Genetic counseling access and service delivery in New York State is variable for parents of infants with complex CFTR genotypes conferring uncertain phenotypes.

BACKGROUND: New York State (NYS) utilizes a three-tiered cystic fibrosis newborn screening (CFNBS) algorithm that includes cystic fibrosis transmembrane conductance regulator (CFTR) gene sequencing. Infants with >1 CFTR variant of potential clinical relevance, including variants of uncertain significance or varying clinical consequence are referred for diagnostic evaluation at NYS cystic fibrosis (CF) Specialty Care Centers (SCCs). AIMS: As part of ongoing quality improvement efforts, demographic, screening, diagnostic, and clinical data were evaluated for 289 CFNBS-positive infants identified in NYS between December 2017 and November 2020 who did not meet diagnostic criteria for CF and were classified as either: CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID) or CF carriers. RESULTS: Overall, 194/289 (67.1%) had CFTR phasing to confirm whether the infant's CFTR variants were in cis or in trans. Eighteen complex alleles were identified in cis; known haplotypes (p.R117H+5T, p.F508del+p.L467F, and p.R74W+p.D1270N) were the most common identified. Thirty-two infants (16.5%) with all variants in cis were reclassified as CF carriers rather than CRMS/CFSPID. Among 263 infants evaluated at an NYS SCC, 70.3% were reported as having received genetic counseling about their results by any provider, with 96/263 (36.5%) counseled by a certified genetic counselor. CONCLUSION: Given the particularly complex genetic interpretation of results generated by CFNBS algorithms including sequencing analysis, additional efforts are needed to ensure families of infants with a positive CFNBS result have CFTR phasing when needed to distinguish carriers from infants with CRMS/CFSPID, and access to genetic counseling to address implications of CFNBS results.

Airway clearance after highly effective CFTR modulators: Normalizing life and reducing treatment burden.

OBJECTIVES: Airway clearance therapy (ACT) is an important component of therapy for cystic fibrosis (CF) but is associated with significant treatment burden. Highly effective CFTR modulator therapy (HEMT) has improved pulmonary function for many people with CF (pwCF). We sought to understand changes in attitudes and practices about ACT in the post-HEMT era. STUDY DESIGN: Surveys of CF community members and CF care team members. METHODOLOGY: Separate surveys were created for the CF community and CF care providers to evaluate attitudes towards ACT and exercise in the post-HEMT era. We solicited answers from pwCF via the CF Foundation's Community Voice and from CF care providers via CF Foundation listservs. Surveys were available between July 20 and August 3, 2021. RESULTS: Surveys were completed by 153 community members (parents of children and pwCF) and 192 CF care providers. Belief that exercise can substitute partially for ACT was endorsed similarly by community members (59%) and providers (68%). After starting HEMT, 36% of parents of children and 51% of adults did fewer ACT treatments including 13% who stopped ACT. Adults reported altering their ACT regimen more than parents of children, though the sample size was limited. Half of providers had changed their ACT recommendations for those on HEMT. Fifty-three percent of respondents had discussed changing ACT with their care team (36% of parents, 58% of pwCF). CONCLUSIONS: Providers should be aware that ACT management changes may have been undertaken by pwCF who have pulmonary benefits of HEMT. Treatment burden should be considered in co-management decisions regarding ACT and exercise.

Airway clearance therapy in the school environment: Retrospective analysis of a cohort of pediatric patients with cystic fibrosis.

BACKGROUND: Adherence to airway clearance therapy (ACT) in pediatric cystic fibrosis (CF) patients is reported to be below 50% and inability to sustain daily care is linked to poor health outcomes7,8,9. Through a collaboration between a CF care center and several schools, we hypothesized that ACT completed at school by pediatric CF patients will improve lung function while decreasing pulmonary exacerbations (PEx), days of antibiotics (abx) and hospitalizations. METHODS: This was a retrospective case-control study at a single CF care center consisting of 50 CF patients age < 18 at time when data was recorded (2012-2020). The case group used high-frequency chest wall oscillation or positive expiratory pressure devices at school for at least 1 year after self-reported or physician identified inadequate use at home. Lung function and measures of healthcare utilization were collected. RESULTS: In the case group (n = 14), paired t-tests showed that after initiation of ACT at school, there were significant reductions in PEx requiring IV or PO abx (P = 0.010), total days of abx (P = 0.032), and visits to the CF care center (P = 0.037). There was no change in these outcomes in the matched control group (n = 36). CONCLUSIONS: This is the first known study to highlight an initiative between a CF care center and schools which utilized airway clearance devices at school to ensure pediatric CF patients completed ACT. Through increased adherence, this relationship was associated with improved health outcomes. Use of alternative strategies may help patients with CF sustain adequate airway clearance.

