Primary Ciliary Dyskinesia Research Articles

Unveiling the complexities of lung transplantation in situs inversus

BackgroundLung transplantation for situs inverse is considered technically challenging because of the reverse positioning of the organs. By providing a detailed description of the surgical procedure, perioperative care, and post-transplant follow-up, we aim to contribute valuable information to the existing knowledge base. We presented two cases of successful bilateral sequential lung transplantation in situs inverse patients.Case presentationOur first patient was a 28-year-old, non-smoking woman with Kartagener syndrome and advanced bronchiectasis that developed into pneumonia and required repeated hospital admissions. She underwent double lung transplantation. During the lung transplant procedure, venoarterial extracorporeal membrane oxygenation (VA ECMO) support was provided. The recipient’s morphologically right (anatomically left) lung was explanted. The right main bronchus was anastomosed, followed by the pulmonary artery and left atrial anastomoses. Afterward, we proceeded with the left side. Similar to the right side, left pneumonectomy and implantation were performed using the same methods. The duration of VA ECMO support was 147 min with a 328-min ischemic time. Because of the significant size mismatch, nonanatomic lung volume reduction over the right middle and left upper lobes was necessary. The patient had no complications postoperatively and was discharged on post-operative day (POD) 12. Our second patient was a 51-year- old man with scleroderma-associated interstitial lung disease with situs inversus. Bilateral sequential lung transplantation was performed. Similar to case 1, a clamshell incision was made at the fourth intercostal space entry. The patient then received VA ECMO support identical to that in case 1. The total VA ECMO support time was 155 min with 295 min of ischemic time. The patient recovered uneventfully and was discharged on POD 13.ConclusionsLung transplantation for situs inverse can be a viable treatment option without modifying established transplantation procedures.

Clinical implications of respiratory ciliary dysfunction in heterotaxy patients with congenital heart disease: elevated risk of postoperative airway complications.

Cardiac surgery in Congenital Heart Disease-Heterotaxy (CHD-HTX) patients often leads to increased postoperative airway complications. Abnormal respiratory ciliary function, resembling primary ciliary dyskinesia, has been observed. We expanded the sample size by retrospectively reviewing Ciliary Dysfunction (CD) in CHD-HTX patients to verify the increased risk of post-surgical respiratory complications. We conducted a retrospective review of 69 CHD-HTX patients undergoing cardiac surgery, assessing abnormal respiratory function using nasal nitric oxide (nNO) levels and nasal ciliary motion observed in video microscopy. Data collected included demographics, surgical details, postoperative complications, length of stay, ICU hours, salvage procedures, intubation duration, and mortality. The CD and no-CD cohorts exhibited notable similarities in risk adjustment in Congenital Heart Surgery-1 (RACHS-1) risk categories, age at the time of surgery, and the duration of follow-up evaluations. We observed a trend toward an increased length of post-operative stay in the CD group (15.0 vs. 14.0; P = 0.0017). CHD-HTX patients with CD showed significantly higher rates of respiratory complications (70% vs. 44.4%; P = 0.008). There were no notable variances observed in postoperative hospitalization duration, mechanical ventilation period, or surgical mortality. Our findings suggest that CHD-HTX patients with CD may face an elevated risk of respiratory complications. These results offer guidance for perioperative management and serve as a reference for further pathological studies.

Functional and structural significance of the inner-arm-dynein subspecies d in ciliary motility.

Motile cilia play various important physiological roles in eukaryotic organisms including cell motility and fertility. Inside motile cilia, large motor-protein complexes called "ciliary dyneins" coordinate their activities and drive ciliary motility. The ciliary dyneins include the outer-arm dyneins, the double-headed inner-arm dynein (IDA f/I1), and several single-headed inner-arm dyneins (IDAs a, b, c, d, e, and g). Among these single-headed IDAs, one of the ciliary dyneins, IDA d, is of particular interest because of its unique properties and subunit composition. In addition, defects in this subspecies have recently been associated with several types of ciliopathies in humans, such as primary ciliary dyskinesia and multiple morphologic abnormalities of the flagellum. In this mini-review, we discuss the composition, structure, and motor properties of IDA d, which have been studied in the model organism Chlamydomonas reinhardtii, and further discuss the relationship between IDA d and human ciliopathies. In addition, we provide future perspectives and discuss remaining questions regarding this intriguing dynein subspecies.

