Do Causes Influence Functional Aspects and Quality of Life in Patients with Nonfibrocystic Bronchiectasis?

Background: The denomination of noncystic fibrosis bronchiectasis (NCFB) includes several causes, and differences may be expected between the patient subgroups regarding age, comorbidities, and clinical and functional evolution. This study sought to identify the main causes of NCFB in a cohort of stable adult patients and to investigate whether such conditions would be different in their clinical, functional, and quality of life aspects. Methods: Between 2017 and 2019, all active patients with NCFB were prospectively evaluated searching for clinical data, past medical history, dyspnea severity grading, quality of life data, microbiological profile, and lung function (spirometry and six-minute walk test). Results: There was a female predominance; mean age was 54.7 years. Causes were identified in 82% of the patients, the most frequent being postinfections (n = 39), ciliary dyskinesia (CD) (n = 32), and chronic obstructive pulmonary disease (COPD) (n = 29). COPD patients were older, more often smokers (or former smokers) and with more comorbidities; they also had worse lung function (spirometry and oxygenation) and showed worse performance in the six-minute walk test (6MWT) (walked distance and exercise-induced hypoxemia). Considering the degree of dyspnea, in the more symptomatic group, patients had higher scores in the three domains and total score in SGRQ, besides having more exacerbations and more patients in home oxygen therapy. Conclusions: Causes most identified were postinfections, CD, and COPD. Patients with COPD are older and have worse pulmonary function and more comorbidities. The most symptomatic patients are clinically and functionally more severe, besides having worse quality of life.

Characteristics of Otologic Disease Among Patients With Primary Ciliary Dyskinesia.

Importance: Otologic disease is common among people with primary ciliary dyskinesia (PCD), yet little is known about its spectrum and severity. Objective: To characterize otologic disease among participants with PCD using data from the Ear-Nose-Throat Prospective International Cohort. Design, Setting, and Participants: This cross-sectional analysis of baseline cohort data from February 2020 through July 2022 included participants from 12 specialized centers in 10 countries. Children and adults with PCD diagnoses; routine ear, nose, and throat examinations; and completed symptom questionnaires at the same visit or within 2 weeks were prospectively included. Exposures: Potential risk factors associated with increased risk of ear disease. Main Outcomes and Measures: The prevalence and characteristics of patient-reported otologic symptoms and findings from otologic examinations, including potential factors associated with increased risk of ear inflammation and hearing impairment. Results: A total of 397 individuals were eligible to participate in this study (median [range] age, 15.2 [0.2-72.4] years; 186 (47%) female). Of the included participants, 204 (51%) reported ear pain, 110 (28%) reported ear discharge, and 183 (46%) reported hearing problems. Adults reported ear pain and hearing problems more frequently when compared with children. Otitis media with effusion-usually bilateral-was the most common otoscopic finding among 121 of 384 (32%) participants. Retracted tympanic membrane and tympanic sclerosis were more commonly seen among adults. Tympanometry was performed for 216 participants and showed pathologic type B results for 114 (53%). Audiometry was performed for 273 participants and showed hearing impairment in at least 1 ear, most commonly mild. Season of visit was the strongest risk factor for problems associated with ear inflammation (autumn vs spring: odds ratio, 2.40; 95% CI, 1.51-3.81) and age 30 years and older for hearing impairment (41-50 years vs ≤10 years: odds ratio, 3.33; 95% CI, 1.12-9.91). Conclusion and Relevance: In this cross-sectional study, many people with PCD experienced ear problems, yet frequency varied, highlighting disease expression differences and possible clinical phenotypes. Understanding differences in otologic disease expression and progression during lifetime may inform clinical decisions about follow-up and medical care. Multidisciplinary PCD management should be recommended, including regular otologic assessments for all ages, even without specific complaints.

Depression, anxiety, and resilience during COVID-19 in Dutch patients with cystic fibrosis or primary ciliary dyskinesia and their caregivers.

