminescence device (Eco Medics CLD 88sp), and two devices based on electrochemical sensors (Medisoft FeNO+ and NIOX Vero) following standardized guidelines. Correlation estimation, Bland-Altman, ROC curve, and one-way ANOVA were used to assess device differences and diagnostic performance. Significantly lower nNO output values were observed in PCD and CF patients compared to controls during exhalation against resistance. The correlation analysis showed high agreement among the three devices. ROC curve analysis demonstrated 100% sensitivity and specificity at different cut-off values for all devices in distinguishing PCD patients from controls (optimal cut-offs: EcoMedics 73, Medisoft 92 and NIOX 87 (nl min-1)). Higher nNO output values were obtained with the Medisoft and NIOX devices as compared to the EcoMedics device, with a bias of-19 nl min-1(95% CI: -73-35) and -21 nl min-1(-73-31) accordingly. These findings indicate that all three tested devices can potentially serve as diagnostic tools for PCD if device specific cut-off values are used. This last-mentioned aspect warrants further studies and consideration in defining optimal cut-offs for individual device.

Airway microbiota correlated with pulmonary exacerbation in primary ciliary dyskinesia patients.

IMPORTANCE: PCD is a rare disease characterized by productive cough, rhinitis, and recurrent infections of the upper and lower airways. Because the diagnosis of PCD is often delayed, patients receive more antibiotics, experience a heavier financial burden, and have a worse prognosis; thus, it is very important to identify the pathogeny and use the correct antibiotic. In this large single-center study of PCD microbiota, we identified an outline of the bacterial microbes from the respiratory tract; furthermore, we found that the microbiota diversity in pediatric sputum was richer than that in pediatric BALF through sequencing, indicating a heterogeneous community structure. The microbiota diversity and richness were lower during pulmonary exacerbation than during pulmonary stabilization. A significantly higher abundance of Pseudomonas had a moderate distinguishing effect for lung exacerbation, which attracted more attention for the study of Pseudomonas therapy in pediatric patients with PCD.

Un cas de situs inversus complet associé à une communication interventriculaire et des anomalies oculaires chez une chienne croisée de 3 ans.

A case of complete situs inversus associated with an interventricular communication and ocular abnormalities in a 3-year-old mixed-breed female dog. A 3-year-old female dog was referred for exploration of a murmur concomitant with lethargy. An echocardiogram reveals an inversion of the position of the cardiac chambers and the presence of an interventricular communication. A computed tomography examination of the thorax and abdomen highlights the known cardiac abnormalities as well as the association of a complete situs inversus. The clinical examination also reveals ocular malformations (deviation of the eyeballs and asymmetry of the fundus). This article highlights the variety of abnormalities that can be associated with the complete inversion of the organs and demonstrates that there may be variants to the more classic picture usually encountered in humans (respiratory manifestations related to Kartagener syndrome).(Translated by Dr Serge Messier).

Siewert-Kartagener's syndrome in a dog.

Siewert-Kartagener's syndrome, a type of primary ciliary dyskinesia, is a complex disease comprising situs inversus, rhinosinusitis, and bronchiectasis. Situs inversus totalis is a condition in which all organs in the thoracic and abdominal cavities are reversed. Furthermore, primary ciliary dyskinesia, an autosomal genetic disease, may coexist with situs inversus totalis. Reports on Siewert-Kartagener's syndrome in veterinary medicine are limited. We report a rare case of primary ciliary dyskinesia with Siewert-Kartagener's syndrome in a dog, concurrently infected with canine distemper virus and type-2 adenovirus. This case highlights that situs inversus totalis can cause primary ciliary dyskinesia, and concurrent infections are possible.

Cross-sectional evaluation of the saccharin transit time test for primary ciliary dyskinesia: did we discard this tool too soon?