P-40 A rare cause of male infertility: 46, XX testicular disorder of sex development

Abstract Introduction 46, XX testicular disorder of sex development (DSD) is a rare condition with an estimated incidence of 1 per 20,000 individuals. The clinical spectrum ranges from ambiguous genitalia that is usually diagnosed at birth, to male infertility that is diagnosed in the adult years. However, the diagnosis of 46, XX DSD in an individual presenting with infertility may be challenging due to occult clinical findings. A thorough physical examination as well as clinical suspicion is required for diagnosis. Clinical Case A 22-year-old male presented to the urology clinic for infertility despite at least 3 years of regular unprotected intercourse. On physical examination, his testicles were palpable bilaterally in the scrotum with small volumes. Laboratory results revealed hypergonadotropic hypogonadism and his spermiogram revealed azoospermia. Abdominopelvic ultrosonagraphy (US) was reported normal except abdominal situs inversus. Tumor markers for a probable testicular tumor were negative. He was referred to medical genetic department. His family history was unremarkable except for parental consanguineouty. The chromosomal analyze revealed a 46, XX karyotype, and fluorescence in situ hybridization (FISH) disclosed that the SRY gene locus was translocated to the X chromosome: 46,x,der(x) t(x;Y) (sry+); SRY + AZF a,b,c microdeletion. The patient was consulted to the endocrinology department for further evaluation of hypogonadism. On physical exam, he had eunuchoid habitus with incomplete virilization, bilateral and symmetric gynecomastia. The height, and body mass index of the patient was 165 cm, and 29.2 kg/m2, respectively. The testicles were bilaterally palpable in the scrotum, with a volume of 4 mL each. His luteinizing hormone (LH), follicle-stimulating hormone (FSH) and total testosterone levels were 14 mUI/mL (laboratory reference: 1.5–9 mUI/mL), 42 mUI/mL (1.4–18 mUI/mL), and 140 ng/dl (197-700 ng/dL), respectively. The bone age matched his chronological age. Bone densitometry revealed osteopenia. A direct X-ray of the thorax showed thoracic situs inversus, he diagnosed with situs inversus totalis. Detailed genetic analyses could not be done concerning this diagnosis due to financial constraints. He had no history of lung infections that ruled out Kartagener's syndrome. Treatment was started with monthly intramuscular testosterone injections of 250 mg/ml. The patient and his family received genetic counseling, including advice that assisted reproduction will not work owing to AZFabc deletion. Conclusion 46, XX DSD is an uncommon genetic disorder that is rarely identified during the evaluation of male infertility. Clinical suspicion and a comprehensive physical exam are keys for diagnosis. Genetic analysis is essential for definitive diagnosis. A multidisciplinary is required for treatment and follow-up. Psychological support and genetic counseling are also critical for the management of these patients.

Magnetic Resonance Imaging of Pulmonary and Paranasal Sinus Abnormalities in Children with Primary Ciliary Dyskinesia Compared to Children with Cystic Fibrosis.