BACKGROUND: The COVID-19 pandemic has spread across the world, leading to government measures associated with a negative impact on mental health. The aim of this study was to evaluate the impact of the pandemic on depression, anxiety and resilience in Dutch people with cystic fibrosis (PwCF) or primary ciliary dyskinesia (PwPCD) and their caregivers. METHODS: Adolescents (12-17 years) and caregivers of children (0-17 years) with CF, and adolescents, adults and caregivers of children with PCD completed questionnaires on depression, anxiety and resilience between September 2020 and February 2021. The psychosocial impact of COVID-19 was measured by the Exposure and Family Impact Survey (CEFIS) Part 2. Mixed model analyses compared depression and anxiety results to participants' prepandemic scores. RESULTS: One hundred ten participants (10 PwCF, 31 PwPCD, 52 CF caregivers, 17 PCD caregivers) completed questionnaires during the pandemic. Prepandemic outcomes were available for 87 participants. The prevalence of symptoms of depression and anxiety (PHQ-9 or GAD-7 scores ≥5) in PwCF and PwPCD and their caregivers before and during the pandemic was high, with an increase in depression in PwCF (2.75; 95% confidence interval: 0.82-4.68) and increase in anxiety in CF caregivers (1.03; 0.09-1.96) during the pandemic. Resilience was within the normal range for all groups, CEFIS scores corresponded to a low to normal impact. CONCLUSION: PwCF and PwPCD and their caregivers were at risk of elevated depression and anxiety symptoms both before and during the pandemic, which emphasizes the importance of mental health screening and psychological care in CF and PCD.

Is RPGR-related retinal dystrophy associated with systemic disease? A case series.

BACKGROUND: Ciliopathies responsible for retinitis pigmentosa can also cause systemic manifestations. RPGR is a ciliary gene and pathogenic variants in RPGR cause a retinal ciliopathy, the commonest cause of X-linked recessive retinitis pigmentosa. The RPGR protein interacts with numerous other ciliary proteins present in the transition zone of both motile and sensory cilia, and may play an important role in regulating ciliary protein transport. There has been a growing, putative association of RPGR variants with systemic ciliopathies: mainly sino-respiratory infections and primary ciliary dyskinesia. MATERIALS AND METHODS: Retrospective case series of patients with RPGR-RP presenting to Oxford Eye Hospital with systemic disease. RESULTS: We report three children with RPGR-related rod-cone dystrophy, all of whom have mutations in the N-terminus of RPGR. Two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. These and all previously reported RPGR co-pathologies relate to ciliopathies and have no other systemic associations. CONCLUSIONS: The link between RPGR variants and a systemic ciliopathy remains plausible, but currently unproven.

Motile Ciliary Disorders of the Nasal Epithelium in Adults With Bronchiectasis.

BACKGROUND: Motile ciliary disorder (MCD) has been implicated in chronic inflammatory airway diseases such as asthma and COPD. RESEARCH QUESTION: What are the characteristics of MCD of the nasal epithelium and its association with disease severity and inflammatory endotypes in adults with bronchiectasis? STUDY DESIGN AND METHODS: In this observational study, we recruited 167 patients with bronchiectasis and 39 healthy control participants who underwent brushing of the nasal epithelium. A subgroup of patients underwent bronchoscopy for bronchial epithelium sampling (n = 13), elective surgery for bronchial epithelium biopsy (n = 18), and blood sampling for next-generation sequencing (n = 37). We characterized systemic and airway inflammatory endotypes in bronchiectasis. We conducted immunofluorescence assays to profile ultrastructural (dynein axonemal heavy chain 5 [DNAH5], dynein intermediate chain 1 [DNAI1], radial spoke head protein 9 [RSPH9]) and ciliogenesis marker expression (Ezrin). RESULTS: MCD was present in 89.8% of patients with bronchiectasis, 67.6% showed secondary MCD, and 16.2% showed primary plus secondary MCD. Compared with healthy control participants, patients with bronchiectasis yielded abnormal staining patterns of DNAH5, DNAI1, and RSPH9 (but not Ezrin) that were more prominent in moderate to severe bronchiectasis. MCD pattern scores largely were consistent between upper and lower airways and between large-to-medium and small airways in bronchiectasis. Coexisting nasal diseases and asthma did not confound nasal ciliary ultrastructural marker expression significantly. The propensity of MCD was unaffected by the airway or systemic inflammatory endotypes. MCD, particularly an ultrastructural abnormality, was notable in patients with mild bronchiectasis who showed blood or sputum eosinophilia. INTERPRETATION: Nasal ciliary markers profiling provides complimentary information to clinical endotyping of bronchiectasis.

