Cystic Fibrosis Foundation Evidence-Based Guideline for the Management of CRMS/CFSPID.

A multidisciplinary committee developed evidence-based guidelines for the management of cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen-positive, inconclusive diagnosis (CRMS/CFSPID). A total of 24 patient, intervention, comparison, and outcome questions were generated based on surveys sent to people with CRMS/CFSPID and clinicians caring for these individuals, previous recommendations, and expert committee input. Four a priori working groups (genetic testing, monitoring, treatment, and psychosocial/communication issues) were used to provide structure to the committee. A systematic review of the evidence was conducted, and found numerous case series and cohort studies, but no randomized clinical trials. A total of 30 recommendations were graded using the US Preventive Services Task Force methodology. Recommendations that received ≥80% consensus among the entire committee were approved. The resulting recommendations were of moderate to low certainty for the majority of the statements because of the low quality of the evidence. Highlights of the recommendations include thorough evaluation with genetic sequencing, deletion/duplication analysis if <2 disease-causing variants were noted in newborn screening; repeat sweat testing until at least age 8 but limiting further laboratory testing, including microbiology, radiology, and pulmonary function testing; minimal use of medications, which when suggested, should lead to shared decision-making with families; and providing communication with emphasis on social determinants of health and shared decision-making to minimize barriers which may affect processing and understanding of this complex designation. Future research will be needed regarding medication use, antibiotic therapy, and the use of chest imaging for monitoring the development of lung disease.

Time to be blunt: Substance use in cystic fibrosis.

BACKGROUND: As the population of people with cystic fibrosis (pwCF) continues to age, attention is shifting towards addressing the unique challenges teenagers and adults face, including substance use. Changing attitudes and legality regarding marijuana and cannabidiol (CBD) may influence their use among pwCF, but data on the rate of use, reasons for use, and administration methods are lacking. OBJECTIVE: Investigate marijuana, CBD, e-cigarette, and cigarette usage among pwCF and explore differences in demographics, disease severity, and cystic fibrosis transmembrane receptor (CFTR) modulator use between recent users and nonusers. METHODS: This cross-sectional study used a one-time electronic survey to assess marijuana, CBD, e-cigarette, and cigarette use in pwCF aged >13 years. Demographic and clinical characteristics were compared between recent users and nonusers. The association between recent substance use and CFTR modulator use was analyzed using logistic regressions. RESULTS: Among 226 participants, 29% used marijuana, 22% used CBD, 27% used e-cigarettes, and 22% used cigarettes in the last 12 months. Users of all substances were more likely to be college-educated or aged 29-39 years than nonusers. E-cigarette users were 2.9 times more likely to use CFTR modulators (95% confidence interval [95% CI]: 0.98-11.00, p = .08) and marijuana users were 2.5 times more likely to use CFTR modulators compared to nonusers, adjusted for confounders. CBD, e-cigarettes, and cigarettes users were more likely to have an abnormal mental health screen compared to nonusers. A high proportion of never-users of marijuana and CBD expressed interest in using. CONCLUSION: Substance use is more prevalent among pwCF than previously reported and needs to be addressed by healthcare providers.

Ethnic differences in staphylococcus aureus acquisition in cystic fibrosis.

BACKGROUND: Hispanic people with CF (pwCF) have increased morbidity than non-Hispanic White pwCF, including increased risk of Pseudomonas aeruginosa. We aimed to determine if Staphylococcus aureus (S. aureus) acquisition varies between Hispanic and non-Hispanic White pwCF. METHODS: This longitudinal cohort study of pwCF ages 0-25 years in the CF Foundation Patient Registry compared acquisition of methicillin-sensitive S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), persistent MRSA between Hispanic and non-Hispanic White pwCF. Risk of acquisition was assessed by Kaplan-Meier survival curves and its association with ethnicity was evaluated using Cox regressions. Adjusted associations were evaluated using multivariate Cox models adjusting for sex, age of entry into CFFPR, CFTR variant severity, pancreatic insufficiency, CF-related diabetes, maternal education, insurance status. RESULTS: Of 10,640 pwCF, 7.5% were Hispanic and 92.5% were non-Hispanic White. Hispanic pwCF had a 19% higher risk of acquiring MSSA (HR 1.19, 95% CI 1.10-1.28, p<0.001) and 13% higher risk of acquiring MRSA (HR 1.13, 95% CI 1.02-1.26, p = 0.02) than non-Hispanic White pwCF. The difference in persistent MRSA between ethnicities did not reach statistical significance. After adjusting for confounding variables, only the risk of MSSA was significantly associated with ethnicity. Compared to non-Hispanic White pwCF, Hispanic pwCF acquired MSSA and MRSA at younger median ages (4.9 vs. 3.8 years (p<0.001), 22.4 vs. 20.8 years (p = 0.02). CONCLUSION: Hispanic pwCF <25 years of age have an increased risk of acquiring MSSA and acquired MSSA and MRSA at an earlier age. Differences in S. aureus acquisition may contribute to increased morbidity in Hispanic pwCF.

How (and why) does iconicity effect lexical access: An electrophysiological study of American sign language.

Prior research has found that iconicity facilitates sign production in picture-naming paradigms and has effects on ERP components. These findings may be explained by two separate hypotheses: (1) a task-specific hypothesis that suggests these effects occur because visual features of the iconic sign form can map onto the visual features of the pictures, and (2) a semantic feature hypothesis that suggests that the retrieval of iconic signs results in greater semantic activation due to the robust representation of sensory-motor semantic features compared to non-iconic signs. To test these two hypotheses, iconic and non-iconic American Sign Language (ASL) signs were elicited from deaf native/early signers using a picture-naming task and an English-to-ASL translation task, while electrophysiological recordings were made. Behavioral facilitation (faster response times) and reduced negativities were observed for iconic signs (both prior to and within the N400 time window), but only in the picture-naming task. No ERP or behavioral differences were found between iconic and non-iconic signs in the translation task. This pattern of results supports the task-specific hypothesis and provides evidence that iconicity only facilitates sign production when the eliciting stimulus and the form of the sign can visually overlap (a picture-sign alignment effect).