Rationale: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are characterized by inherited impaired mucociliary clearance leading to chronic progressive lung disease as well as chronic rhinosinusitis (CRS). The diseases share morphological and functional commonalities on magnetic resonance imaging (MRI) of the lungs and paranasal sinuses, but comparative MRI studies are lacking. Objectives: To determine whether PCD shows different associations of pulmonary and paranasal sinus abnormalities on MRI and lung function test results in children (infants to adolescents) compared with children with CF. Methods: Eighteen children with PCD (median age, 9.5 [IQR, 3.4-12.7] yr; range, 0-18 yr) and 36 age-matched CF transmembrane conductance regulator modulator-naive children with CF (median age, 9.4 [3.4-13.2] yr; range, 0-18 yr) underwent same-session chest and paranasal sinus MRI as well as spirometry (to determine forced expiratory volume in 1 s percent predicted) and multiple-breath washout (to determine lung clearance index z-score). Pulmonary and paranasal sinus abnormalities were assessed using previously validated chest MRI and CRS-MRI scoring systems. Results: Mean chest MRI global score was similar in children with PCD and CF (15.0 [13.5-20.8] vs. 15.0 [9.0-15.0]; P = 0.601). Consolidations were more prevalent and severe in children with PCD (56% vs. 25% and 1.0 [0.0-2.8] vs. 0.0 [0.0-0.3], respectively; P < 0.05). The chest MRI global score correlated moderately with forced expiratory volume in 1 second percent predicted in children with PCD and children with CF (r = -0.523 and -0.687; P < 0.01) and with lung clearance index in children with CF (r = 0.650; P < 0.001) but not in PCD (r = 0.353; P = 0.196). CRS-MRI sum score and mucopyocele subscore were lower in children with PCD than in children with CF (27.5 [26.3-32.0] vs. 37.0 [37.8-40.0] and 2.0 [0.0-2.0] vs. 7.5 [4.8-9.0], respectively; P < 0.01). CRS-MRI sum score did not correlate with chest MRI score in PCD (r = 0.075-0.157; P = 0.557-0.788) but correlated moderately with MRI morphology score in CF (r = 0.437; P < 0.01). Conclusions: MRI detects differences in lung and paranasal sinus abnormalities between children with PCD and those with CF. Lung disease does not correlate with CRS in PCD but correlates in CF.

Multi-scale structures of the mammalian radial spoke and divergence of axonemal complexes in ependymal cilia

Radial spokes (RS) transmit mechanochemical signals between the central pair (CP) and axonemal dynein arms to coordinate ciliary motility. Atomic-resolution structures of metazoan RS and structures of axonemal complexes in ependymal cilia, whose rhythmic beating drives the circulation of cerebrospinal fluid, however, remain obscure. Here, we present near-atomic resolution cryo-EM structures of mouse RS head-neck complex in both monomer and dimer forms and reveal the intrinsic flexibility of the dimer. We also map the genetic mutations related to primary ciliary dyskinesia and asthenospermia on the head-neck complex. Moreover, we present the cryo-ET and sub-tomogram averaging map of mouse ependymal cilia and build the models for RS1-3, IDAs, and N-DRC. Contrary to the conserved RS structure, our cryo-ET map reveals the lack of IDA-b/c/e and the absence of Tektin filaments within the A-tubule of doublet microtubules in ependymal cilia compared with mammalian respiratory cilia and sperm flagella, further exemplifying the structural diversity of mammalian motile cilia. Our findings shed light on the stepwise mammalian RS assembly mechanism, the coordinated rigid and elastic RS-CP interaction modes beneficial for the regulation of asymmetric ciliary beating, and also facilitate understanding on the etiology of ciliary dyskinesia-related ciliopathies and on the ependymal cilia in the development of hydrocephalus.

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

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. 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. 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. 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.

Diagnosis of Primary Ciliary Dyskinesia via Whole Exome Sequencing and Histologic Findings.