Type II congenital pulmonary airway malformation with primary ciliary dyskinesia in a 4-year-old child: A case report.

A congenital pulmonary airway malformation (CPAM) combined with primary ciliary dyskinesia (PCD) has not been described in literature. Herein, we described the case of a 4-year-old boy who presented to us with recurrent productive cough and rhinorrhea for 2 years. High resolution computed tomography of the thorax revealed multiple, cystic, transparent shadows of different sizes near the posterior thoracic cavity in the lower lobe of the left lung. Thoracoscopic segmentectomy was carried out and histology confirmed a type II CPAM. Whole-exome sequencing revealed a compound heterozygous mutation (c.10568+1G>A, c.9484delG) in the DNAH11 gene associated with PCD that originated from the boy's mother and father, respectively. This report showed that when a child with CPAM presents with a productive cough and recurrent sinusitis, irrespective of situs inversus, PCD should be suspected. Genetic testing can aid in diagnosis.

Familial Recurrence Patterns in Congenitally Corrected Transposition of the Great Arteries: An International Study.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. METHODS: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. RESULTS: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. CONCLUSIONS: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Coexistence of pan-hypogammaglobulinaemia and primary ciliary dyskinesia.

A patient, an adolescent male, presented to us with complaints of recurrent respiratory tract infections since childhood. Differentials considered were cystic fibrosis (CF), bronchial asthma with allergic bronchopulmonary aspergillosis (ABPA), primary ciliary dyskinesia (PCD) and primary immunodeficiency disorders. Sweat chloride test, total IgE and Aspergillus fumigatus specific serum IgE and IgG levels were normal ruling out CF and ABPA. Nasal nitric oxide (NO) screening test showed reduced NO levels, and high-speed video microscopy of nasal scrapings showed stiff beating cilia with reduced ciliary beat frequency confirming the diagnosis of PCD. Immunodeficiency workup showed reduced serum IgG, IgA and IgM, when repeated on two separate occasions when the patient was not harbouring any active infection, suggestive of pan-hypogammaglobulinaemia. Thus, a diagnosis of coexistent PCD and pan-hypogammaglobulinaemia was made. Detection of immunodeficiency disorders is important in patients with PCD as they may benefit from immunoglobulin replacement.

Primary ciliary dyskinesia and fungal infections: Two cases of allergic bronchopulmonary aspergillosis in children.

Primary ciliary dyskinesia (PCD) is a rare inherited disease that affects the movement of the respiratory cilia. The main clinical manifestations are chronic upper and lower respiratory symptoms and recurrent lung infections, particularly bacterial and viral infections. Fungal infections are not usually associated with PCD. Allergic bronchopulmonary aspergillosis (ABPA) is a rare complex immune hypersensitivity reaction to Aspergillus fumigatus reported in patients with asthma and cystic fibrosis. Only three cases of ABPA associated with adult PCD have been described in the literature. Herein, we reported on two cases of ABPA in two boys aged 10 and 13 years with PCD. Both had severe lung disease and chronic Pseudomonas aeruginosa infections. One patient was diagnosed according to the typical clinical features of ABPA, while the other was diagnosed during a scheduled visit with no clinical changes but worsening pulmonary function and radiologic anomalies. The diagnosis of ABPA was confirmed in the two patients who then improved after receiving specific treatment. These two cases were the first to describe the occurrence of ABPA in children with PCD. We recommend that physicians involved in the management of children with PCD be aware of this potential complication.

