CFTR mutations and phenotypic correlations in people with cystic fibrosis: a retrospective study from a single centre in south India.

Background: Emerging data reveal higher-than-expected prevalence of cystic fibrosis (CF) among non-European populations worldwide including in the Indian subcontinent. Systematic analyses of the CFTR mutation profile, and genotype-phenotype correlations among people with CF from south, east, or northeast India have not been reported before. We wanted to identify CFTR mutations in people with CF, and highlight novel variants, selective phenotypic correlations, and regional variances within India. Methods: A retrospective study was conducted at Christian Medical College, Vellore, India (single tertiary referral hospital) from September 2010 to August 2022, involving 120 people with CF from (i) four south Indian states (Tamil Nadu, Andhra Pradesh, Kerala, Karnataka), (ii) in and nearby regions of West Bengal, India and (iii) Bangladesh. Comprehensive CFTR mutation analyses were done by Next-Generation Sequencing, and variants were categorized per American College of Medical Genetics guidelines and compared with validated Locus-specific databases. Demographic characteristics, mutation profile, novel mutations, selective phenotype correlations, and regional variances were assessed. Findings: In 120 people with CF, 55 CFTR variants were identified, including six novel variants. F508del was the predominant mutation, yet with a lower allele frequency than reported among European populations (27% versus 70%). Phenotypic correlations suggested high mutational pathogenicity causing severe multi-organ morbidity, and death in 27%. Milder variants associated with pancreatic sufficiency were also evident in 23% of people with CF. Statistically significant regional variances were noted in genotype frequency, and clinical phenotype among people with CF from the two regions. Hotspot exons and introns that could potentially help create targeted mutation panels were identified. Interpretation: The identification of 55 different CFTR variants among 120 people with CF describes the diversity of mutations noted in India, while also revealing the challenges that providers may encounter in timely diagnosis and treatment of CF. However, these single-centre data have specific limitations and cannot be generalised to all people with CF from India or to those of non-European origin. Our data on regional CFTR mutations contribute to the emerging national registry on CF epidemiology in India, help formulate diagnostic and newborn screening algorithms, help optimise clinical care, and highlight urgency to improve access to life-changing modulator therapy. Funding: Cystic Fibrosis Foundation, USA (towards the CF-India Demonstration Project) and Christian Medical College, Vellore, India.

Clinical management of pediatric patients with cystic fibrosis and autism spectrum disorder.

BACKGROUND: Cystic Fibrosis (CF) and autism spectrum disorder (ASD) are life-long conditions with intense treatment burdens for patients and families. Patients with a concurrent diagnosis (CF-ASD) experience unique obstacles to CF care. This study describes the experiences of our multidisciplinary CF team in caring for patients with CF-ASD and provides insight into provider and parental perspectives on clinical management. METHODS: This is a three-part qualitative study involving (1) retrospective chart review of patients with CF-ASD, (2) surveys with multidisciplinary care team members, and (3) semistructured interviews with caregivers of patients with CF-ASD. Challenges in clinical management of this specific cohort were compiled using data from chart review and care team surveys. Strategies to address these concerns were identified and rated by individual families based on relevance and practicality. RESULTS: Within our CF center, 12 patients have an official diagnosis of ASD. Median age of patients with CF-ASD was 8.5 years (range 3-20 years), 67% were male, and 83% were on highly effective modulator therapy. Clinical barriers included sensory processing issues, environmental overstimulation, intolerance to procedures and to disrupted routines. Potentially impactful strategies include patient-specific coping plans, guided behavioral interventions, parental advocacy, and improved communication between the family and multidisciplinary team. CONCLUSION: Children with CF-ASD face extraordinary challenges beyond the experience of neurotypical children with CF. Increased awareness of this complex dual diagnosis will help providers be sensitive to the unique needs of these patients, help build consistent and trustworthy relationships with their families and deliver effective clinical care despite limitations.

What Are the Factors Affecting Total Sleep Time During Video Polysomnography in Infants?