Review of CFTR modulators 2020.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are small molecules that directly impact the CFTR protein, improving the function of the CFTR chloride and bicarbonate channel. Beginning in 2012 with the Food and Drug Administration approval of the first CFTR modulator, ivacaftor, this class of medications has had largely positive effects on many outcomes in people with cystic fibrosis (PwCF), including lung function, growth, and other clinical parameters. There have been continued exciting developments in the current research on CFTR modulators, expanding beyond original studies. This first part of a three-part cystic fibrosis (CF) year in review 2020 will focus on research on CFTR modulators. In addition to reviewing new clinical insights, we describe work done on novel outcomes, adverse effects, issues related to cost, and next steps for clinical trials. The review focuses on articles from Pediatric Pulmonology published in 2020, but it includes articles from other journals that are of particular interest to clinicians. New developments in CF research continue to be brought forth to the CF community, deepening the understanding of this disease and improving clinical care.

Systematic depression and anxiety screening for patients and caregivers: implementation and process improvement in a cystic fibrosis clinic.

INTRODUCTION: Depression and anxiety are common. Rates are significantly higher in cystic fibrosis (CF), and impact health outcomes. Screening is recommended, but is difficult to implement/sustain annually in a busy CF centre. The aim was to develop an acceptable model for depression and anxiety screening in adolescents/adults with CF and their caregivers that could be sustained and shared. METHODS: Quality improvement methodology with plan-do-study-act cycles, flow diagrams, review of data monthly with our designated 'Mental Health Team' and caregiver satisfaction surveys, were used to begin screening in clinics and to improve the process. We then piloted our process at a larger paediatric CF centre. RESULTS: Prior to 2013, screening was not performed at our CF centre. After the first quarter of depression screening, 88% of adolescents and 69% of adults with CF were screened. The process was refined. By the second year, 99% of patients were screened. Anxiety screening began in year three; 97%-99% of patients were screened for both anxiety and depression in years 3-5. Annual caregiver screening rates were >95%. Screening was changed from Patient Health Questionnaire-2 (PHQ-2) to PHQ-9 due to better sensitivity in caregivers, and expanded to patients. Anxiety screening began in year 3 with the Generalised Anxiety Disorder-7 questionnaire. Patients and caregivers reported acceptance of screening. At the larger paediatric centre used as a pilot, 89.6% of patients were screened in year 1. Feedback included recommendations to improve tracking/follow-up of positive screens. CONCLUSIONS: Development and implementation of a stepwise process for depression and anxiety screening was successful in a paediatric/adult CF clinic, due to constant re-evaluation by an engaged team with feedback from patients via survey. A systematic approach at a busy CF centre can serve as a model to implement screening in a clinic.

Survey of patients with cystic fibrosis and caregivers decisions regarding CFTR modulators.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a novel approach to CF management that has become more readily available chronic CF therapies for certain populations of patients with CF. A cross-sectional survey of adults with CF and caregivers of pediatric patients with CF was done in two CF Centers to better understand the decision-making process including the potential influence of social media, CF care-teams, and family members on their decision whether to begin a CFTR modulator. For the 90 participants, the most common influences in the decision to start modulator therapy were the CF providers/care teams (n = 63), parents (n = 49), and individuals with CF (n = 27). The most impactful influence in the decision-making process were providers/care team (n = 47) and parents (n = 18). Social media was an influence for only 12 respondents, with an overall positive impact. Information from the CF Foundation was an influence for 12 participants and the main influence for six participants. The most common reasons for stopping lumacaftor-ivacaftor were having tezacaftor-ivacaftor as an option (n = 25) and side-effects (n = 15). Family and CF clinicians were the two main influences on the decision to initiate modulator therapy. CF clinicians were seen to be the most influential source. Social media had less influence on the decision-making process than expected despite the wide presence of the CF community online.