To assess the diagnostic potential of whole-exome sequencing (WES) and elucidate the clinical and genetic characteristics of primary ciliary dyskinesia (PCD) in the Korean population. Forty-seven patients clinically suspected of having PCD were enrolled at a tertiary medical center. WES was performed in all patients, and seven patients received biopsy of cilia and transmission electron microscopy (TEM). Overall, PCD was diagnosed in 10 (21.3%) patients: eight by WES (8/47, 17%), four by TEM. Among patients diagnosed as PCD based on TEM results, two patients showed consistent results with WES and TEM of PCD (2/4, 50%). In addition, five patients, who were not included in the final PCD diagnosis group, had variants of unknown significance in PCD-related genes (5/47, 10.6%). The most frequent pathogenic (P)/likely pathogenic (LP) variants were detected in DNAH11 (n=4, 21.1%), DRC1 (n=4, 21.1%), and DNAH5 (n=4, 21.1%). Among the detected 17 P/LP variants in PCD-related genes in this study, 8 (47.1%) were identified as novel variants. Regarding the genotype-phenotype correlation in this study, the authors experienced severe PCD cases caused by the LP/P variants in MCIDAS, DRC1, and CCDC39. Through this study, we were able to confirm the value of WES as one of the diagnostic tools for PCD, which increases with TEM, rather than single gene tests. These results will prove useful to hospitals with limited access to PCD diagnostic testing but with relatively efficient in-house or outsourced access to genetic testing at a pre-symptomatic or early disease stage.

A case of primary ciliary dyskinesis with DRC1 deletion and literature review: Additional evidence on the founder effect.

Primary ciliary dyskinesia (PCD) is a rare genetic disease caused by defects in various genes affecting ciliary function. It is currently unclear why DRC1 gene variants are a relatively frequent cause of disease in Japanese and Korean patients. A 12-year-old Japanese girl with bronchiectasis was suspected of PCD and examined using whole-exome sequencing (WES). The breakpoint region was confirmed by Sanger sequencing and evaluation of transposable elements. Whole-exome sequencing revealed a deletion of DRC1 exons 1-4 in the patient, followed by validation with Sanger sequencing. A DRC1 exon 1-4 deletion is recurrently observed in Japanese and Korean patients with PCD. All reported patients carry the same breakpoint region, which shows signs of Alu-mediated recombination. Intriguingly, common haplotypes were observed around the DRC1 gene in Japanese and Korean patients. The recurrent DRC1 exon 1-4 deletion is therefore likely to be a founder variant and should be considered a major genetic cause of PCD in Japanese and Korean patients with PCD.

Семейный случай мужского бесплодия с тотальной астенозооспермией, обусловленной структурными нарушениями в аксонеме жгутика сперматозоидов

The article describes a family case of primary male infertility caused by primary ciliary dyskinesia (PCD). According to the data of electron microscopy ofspermatozoa,two siblings with total asthenotheratozoospermia have a total absence of external and internal dynein axoneme handlesin the flagella ofspermatozoa, indicating the presence of PCD. Both patients had a history of repeated failures ofIVF/ICSI programs. The patients did not have situs viscerum inversus and signs of damage to the respiratory system. The othertwo brothers were healthy and fertile, and both have two children. Non-severe asthenozoospermia was revealed in one of fertile brothers(who isin a consanguineous marriage), and situs viscerum inversus was mentioned in hisson. Whole-exome sequencing revealed a pathogenic variant ofthe c.461A&gt;C in exon 4 ofthe CCDC103 gene in a homo/hemizygous state in both siblings with PCD, in their fertile brother – in a heterozygousstate. The use oftransmission electron microscopy of spermatozoa with exome sequencing made it possible to identify the cause oftotal asthenotheratozoospermia and diagnose the genetic form of male infertility associated with an ultrastructure anomaly ofthe axoneme.

Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia.

We report the case of a 42-year-old man with bronchiectasis who had a history of infertility treatment for obstructive azoospermia. Young's syndrome was suspected based on the triad of obstructive azoospermia, sinusitis, and bronchiectasis. He had normal electron microscopy findings, normal nasal nitric oxide levels (116 nL/min), and no situs inversus. However, we found compound heterozygous variants in CFAP221. This led to a diagnosis of primary ciliary dyskinesia (PCD). Distinguishing PCD from Young's syndrome in patients with the triad of obstructive azoospermia, sinusitis, and bronchiectasis is challenging. Young's syndrome may be a phenotype of PCD.

Primary Ciliary Dyskinesia

Primary ciliary dyskinesia, also known as immotile-ciliary syndrome causes impaired mucociliary clearance most notably in the upper and lower airways. We describe a middle aged man with a history of primary ciliary dyskinesia who presented to the hospital following a witnessed seizure at home.