OBJECTIVE: The aim of the study is to investigate factors affecting total sleep time (TST) during infant polysomnography (PSG) and assess if <4 hours of TST is sufficient for accurate interpretation. STUDY DESIGN: Overall, 242 PSGs performed in 194 infants <6 months of chronological age between March 2013 and December 2015 were reviewed to identify factors that affect TST, including age of infant, location and timing of study, presence of medical complexity, and presence of nasal tubes. A continuum of apnea-hypopnea index (AHI) in relation to TST was reviewed. Data were examined in infants who had TST <4 hours and low AHI. RESULTS: Greater TST (p < 0.001) was noted among infants during nocturnal PSGs, at older chronological and post-menstrual ages, and without medical complexity. The presence of nasogastric/impedance probes reduced TST (p = 0.002). Elevated AHIs were identified even in PSGs with TST <4 hours. Short TST may have affected interpretation and delayed initial management in one infant without any inadvertent complications. CONCLUSION: Clinical factors such as PMA and medical complexity, and potentially modifiable factors such as time of day and location of study appeared to affect TST during infant PSGs. TST < 4 hours can be sufficient to identify high AHI allowing physician interpretation. KEY POINTS: · Less than 4 hours of TST is enough for interpretation of infant polysomnography.. · Shorter TST appears related to infant age, medical complexity, and higher apnea-hypopnea index.. · Modifiable factors seen with higher TST were time of day, environment, and presence of nasal tubes..

Aquagenic wrinkling in children under two years of age: Could this be a potential clinical referral tool for cystic fibrosis among non-screened populations?

BACKGROUND: Early diagnosis via newborn screening is crucial to improve clinical outcomes in patients with cystic fibrosis (CF). In resource-limited areas where newborn screening is unavailable and CF-related morbidity is high, clinical tools such as palmar aquagenic wrinkling (AW) have been considered. We report the utility of AW for possible early identification of CF in children <2 years old. METHODS: This pilot case-control study included 55 total children, 20 with confirmed CF, 10 CF carriers, and 25 healthy controls. The time to wrinkling (TTW) after hand immersion in water was recorded, and relationships between TTW, demographic and clinical variables, and validated diagnostic tests were analyzed. RESULTS: Wrinkling was observed in children <2 years of age, and median TTW was significantly lower among those with CF (3 min) compared to carriers or healthy controls (12 and 14 min, respectively). Higher immunoreactive trypsinogen and sweat chloride levels were associated with lower TTW (p < 0.001). In this predominantly Caucasian cohort, children with F508del had the lowest TTW. Six minutes of hand immersion offered a sensitivity of 85% and a specificity of 91%, suggesting a practical and effective test duration for this age. There was no evidence that nutritional status affected TTW. CONCLUSION: Our data confirm the role of AW in CF, validate test utility among young children, and analyze relationships between TTW, immunoreactive trypsinogen, sweat chloride levels, and CF-causing mutations. Despite test limitations, in children with suspected CF from non-screened populations, utility of AW in enabling early referral and diagnosis needs further exploration.

A 17-Year-Old With Becker Muscular Dystrophy and Unusual Polysomnography Findings.

CASE PRESENTATION: A 17-year-old male patient who was diagnosed with Becker muscular dystrophy (nonsense mutation [c.3822C>A] within exon 28 of the DMD gene) at 6 years of age was evaluated in the multidisciplinary neuromuscular clinic for loss of ambulation for 1 year. From a pulmonary perspective, there were no acute or chronic respiratory symptoms, and no history of pneumonia or aspiration. Clinical examination revealed a nonambulant teenager, with normal oxygen saturation and end-tidal CO2 when awake, no respiratory distress, and symmetrically diminished aeration due to obesity (BMI 40 kg/m2). Results of pulmonary function testing revealed FVC of 83% predicted with actual volume of 3.5 L and peak cough flow of 445 L/min (all within normal limits).

The respiratory impact of novel therapies for spinal muscular atrophy.