Review of Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection. This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. Diagnosis of CF is confirmed by demonstration of elevated sweat chloride. Most cases of CF are identified through newborn screening (NBS). There are also infants with positive NBS but inconclusive diagnostic testing; a small proportion of these infants may go on to develop CF. CF is a lifelong, life-limiting disease, but an organized care center network with multidisciplinary approach, quality improvement initiatives, and research has led to markedly increased survival and development of adult CF care programs. In the past few years, medications that directly target the underlying CF defect have been developed, which should result in even greater survival benefits. [Pediatr Ann. 2019;48(4):e154-e161.].

Pulmonary findings in infants with cystic fibrosis during the first year of life: Results from the Baby Observational and Nutrition Study (BONUS) cohort study.

IMPORTANCE: Treatment recommendations for infants with CF standardize care, but most surveillance or treatment guidance of pulmonary manifestations are consensus-based due to sparse evidence. OBJECTIVE: To report observations about pulmonary correlates of growth and other clinical features in infants with CF. METHODS: We analyzed data from the prospective Baby Observational and Nutrition Study conducted in 28 centers across the US, including clinical features, medications, guardian diaries of respiratory symptoms, oropharyngeal swab cultures and chest radiographs (CXR) collected over the first year of life. RESULTS: Cough was reported in 84% of infants in the first year. Up to 30% had clinically important cough but only 6.3% had crackles; 16.5% had wheeze. Wisconsin CXR score was above 5 in 23% (normal = 0; maximum score = 100). Pseudomonas was recovered from at least one respiratory culture in 24% of infants and was associated with crackles/wheezes and use of proton pump inhibitors (PPI) (OR = 5.47; 95%CI = 1.36, 21.92; P = 0.02) or PPI plus histamine-2 (H2) blocker (OR = 8.2; 95%CI = 2.41, 27.93; P = 0.001), but not H2 blocker alone. Hospitalization for respiratory indications occurred in 18% of infants and was associated with crackles/wheeze and abnormal CXR but not low weight, Pseudomonas or use of acid blockade. CONCLUSIONS: Cough is common in infants with CF, but few present with crackles/wheeze or CXR changes. Pseudomonas is associated with use of PPI or PPI plus H2 blocker, but not with respiratory hospitalization. These observations cannot prove cause and effect but add to our understanding of pulmonary manifestations of CF in infants. TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).

RNA sequencing data from neutrophils of patients with cystic fibrosis reveals potential for developing biomarkers for pulmonary exacerbations.

BACKGROUND: There is no effective way to predict cystic fibrosis (CF) pulmonary exacerbations (CFPE) before they become symptomatic or to assess satisfactory treatment responses. METHODS: RNA sequencing of peripheral blood neutrophils from CF patients before and after therapy for CFPE was used to create transcriptome profiles. Transcripts with an average transcripts per million (TPM) level > 1.0 and a false discovery rate (FDR) < 0.05 were used in a cosine K-nearest neighbor (KNN) model. Real time PCR was used to corroborate RNA sequencing expression differences in both neutrophils and whole blood samples from an independent cohort of CF patients. Furthermore, sandwich ELISA was conducted to assess plasma levels of MRP8/14 complexes in CF patients before and after therapy. RESULTS: We found differential expression of 136 transcripts and 83 isoforms when we compared neutrophils from CF patients before and after therapy (>1.5 fold change, FDR-adjusted P < 0.05). The model was able to successfully separate CF flare samples from those taken from the same patients in convalescence with an accuracy of 0.75 in both the training and testing cohorts. Six differently expressed genes were confirmed by real time PCR using both isolated neutrophils and whole blood from an independent cohort of CF patients before and after therapy, even though levels of myeloid related protein MRP8/14 dimers in plasma of CF patients were essentially unchanged by therapy. CONCLUSIONS: Our findings demonstrate the potential of machine learning approaches for classifying disease states and thus developing sensitive biomarkers that can be used to monitor pulmonary disease activity in CF.

A case of sulfhemoglobinemia in a child with chronic constipation.