High-speed video analysis of nasal ciliary beating in primary ciliary dyskinesia

High-speed video analysis of nasal ciliary beating in primary ciliary dyskinesia

A comparative study among adolescents with cystic fibrosis and primary ciliary dyskinesia and their caregivers: psychological aspects

A comparative study among adolescents with cystic fibrosis and primary ciliary dyskinesia and their caregivers: psychological aspects

A Case of Primary Ciliary Dyskinesia Syndrome with Situs Ambiguous

A Case of Primary Ciliary Dyskinesia Syndrome with Situs Ambiguous

Pulmonary functions, nasal symptoms, and quality of life in patients with primary ciliary dyskinesia (PCD).

Several factors may influence quality of life (QOL) for patients with primary ciliary dyskinesia (PCD). We aimed to evaluate the association between pulmonary functions, nasal symptoms and QOL in PCD patients. A prospective single center study. Patients performed spirometry, whole body plethysmography, forced oscillation technique (FOT), lung clearance index (LCI), 6-min walk test (6MWT), and filled two questionnaires: a specific PCD QOL questionnaire (PCD-QOL) and Sino-nasal outcome test (SNOT-22) questionnaire, assessing symptoms of chronic rhinosinusitis and health related QOL. Twenty-seven patients (56% females), age 19.4 ± 10.5 years were included; their, FEV1 was 74.6 ± 22.7%, and RV/TLC was (157.3 ± 39.3% predicted). Health perception and lower respiratory symptoms domains of PCD-QOL had the lowest score (median [IQR]: 50 [33.3-64.6] and 57.1 [38.9-72.2], respectively). FOT parameters correlated with several PCD-QOL domains. R5 z-score (indicating total airway resistance) and AX z-score (indicating airway reactance) correlated negatively with physical domain (r = -0.598, p = .001, and r = -0.42, p = .03, respectively); R5 z-score also correlated negatively with hearing domain (r = -0.57, p = .002). R5-20 z-score (indicating small airway resistance) correlated negatively with role domain (r = -0.49, p = .03). SNOT-22 score correlated negatively with several PCD-QOL domains (lower respiratory symptoms r = -0.77, p < .001; physical r = -0.72, p < .001; upper respiratory symptoms r = -0.66, p < .001). No correlations were found between spirometry values, LCI, 6MWT, and PCD-QOL. FOT suggested small airway dysfunction, and correlated negatively with several PCD-QOL domains. Nasal symptoms had strong negative correlations with PCD-QOL. Larger longitudinal studies will further elucidate factors affecting QOL in PCD.

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.

Classification of primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a rare hereditary disease from the group of ciliopathies with extensive locus and allelic heterogeneity (ORPHA 244, 98861; OMIM 242650, 244000). This disease is inherited by autosomal dominant or autosomal recessive type and, less often, by X-linked type (OMIM 300424). Retinitis pigmentosa develops in the X-linked PCD variant. The overall minimum global prevalence of PCD according to European data is 1 : 7554. There is no generally accepted classification of PCD in the international classification of diseases (ICD), 10th revision. PCD is not presented in ICD-10 as a separate medical entity, and the code Q32.4 – Other congenital bronchial anomalies – is used for coding. In the new edition of ICD-11, the code LA75.Y is highlighted – Other specified structural abnormalities of the lungs.Primary ciliary dyskinesia. However, there is no generally accepted classification of PCD. The aim of the study was to develop a classification of primary ciliary dyskinesias to improve the efficiency of medical care for patients during follow-up.Methods. European and Russian clinical recommendations, as well as ICD 10th and 11th revision, Classification of Respiratory Insufficiency (2020), Order of 27.08.19 No.585n “On classifications and criteria used in the implementation of medical and social expert assessment of citizens by federal state institutions of medical and social expert assessment” (as amended on 06.10.21) were used to create the classification.Results. The classification of PCD was created and can be recommended for use in clinical practice. The classification was based on the presence or absence of the Sievert – Kartagener syndrome (complete, not complete), as well as clinical and instrumental characterization of bronchopulmonary changes based on the presence of chronic obstructive bronchitis, bronchiectasis (specifying the type and localization), pneumofibrosis with the process activity (exacerbation, remission), and the degree of respiratory failure. It is recommended to take into account extrapulmonary manifestations of PCD, such as rhinosinusitis, media otitis, congenital heart defect, and complications. It is recommended to use the PICADAR (PrImary CiliAry DyskinesiA Rule) score and to include the results of video microscopy, DNA diagnosis, and microbiological examination in the diagnosis.Conclusion. The application of the proposed classification can be useful in the dynamic observation of the patient, therapy and in the conduct of medical and social expert assessment.