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare and heterogeneous disease that is difficult to diagnose and requires complex and expensive diagnostic tools. The saccharin transit time test is a simple and inexpensive tool that may assist in screening patients with PCD. OBJECTIVES: This study aimed to compare changes in the electron microscopy findings with clinical variables and saccharin tests in individuals diagnosed with clinical PCD (cPCD) and a control group. DESIGN AND SETTING: An observational cross-sectional study was conducted in an otorhinolaryngology outpatient clinic from August 2012 to April 2021. METHOD: Patients with cPCD underwent clinical screening questionnaires, nasal endoscopy, the saccharin transit time test, and nasal biopsy for transmission electron microscopy. RESULTS: Thirty-four patients with cPCD were evaluated. The most prevalent clinical comorbidities in the cPCD group were recurrent pneumonia, bronchiectasis, and chronic rhinosinusitis. Electron microscopy confirmed the clinical diagnosis of PCD in 16 of the 34 (47.1%) patients. CONCLUSION: The saccharin test could assist in screening patients with PCD due to its association with clinical alterations related to PCD.

First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit.

BACKGROUND: Primary ciliary dyskinesia (PCD) is typically an autosomal recessive disease characterized by recurrent infections of the lower respiratory tract, frequent and severe otitis media, chronic rhinosinusitis, neonatal respiratory distress, and organ laterality defects. While severe lower respiratory tract infections and bronchiectasis are common in Inuit, PCD has not been recognized in this population. METHODS: We report a case series of seven Inuit patients with PCD identified by genetic testing in three Canadian PCD centers. RESULTS: Patients ranged from 4 to 59 years of age (at time of last evaluation) and originated in the Qikiqtaaluk region (Baffin Island, n = 5), Nunavut, or Nunavik (northern Quebec, n = 2), Canada. They had typical features of PCD, including neonatal respiratory distress (five patients), situs inversus totalis (four patients), bronchiectasis (four patients), chronic atelectasis (six patients), and chronic otitis media (six patients). Most had chronic rhinitis. Genetic evaluation demonstrated that all had homozygous pathogenic variants in DNAH11 at NM_001277115.1:c.4095+2C>A. CONCLUSIONS: The discovery of this homozygous DNAH11 variant in widely disparate parts of the Nunangat (Inuit homelands) suggests this is a founder mutation that may be widespread in Inuit. Thus, PCD may be an important cause of chronic lung, sinus, and middle ear disease in this population. Inuit with chronic lung disease, including bronchiectasis or laterality defects, should undergo genetic testing for PCD. Consideration of including PCD genetic analysis in routine newborn screening should be considered in Inuit regions.

Evaluation of otorhinolaryngological manifestations in patients with primary ciliary dyskinesia.

OBJECTIVES: Primary ciliary dyskinesia (PCD) is a genetic disease characterized by congenital impairment of mucociliary clearance causing recurrent respiratory tract infections. Pulmonary manifestations of PCD are well-known whereas adequate data on otorhinolaryngological complications is lacking. The aim of this study was to investigate clinical features, course and related factors of otorhinolaryngologic domains in PCD patients. METHODS: Patients with a diagnosis of PCD who were on follow-up in the ear-nose-throat (ENT) department of our center between 2000 and 2021 were enrolled. Demographic and clinical data, frequency of sinonasal and otological complaints, examination findings and possible risk factors associated with otorhinolaryngological diseases were obtained via electronic medical charts retrospectively. RESULTS: Of the 121 patients, 53% were male, median age at PCD diagnosis was 7 years (1 month - 20 yrs). The most common ENT manifestation was otitis media with effusion (OME) (66.1%, n = 80), followed by acute otitis media (43.8%, n = 53), acute rhinosinusitis (ARS) (28.9%, n = 35), chronic rhinosinusitis (CRS) (27.3%, n = 33) and chronic otitis media (10.7%, n = 13). Patients with ARS and CRS were significantly older than patients who did not have ARS and CRS (p = 0.045 and p = 0.028, respectively). The annual number of ARS attacks also correlated with age of patients positively (r = 0.170, p = 0.06). Of the 45 patients with pure-tone audiometry, most common finding was conductive hearing loss (CHL) in 57,8% (n = 26). Presence of OME significantly increased tympanic membrane injury which was observed as sclerosis, perforation, retraction or changes due to ventilation tube insertion (VTI). (OR: 8.6, 95% CI: 3.6-20.3, p < 0.001). CONCLUSIONS: Otorhinolaryngologic diseases are common, variable and complicated in PCD patients, consequently ENT physicians' awareness should be improved through shared experiences. ARS and CRS seem to appear in older PCD patients. Presence of OME is the most important risk factor for tympanic membrane damage.

