Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Hereditary pulmonary alveolar proteinosis as collateral damage from a large chromosomal deletion.

A girl with a known chromosomal deletion at Xp22.33, learning difficulties and short stature presented with dyspnea and dry cough and an abnormal chest X-ray. Computed tomography was typical for pulmonary alveolar proteinosis (PAP), and the diagnosis was confirmed invasively. More detailed genetic analysis detected a homozygous deletion of the colony-stimulating factor-2-receptor alpha subunit (CSF2RA) gene. In this patient, the Xp22.33 deletion affected 8 genes, including CSF2RA, leading to GM-CSF receptor dysfunction and hereditary PAP. This is the first report of childhood interstitial lung disease (chILD) as collateral damage from a large chromosomal deletion.

Paediatric and adolescent asthma: A narrative review of telemedicine and emerging technologies for the post-COVID-19 era.

Children and young people with asthma need regular monitoring to maintain good asthma control, prevent asthma attacks and manage comorbidities. The COVID-19 pandemic has resulted in healthcare professionals making fundamental changes to the way healthcare is delivered and for patients and families adapting to these changes. Comprehensive remotely delivered, technology-based healthcare, closer to the patients home (reducing hospital footfall and possibly reducing carbon footprint) is likely to be one of the important collateral effects of the pandemic. Telemedicine is anticipated to impact everyone involved in healthcare - providers and patients alike. It is going to bring changes to organization, work areas and work culture in healthcare. Healthcare providers, policymakers and those accessing healthcare services will experience the impact of technology-based healthcare delivery. Telemedicine can play an exciting role in the management of childhood asthma by delivering high-quality care closer to the child's home. However, unlike adults, children still need to be accompanied by their carers for virtual care. Policymakers will need to take into account potential additional costs as well as the legal, ethical and cultural implications of large scale use of telemedicine. In this narrative review, we review evidence regarding the role of telemedicine and related emerging technologies in paediatric and adolescent asthma. Although there are gaps in the current knowledge, there is evidence demonstrating the important role of telemedicine in management of childhood and adolescent asthma. However, there is an urgent need for healthcare researchers and policymakers to focus on improving the technologies and address the disparities in accessing novel technology-based management strategies to improve asthma care.

Hydrocephalus and diffuse choroid plexus hyperplasia in primary ciliary dyskinesia-related MCIDAS mutation.

OBJECTIVE: To report a neuroradiologic phenotype associated with reduced generation of multiple motile cilia (RGMC) and mutations in the multicilin gene. We hypothesize that the observed phenotype may reflect the emerging role that ependymal cilia play in regulating CSF production. METHOD: Clinical and radiologic records were retrospectively reviewed for 7 consecutive patients diagnosed by the Leicester UK national primary ciliary dyskinesia (PCD) diagnostic laboratory. RESULTS: On MRI scanning, all patients demonstrated hydrocephalus, choroid plexus hyperplasia (CPH), and arachnoid cysts. No patient had any sign of neurologic deficit. All patients had significant lung disease. CONCLUSIONS: We conclude that there is a high incidence of hydrocephalus, arachnoid cysts, and CPH in MCIDAS-associated RGMC. In all cases, the observed hydrocephalus seems arrested in childhood without progression or adverse neurologic sequelae. Our new observation of CPH, which is associated with CSF overproduction, is the first macroscopic evidence that ependymal cilia may be involved in the regulation of CSF production and flow. We suggest that brain imaging should be performed in all cases of RGMC and that a diagnosis of PCD or RGMC be strongly considered in patients with unexplained hydrocephalus and a lifelong "wet"-sounding cough.

Clinical features and management of children with primary ciliary dyskinesia in England.

OBJECTIVE: In England, the National Health Service commissioned a National Management Service for children with primary ciliary dyskinesia (PCD). The aims of this study were to describe the health of children seen in this Service and compare lung function to children with cystic fibrosis (CF). DESIGN: Multi-centre service evaluation of the English National Management PCD Service. SETTING: Four nationally commissioned PCD centres in England. PATIENTS: 333 children with PCD reviewed in the Service in 2015; lung function data were also compared with 2970 children with CF. RESULTS: Median age at diagnosis for PCD was 2.6 years, significantly lower in children with situs inversus (1.0 vs 6.0 years, p<0.001). Compared with national data from the CF Registry, mean (SD) %predicted forced expiratory volume in one second (FEV1) was 76.8% in PCD (n=240) and 85.0% in CF, and FEV1 was lower in children with PCD up to the age of 15 years. Approximately half of children had some hearing impairment, with 26% requiring hearing aids. Children with a lower body mass index (BMI) had lower FEV1 (p<0.001). One-third of children had positive respiratory cultures at review, 54% of these grew Haemophilus influenzae. CONCLUSIONS: We provide evidence that children with PCD in England have worse lung function than those with CF. Nutritional status should be considered in PCD management, as those with a lower BMI have significantly lower FEV1. Hearing impairment is common but seems to improve with age. Well-designed and powered randomised controlled trials on management of PCD are needed to inform best clinical practice.

Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort.

BACKGROUND: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests. METHODS: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries. RESULTS: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results. CONCLUSIONS: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.

Risk factors for situs defects and congenital heart disease in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is associated with abnormal organ positioning (situs) and congenital heart disease (CHD). This study investigated genotype-phenotype associations in PCD to facilitate risk predictions for cardiac and laterality defects. This retrospective cohort study of 389 UK patients with PCD found 51% had abnormal situs and 25% had CHD and/or laterality defects other than situs inversus totalis. Patients with biallelic mutations in a subset of nine PCD genes had normal situs. Patients with consanguineous parents had higher odds of situs abnormalities than patients with non-consanguineous parents. Patients with abnormal situs had higher odds of CHD and/or laterality defects.