Vestibular and Balance Impairment Is Common in Children With Primary Ciliary Dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a rare genetic disorder that presents with a wide range of respiratory complaints. The most common otologic associated disorder is middle ear effusion. We ask if children with PCD suffer from vestibular impairment. STUDY DESIGN: Cross-sectional cohort study. SETTING: Tertiary pediatric referral hospital. PATIENTS/PARTICIPANTS: Children with confirmed PCD. INTERVENTION/METHODS: All included participants were clinically assessed to be at baseline then basic demographics and medical histories were collected, including the specific genetic mutation these patients have. After which, all patients underwent two vestibular tests. The first was to assess their ability to stand on one foot with their eyes open and then with their eyes closed and the second was video head impulse test (vHIT). MAIN OUTCOME MEASURES: Ability standing on one foot with the eyes closed and vHIT. RESULTS: During this period, 25 children with PCD were recruited for the study. The mean age at recruitment was 11.26 years (4-18 yr). There were 11 women and 14 men. All patients were able to participate in both tests. Nineteen participants (76%) had vestibular impairment. Fifteen of them failed to stand on one foot with their eyes closed and six of 25 had abnormal vHIT. The most common involved gene was DNAH5 8/25 (32%) and it was associated with vestibular impairment in seven of eight participants (87.5%). CONCLUSION: The majority of children with PCD that we tested suffered from vestibular impairment that was previously undiagnosed. This potentially indicates that imbalance and vestibular pathology is under-diagnosed in children with PCD.

Variations in infection control practices suggest a need for guidelines in primary ciliary dyskinesia patient care.

Primary ciliary dyskinesis (PCD) is an autosomal recessive disorder associated with impaired mucociliary clearance caused by defects in ciliary structure and function. The major clinical feature of PCD is recurring or persistent respiratory tract infection. Respiratory tract colonization with drug-resistant organisms impacts the frequency of infections and lung function decline. Protective gear has been employed by caregivers in an attempt to control respiratory tract bacterial spread between patients with cystic fibrosis, but use in PCD is not known. We conducted a web-based survey to investigate infection control and prevention practices of PCD centers in North America, and how practices have been influenced by the COVID-19 pandemic. The response rate was 87.0%. Before the COVID-19 pandemic, glove, gown, and mask use were variable, and only 3.7% of centers used masks during encounters with PCD outpatients. After COVID-19 mandates are lifted, 48.1% of centers plan to continue to use masks during outpatient care, while the practice regarding the use of gloves and gowns was not influenced by the current pandemic. There is no uniform practice for infection control in PCD care indicating the need for practice guidelines. Mitigation of respiratory virus transmission learned during the COVID-19 pandemic may impact future infection control approaches used for patients with PCD and other lung diseases.

Pregnancy and delivery in a patient with a Fontan circulation and primary ciliary dyskinesia: A case report.

A patient had primary ciliary dyskinesia with a complex cardiac malformation. As a child, she had benefited from a Fontan surgery to maintain a proper cardiac function. In such patients, whether it is safe to become pregnant is controversial. This case illustrates the possibility of carrying a pregnancy to term and providing a vaginal birth if a rigorous preconception consultation is performed to ensure care by a multidisciplinary specialized team, and the patient is properly informed of the risks.

A novel heterotaxy gene: Expansion of the phenotype of TTC21B-spectrum disease.