The RSPH4A Gene in Primary Ciliary Dyskinesia.

The radial spoke head protein 4 homolog A (RSPH4A) gene is one of more than 50 genes that cause Primary ciliary dyskinesia (PCD), a rare genetic ciliopathy. Genetic mutations in the RSPH4A gene alter an important protein structure involved in ciliary pathogenesis. Radial spoke proteins, such as RSPH4A, have been conserved across multiple species. In humans, ciliary function deficiency caused by RSPH4A pathogenic variants results in a clinical phenotype characterized by recurrent oto-sino-pulmonary infections. More than 30 pathogenic RSPH4A genetic variants have been associated with PCD. In Puerto Rican Hispanics, a founder mutation (RSPH4A (c.921+3_921+6delAAGT (intronic)) has been described. The spectrum of the RSPH4A PCD phenotype does not include laterality defects, which results in a challenging diagnosis. PCD diagnostic tools can combine transmission electron microscopy (TEM), nasal nitric oxide (nNO), High-Speed Video microscopy Analysis (HSVA), and immunofluorescence. The purpose of this review article is to provide a comprehensive overview of current knowledge about the RSPH4A gene in PCD, ranging from basic science to human clinical phenotype.

Cystic fibrosis and primary ciliary dyskinesia: Similarities and differences.

Cystic fibrosis (CF) and Primary ciliary dyskinesia (PCD) are both rare chronic diseases, inherited disorders associated with multiple complications, namely respiratory complications, due to impaired mucociliary clearance that affect severely patients' lives. Although both are classified as rare diseases, PCD has a much lower prevalence than CF, particularly among Caucasians. As a result, CF is well studied, better recognized by clinicians, and with some therapeutic approaches already available. Whereas PCD is still largely unknown, and thus the approach is based on consensus guidelines, expert opinion, and extrapolation from the larger evidence base available for patients with CF. Both diseases have some clinical similarities but are very different, necessitating different treatment by specialists who are familiar with the complexities of each disease.This review aims to provide an overview of the knowledge about the two diseases with a focus on the similarities and differences between both in terms of disease mechanisms, common clinical manifestations, genetics and the most relevant therapeutic options. We hoped to raise clinical awareness about PCD, what it is, how it differs from CF, and how much information is still lacking. Furthermore, this review emphasises the fact that both diseases require ongoing research to find better treatments and, in particular for PCD, to fill the medical and scientific gaps.

Nasal nitric oxide measurement in children for the diagnosis of primary ciliary dyskinesia: European Respiratory Society technical standard.

Nasal nitric oxide (nNO) is extremely low in most people with primary ciliary dyskinesia (PCD) and its measurement is an important contributor to making the diagnosis. Existing guidelines and technical standards focus on nNO measurements in older, cooperative children using chemiluminescence analysers. However, measurements of nNO in pre-school-age children (age 2-5 years) may facilitate early diagnosis and electrochemical rather than chemiluminescence analysers are widely used. Pre-schoolers often need different methods to be employed when measuring nNO. Hence, a European Respiratory Society Task Force has developed this technical standard as the first step towards standardising sampling, analysis and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups, including pre-school-age children. Furthermore, we considered both chemiluminescence and electrochemical analysers that are in use worldwide. There was a paucity of quality evidence for electrochemical analysers and sampling methods used in young children, and the Task Force proposes future research priorities to allow updates of this technical standard.