High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations.

RATIONALE: Primary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal. OBJECTIVES: To determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive. METHODS: Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay. RESULTS: Sixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed. CONCLUSIONS: The CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests.

Pneumococcal polysaccharide vaccine responses are impaired in a subgroup of children with cystic fibrosis.

BACKGROUND: Pneumococcal immunization is recommended in children with cystic fibrosis (CF). To date, however, there are no published studies on the efficacy of pneumococcal vaccination in this group of patients. METHODS: We carried out a retrospective study of serotype-specific pneumococcal antibody responses to immunization with Prevenar 7 and Pneumovax II in a cohort of children with CF. RESULTS: Nine children had been immunized with Prevenar 7, and all had serotype-specific pneumococcal antibody levels in the protective range (>0.35mg/L) to all 7 immunizing serotypes. In contrast, only 7 of 33 patients (21%) immunized with Pneumovax II made protective antibody responses to all 7 serotypes, and 3 failed to make protective antibodies to any of the serotypes. Controlling for age as a confounder in the analysis, children with impaired antibody responses to pneumococcal polysaccharide (Pneumovax II) immunization had lower Shwachman-Kulczycki scores than children with normal polysaccharide antibody responses. All isolates of Pseudomonas aeruginosa occurred in patients with impaired anti-pneumococcal antibody responses, and a broader range of respiratory pathogens was isolated from these children. CONCLUSIONS: Impaired antibody responses to immunization with Pneumovax II are common in children with CF and this may be associated with increased disease severity.

Oral prednisolone for preschool children with acute virus-induced wheezing.

BACKGROUND: Attacks of wheezing induced by upper respiratory viral infections are common in preschool children between the ages of 10 months and 6 years. A short course of oral prednisolone is widely used to treat preschool children with wheezing who present to a hospital, but there is conflicting evidence regarding its efficacy in this age group. METHODS: We conducted a randomized, double-blind, placebo-controlled trial comparing a 5-day course of oral prednisolone (10 mg once a day for children 10 to 24 months of age and 20 mg once a day for older children) with placebo in 700 children between the ages of 10 months and 60 months. The children presented to three hospitals in England with an attack of wheezing associated with a viral infection; 687 children were included in the intention-to-treat analysis (343 in the prednisolone group and 344 in the placebo group). The primary outcome was the duration of hospitalization. Secondary outcomes were the score on the Preschool Respiratory Assessment Measure, albuterol use, and a 7-day symptom score. RESULTS: There was no significant difference in the duration of hospitalization between the placebo group and the prednisolone group (13.9 hours vs. 11.0 hours; ratio of geometric means, 0.90; 95% confidence interval, 0.77 to 1.05) or in the interval between hospital admission and signoff for discharge by a physician. In addition, there was no significant difference between the two study groups for any of the secondary outcomes or for the number of adverse events. CONCLUSIONS: In preschool children presenting to a hospital with mild-to-moderate wheezing associated with a viral infection, oral prednisolone was not superior to placebo. (Current Controlled Trials number, ISRCTN58363576.)

Does inhaling menthol affect nasal patency or cough?

OBJECTIVE: There is widespread use of menthol in over-the-counter medications, despite scant information on any beneficial effects. Our aim was to assess the effect of menthol on nasal air flow, perception of nasal patency and cough challenge testing. MATERIALS AND METHODS: Subjects comprised 42 healthy children aged 10 and 11 in a school setting. We used a single-blind pseudo-randomized cross-over trial to compare the effect of an inhalation of either menthol or placebo(eucalyptus oil). Baseline and post-intervention measurements were made on each of 2 consecutive days. Main outcome measures were (i) nasal expiratory and inspiratory flows and volumes, measured by spirometer, (ii) perception of nasal patency, assessed with a visual analogue scale (VAS), and (iii) the number of coughs in response to nebulized citric acid. RESULTS: There was no effect of menthol on any of the spirometric measurements. Following menthol, there was a significant increase in the perception of nasal patency (mean difference in log VAS (menthol-placebo) = -0.207, 95%CI -0.329, -0.085). The cough count after menthol inhalation was reduced when compared to baseline but the change was not different from that after placebo (mean difference in cough count (menthol-placebo) = -1.71, 95%CI -4.11, 0.69). CONCLUSION: Menthol has no effect on objective measures of flow but significantly increases the perception of nasal patency. It may not be possible to extrapolate these findings to younger children and those with rhinitis. Extending the study of menthol to these groups, including investigations of the efficacy and safety profiles, will provide further valuable evidence for its common use.

Intramuscular triamcinolone for difficult asthma.

We treated a selected group of children attending a difficult asthma clinic with intramuscular triamcinolone acetonide. This study retrospectively reviews markers of asthma severity in those who received one or more monthly doses for three periods: 1) 3 months preceding the first injection (pretreatment), 2) from the first injection to 1 month after the last injection (treatment period), and 3) 3 months after the treatment period (follow-up period). Severity markers during the treatment and follow-up periods were compared with the pretreatment period by paired t-test. Five children (5-13 years old) received a single dose, and 8 children (12-15 years old) received multiple doses. Multiple doses of triamcinolone (n = 3-5) were associated with a fall in the number of asthma exacerbations (P < 0.01) and hospital admissions (P < 0.01) in both the treatment and follow-up periods. A single dose reduced exacerbations (P < 0.05, treatment vs. pretreatment) but not hospital admissions. We conclude that intramuscular triamcinolone is a useful short-term therapy in difficult asthma. Whether its efficacy is due to improved compliance, or an improved anti-inflammatory profile compared with oral steroids, remains unclear.