TTC21B encodes the protein IFT139, a critical component of the retrograde transport system within the primary cilium. Biallelic, pathogenic TTC21B variants are associated with classic ciliopathy syndromes, including nephronophthisis, Jeune asphyxiating thoracic dystrophy, and Joubert Syndrome, with ciliopathy-spectrum traits such as biliary dysgenesis, primary ciliary dyskinesia, and situs inversus, and also with focal segmental glomerulosclerosis. We report a 9-year-old male with focal segmental glomerulosclerosis requiring kidney transplant, primary ciliary dyskinesia, and biliary dysgenesis, found by research-based exome sequencing to have biallelic pathogenic TTC21B variants. A sibling with isolated heterotaxy was found to harbor the same variants. This case highlights the phenotypic spectrum and unpredictable manifestations of TTC21B-related disease, and also reports the first association between TTC21B and heterotaxy, nominating TTC21B as an important new heterotaxy gene.

The effect of a novel LRRC6 mutation on the flagellar ultrastructure in a primary ciliary dyskinesia patient.

PURPOSE: There are limited genes known to cause primary ciliary dyskinesia (PCD)-associated asthenozoospermia. In the present study, we aimed to expand the spectrum of mutations in PCD and to provide new information for genetic counseling diagnoses and the treatment of male infertility in PCD. METHODS: One sterile patient with typical situs inversus was recruited to our center, and semen sample was collected. We performed whole-exome sequencing (WES) on the patient to identify the pathogenic mutations associated with PCD and used transmission electron microscopy to investigate spermatozoal ultrastructure. In addition, western blotting and immunofluorescence staining were used to confirm the untoward impact of the variant on the expression of LRRC6, as well as on the dynein arm proteins in the patient's spermatozoa. RESULTS: We identified a homozygous nonsense variant c.749G>A (p.W250*) of LRRC6 in the PCD patient. This variant severely impaired LRRC6 expression and further led to negative effects on dynein arm protein expression in the spermatozoa of the affected individual, which eventually caused defects in sperm ultrastructure and motility. Moreover, we are the first to report a positive prognosis using intracytoplasmic sperm injection (ICSI) for LRRC6-associated male infertility. CONCLUSIONS: Our findings strongly implicated the homozygous mutation of c.749G>A (p.W250*) in LRRC6 as a new genetic cause of PCD, uncovering its involvement in defective sperm flagella and poor sperm motility. Furthermore, we posit that patients with LRRC6 mutations may have good outcomes with ICSI treatment. These findings add to the literature on the genetic diagnoses and treatment of male infertility associated with PCD.

Changing clinical characteristics of non-cystic fibrosis bronchiectasis in children.

BACKGROUND: The prevalence of non-cystic fibrosis (CF) bronchiectasis is increasing in both developed and developing countries in recent years. Although the main features remain similar, etiologies seem to change. Our aim was to evaluate the clinical and laboratory characteristics of our recent non-CF bronchiectasis patients and to compare these with our historical cohort in 2001. METHODS: One hundred four children with non-CF bronchiectasis followed between 2002 and 2019 were enrolled. Age of diagnosis, underlying etiology and microorganisms in sputum culture were recorded. Clinical outcomes were evaluated in terms of lung function tests and annual pulmonary exacerbation rates at presentation and within the last 12 months. RESULTS: Mean FEV1 and FVC %predicted at presentation improved compared to historical cohort (76.6 ± 17.1 vs. 63.3 ± 22.1 and 76.6 ± 15.1 vs. 67.3 ± 23.1, respectively; p <  0.001). There was a significant decrease in pulmonary exacerbation rate from 6.05 ± 2.88 at presentation to 3.23 ± 2.08 during follow-up (p <  0.0001). In 80.8% of patients, an underlying etiology was identified. There was an increase in primary ciliary dyskinesia (PCD) (32.7% vs. 6.3%; p = 0.001), decrease in idiopathic cases (19.2% vs. 37.8%; p = 0.03) with no change in postinfectious and immunodeficiencies as underlying etiology. Sputum cultures were positive in 77.9% of patients which was 46.9% in the historical cohort (p = 0.001). CONCLUSION: Baseline pulmonary function tests were better and distribution of underlying etiology had changed with a remarkable increase in diagnosis of PCD in the recent cohort.