The phenotype of spinal muscular atrophy (SMA) has been changing with the recent availability of three FDA-approved treatments: intrathecal nusinersen, intravenous onasemnogene abeparvovec-xioi, and enteral risdiplam. The degree of improvement in muscle strength and respiratory health varies with SMA genotype, severity of baseline neuromuscular and pulmonary impairment, medication used, and timing of the first dose. A spectrum of pulmonary outcomes has been reported with these novel medications when used early and in conjunction with proactive multidisciplinary management of comorbidities. In this review, we summarize the reported impact of these novel therapies on pulmonary well-being and the improving trajectory of pulmonary morbidity, compared to the natural history of SMA. The importance of ongoing clinical monitoring albeit the improved phenotype is reiterated. We also discuss the limitations of the current SMA-therapy trials and offer suggestions for future clinical-outcome studies and long-term monitoring.

Identification of Mycobacterium porcinum in patients with cystic Fibrosis: Pathogen or contaminant?

BACKGROUND: Mycobacterium porcinum is a non-tuberculous mycobacterium (NTM) identified in potable water. The identification and clinical impact of M. porcinum in patients with cystic fibrosis (CF) has not been described. In our institution, M. porcinum was isolated exclusively during hospitalization in a cluster of patients with CF. METHODS: Patients with CF who were hospitalized between September 2016 and September 2018 and could expectorate sputum were included, and samples were processed per institutional guidelines. Post-hospitalization and one-year clinical outcomes on those who isolated M. porcinum in respiratory cultures were reviewed. Whole genome sequencing was performed on M. porcinum isolates obtained from patients and environmental sources to identify source of acquisition. RESULTS: Review of 14 CF patients with 16 M. porcinum isolates revealed rapid time to culture positivity within 0.8 (0.04-8.0) days after admission. M. porcinum was isolated in teenagers and adults irrespective of baseline pulmonary function, body mass index, or CF genotype. Whole genome sequencing suggested all isolates belong to the same M. porcinum strain and confirmed the source of acquisition to the ice machine. Review of patients' clinical course, including three patients who underwent lung transplantation, suggested a pseudo-outbreak with minimal clinical impact. CONCLUSIONS: NTM, including M. porcinum, are ubiquitous in potable water and institutional water reservoirs. Our findings suggest M. porcinum is a transient colonizer rather than a pathogen. Challenges exist in discerning the role of NTM as a contributor of pulmonary morbidity in patients with CF, and adherence to established guidelines regarding NTM related pulmonary disease remains important.

Sleep and the Cardiovascular System in Children.

Subspecialty pediatric practice provides comprehensive medical care for a range of ages, from premature infants to children, and often includes adults with complex medical and surgical issues that warrant multidisciplinary care. Normal physiologic variations involving different body systems occur during sleep and these vary with age, stage of sleep, and underlying health conditions. This article is a concise review of the cardiovascular (CV) physiology and pathophysiology in children, sleep-disordered breathing (SDB) contributing to CV morbidity, congenital and acquired CV pathology resulting in SDB, and the relationship between SDB and CV morbidity in different clinical syndromes and systemic diseases in the expanded pediatric population.

Pretransplant Panel Reactive Antibodies and Lung Transplant Outcomes in Children.

Background Pre-lung transplant (LTx) panel reactive antibody (PRA) levels are associated with adverse outcomes in adult LTx recipients, but their impact in pediatric LTx recipients is unknown. Methods The United Network for Organ Sharing registry was queried from 2004 to 2013 to compare survival between pediatric LTx recipients with PRA class I and II levels = 0 versus > 0. Results Overall, 333 pediatric LTx recipients had data on class I or II PRA and were included in the analysis. Univariate analysis demonstrated that PRA > 0 was not associated with survival benefit for class I (hazard ratio [HR] = 0.985; 95% confidence interval [CI]: 0.623, 1.555; p = 0.947) or class II (HR = 1.080; 95% CI: 0.657, 1.774; p = 0.762) PRA. Multivariate Cox models confirmed no significant association with mortality hazard for both class I (HR = 1.230; 95% CI: 0.641, 2.363; p = 0.533) and class II (HR = 0.847; 95% CI: 0.359, 1.997; p = 0.704) PRA. Multivariate logistic regression models identified no association between class I or class II and acute rejection within 3 years of LTx. Conclusions Pretransplant class I and II PRA levels > 0 were not associated with mortality or acute rejection in pediatric LTx recipients.