Changes in Sleep in Children and Adults with Cystic Fibrosis and Primary Ciliary Dyskinesia over Time and after CFTR Modulator Therapy.

Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are associated with sleep disturbances affecting quality of life (QOL) in both children and adults. However, little is known about the progression of these complaints over time, and the effect of CFTR modulator (CFTRm) therapies. Participants completed sleep quality (SDSC, PSQI) and quality of life questionnaires (PedQL, QOL-BE) as well as the Epworth sleepiness scale (ESS) at baseline and after 4 years. Medical records were reviewed for clinical data and correlations were sought between sleep, QOL, and clinical parameters. A total of 67 patients (33 pediatric), 37 pancreatic insufficient CF (CF-PI), 15 pancreatic sufficient CF (CF-PS), and 15 PCD patients, completed the study. In adults, global sleep quality decreased from 85.8% (76.2-90.5) to 80.9% (71.4-85.7); (p = 0.009). Analysis by disease cohort showed a significant deterioration only in the CF-PS group. In adults off CFTRm, sleep quality decreased from 85.7% (78.6-88.2) to 80.9% (71.4-87.3); (p = 0.021) and from 85.8% (76.2-92.9) to 76.2% (71.4-85.8); (p = 0.078) in people on CFTRm. Changes in sleep quality and changes in QOL over time were strongly associated with each other. In conclusion sleep quality deteriorates over time, correlates with QOL, and is driven primarily by adults and CF-PS patients. CFTRm has a possible effect on sleep initiation; however, results are mixed, and further long-term studies are required.

Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia

BackgroundPrimary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement [situs solitus (SS)] or mirror image inversion [situs inversus totalis (SIT)]. Research QuestionDo patients with PCD and SA have worse clinical outcomes compared to those with SS or SIT? Study Design and MethodsThis cross-sectional, multicenter study evaluated participants ≤21 years with PCD. Participants were classified as SA, including heterotaxy, or non-SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39/CCDC40 genotype, using generalized linear models, logistic and Poisson regression. ResultsIn 397 participants with PCD (mean age 8.4 years, range 0.1-21), 42 were classified as SA, including 16 (38%) with complex cardiovascular malformations (CVM) or atrial isomerism, 13 (31%) with simple CVM, and 13 (31%) without CVM. Of these, 15 (36%) underwent cardiac surgery, 24 (57%) had an anatomic spleen abnormality, and 7 (17%) had both. The remaining 355 participants were non-SA, including 152 with SIT and 203 with SS. Overall, 70 (17%) participants had the severe CCDC39/CCDC40 genotype. Compared to non-SA participants, those with SA had lower median body mass index Z-scores (p=0.03), lower forced vital capacity Z-scores (p=0.01), more hospitalizations and intravenous antibiotic courses for acute respiratory infections during the 5-years before enrollment (p<0.01). Participants with CVM requiring surgery or anatomic spleen abnormalities had lower median body mass index Z-scores and more hospitalizations and intravenous therapies for respiratory illnesses compared to non-SA participants. InterpretationChildren with PCD and SA have worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in SA participants with PCD are associated with CVM requiring cardiac surgery and/or splenic anomalies. ClinicalTrials.gov: NCT02389049, NCT00323167