Sulfhemoglobinemia is a rare condition in which a sulfur atom oxidizes the heme moiety in hemoglobin, making the hemoglobin incapable of carrying oxygen and leading to hypoxia and cyanosis. This condition has been described in patients taking sulfur medications or who have cultured hydrogen sulfide producing intestinal bacteria such as Morganella morganii. This case describes a pediatric patient who was found to have cyanosis on two occasions of urinary tract infection in the setting of chronic constipation, with confirmed sulfhemoglobinemia during the second admission. Sulfhemoglobinemia due to increases in sulfur producing intestinal bacteria led to cyanosis and low oxygen saturations. The patient had an incidental finding of a pulmonary arteriovenous malformation (AVM) but had a normal PAO2 so was not hypoxemic though she was cyanotic. Low oxygen saturations by pulse oximetry may be explained by dyshemoglobinemia as opposed to true arterial hypoxemia; the importance of measuring an arterial blood gas in cases of cyanosis is paramount.

Respiratory System Disease.

Respiratory system involvement in cystic fibrosis is the leading cause of morbidity and mortality. Defects in the cystic fibrosis transmembrane regulator (CFTR) gene throughout the sinopulmonary tract result in recurrent infections with a variety of organisms including Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and nontuberculous mycobacteria. Lung disease occurs earlier in life than once thought and ideal methods of monitoring lung function, decline, or improvement with therapy are debated. Treatment of sinopulmonary disease may include physiotherapy, mucus-modifying and antiinflammatory agents, antimicrobials, and surgery. In the new era of personalized medicine, CFTR correctors and potentiators may change the course of disease.

Clinical Sensitivity of Cystic Fibrosis Mutation Panels in a Diverse Population.

Infants are screened for cystic fibrosis (CF) in New York State (NYS) using an IRT-DNA algorithm. The purpose of this study was to validate and assess clinical validity of the US FDA-cleared Illumina MiSeqDx CF 139-Variant Assay (139-VA) in the diverse NYS CF population. The study included 439 infants with CF identified via newborn screening (NBS) from 2002 to 2012. All had been screened using the Abbott Molecular CF Genotyping Assay or the Hologic InPlex CF Molecular Test. All with CF and zero or one mutation were tested using the 139-VA. DNA extracted from dried blood spots was reliably and accurately genotyped using the 139-VA. Sixty-three additional mutations were identified. Clinical sensitivity of three panels ranged from 76.2% (23 mutations recommended for screening by ACMG/ACOG) to 79.7% (current NYS 39-mutation InPlex panel), up to 86.0% for the 139-VA. For all, sensitivity was highest in Whites and lowest in the Black population. Although the sample size was small, there was a nearly 20% increase in sensitivity for the Black CF population using the 139-VA (68.2%) over the ACMG/ACOG and InPlex panels (both 50.0%). Overall, the 139-VA is more sensitive than other commercially available panels, and could be considered for NBS, clinical, or research laboratories conducting CF screening.

Effect of enterovirus D68 on Lung Clearance Index in patients with cystic fibrosis: A case report.

Cystic fibrosis (CF) causes airways obstruction and a decline in percent predicted forced expiratory volume in 1 s (FEV1%). FEV1% is an objective measure of a pulmonary exacerbation of CF; improvement in FEV1% is the endpoint used often to determine success of treatment of these acute declines in pulmonary health. Lung Clearance Index (LCI), derived from multiple breath inert gas washout (MBW) test, measures ventilation inhomogeneity and small airways dysfunction. In the United States in 2014-2015, enterovirus D68 (EV-D68), a novel virus, led to hospitalizations in children because of respiratory distress. This report describes 2 patients with CF admitted for pulmonary exacerbations who were enrolled in an inpatient study to assess patient satisfaction and utility of MBW to measure LCI. Diagnostic testing indicated that these patients were infected with EV-D68. Although their FEV1% improved to their previous baseline following treatment for pulmonary exacerbation, it was discordant with LCI. We discuss LCI as a novel measure of pulmonary function and hypothesize that, based on these cases, it may be a more sensitive indicator of ongoing post-viral airways dysfunction as compared to FEV1%.

Late presentation of congenital diaphragmatic hernia in patients with cystic fibrosis.

Late presentation of congenital diaphragmatic hernia (CDH) is unusual, especially in patients with cystic fibrosis (CF). To our knowledge, cases of CDH in CF patients and the combined effects on lung function have not been previously described. Here we report two cases of late presenting CDH in CF patients and describe effects on lung function. Late presentation of CDH in CF patients can cause gastrointestinal or respiratory symptoms and requires a high index of suspicion as well as proper interpretation of imaging. In patients with CF and CDH, lung function abnormalities could include obstructive, restrictive defects, or combined defects.