Detection of disease-causing CFTR variants in state newborn screening programs.

BACKGROUND: Newborn screening (NBS) algorithms for cystic fibrosis (CF) vary in the United State of America and include different cystic fibrosis transmembrane conductance regulator (CFTR) variants. CFTR variant distribution varies among racial and ethnic groups. OBJECTIVE: Our objectives were to identify differences in detection rate by race and ethnicity for CFTR variant panels, identify each US state detection rate for CFTR variant panels, and describe the rate of false-negative NBS and delayed diagnoses by race and ethnicity. METHODS: This is a cross-sectional analysis of the detection rate of at least 1 CFTR variant for seven panels by race and ethnicity in genotyped people with CF (PwCF) or CFTR-related metabolic syndrome (CRMS)/CFTR-related disorders in CF Foundation Patient Registry (CFFPR) in 2020. We estimated the case detection rate of CFTR variant panels by applying the detection rate to Census data. Using data from CFFPR, we compared the rate of delayed diagnosis or false-negative NBS by race and ethnicity. RESULTS: For all panels, detection of at least 1 CFTR variant was highest in non-Hispanic White PwCF (87.5%-97.0%), and lowest in Black, Asian, and Hispanic PwCF (41.9%-93.1%). Detection of at least 1 CFTR variant was lowest in Black and Asian people with CRMS/CFTR-related disorders (48.4%-64.8%). States with increased racial and ethnic diversity have lower detection rates for all panels. Overall, 3.8% PwCF had a false-negative NBS and 11.8% had a delayed diagnosis; Black, Hispanic, and mixed-race PwCF were overrepresented. CONCLUSION: CFTR variant panels have lower detection rates in minoritized racial and ethnic groups leading to false-negative NBS, delayed diagnosis, and likely health disparities.

Changes in the Use of Invasive and Noninvasive Mechanical Ventilation in Pediatric Asthma: 2009-2019.

Rationale: Despite lower overall hospitalization rates for asthma in recent years, there has been an increase in the number of pediatric patients receiving intensive care management in the United States. Objectives: To investigate how the use of invasive and noninvasive mechanical ventilation for asthma has changed in the context of an evolving cohort of critically ill pediatric patients with asthma. Methods: We analyzed children admitted to intensive care units for asthma from 2009 through 2019 in the Virtual Pediatric Systems database. Regression analyses were used to evaluate how respiratory support interventions, mortality, and patient characteristics have changed over time. Odds ratios were calculated to determine how patient characteristics were associated with respiratory support needs. Stratified analyses were performed to determine how changing practice patterns may have differed between patient subgroups. Results: There were 67,614 admissions for 56,727 patients analyzed. Intubation occurred in 4.6% of admissions and decreased from 6.9% to 3.4% over time (P < 0.001), whereas noninvasive ventilation as the maximal respiratory support increased from 8.9% to 20.0% (P < 0.001). Over time, the cohort shifted to include more 2- to 6-year-olds and patients of Asian/Pacific Islander or Hispanic race/ethnicity. Although intubation decreased and noninvasive ventilation increased in all subgroups, the changes were most pronounced in the youngest patients and slightly less pronounced for obese patients. Conclusions: In pediatric asthma, use of intubation has halved, whereas use of noninvasive ventilation has more than doubled. This change in practice appears partially related to a younger patient cohort, although other factors merit exploration.

Left behind: The potential impact of CFTR modulators on racial and ethnic disparities in cystic fibrosis.

The advent of CFTR modulators, a genomic specific medication, revolutionized the treatment of CF for many patients. However, given that these therapeutics were only developed for specific CFTR mutations, not all people with CF have access to such disease-modifying drugs. Racial and ethnic minority groups are less likely to have CFTR mutations that are approved for CFTR modulators. This exclusion has the potential to widen existing health disparities.

Food insecurity and mental health during the COVID-19 pandemic in cystic fibrosis households.

BACKGROUND: The COVID-19 pandemic impacted many households due to shelter-in-place orders and economic hardship. People with cystic fibrosis (CF) experienced increased food insecurity compared to the general population before the pandemic, even though adequate food access is needed to maintain nutrition goals associated with improved health-related outcomes. Little is known about the impact the pandemic had on the food insecurity of people with CF and their families. OBJECTIVE: To investigate how the COVID-19 pandemic impacted food insecurity, mental health, and self-care in people with CF. METHODS: Adults with CF and parents/guardians of children with CF were recruited via social media to complete online questionnaires from May 2020 to February 2021. Questionnaires in English and Spanish included USDA 2-question food insecurity screening, Patient Health Questionnaire-4 for mental health screening, and directed questions on the impact of the pandemic. RESULTS: Of 372 respondents, 21.8% of the households experienced food insecurity during the pandemic compared to 18.8% prepandemic (p < .001). More food insecure patients with CF reported weight loss (32.1% vs. 13.1%, p < .001), worse airway clearance adherence (13.6% vs. 5.8%, p < .01), and worse medication adherence (12.4% vs. 1.7%, p < .01) compared to food secure patients. Food insecure subjects were more likely to have an abnormal mental health screen compared to food secure subjects (53.1% vs. 16.2%, p < .001). CONCLUSION: Food insecurity increased in the CF population during the COVID-19 pandemic. Food insecure subjects reported worse mental health and self-care during the pandemic compared to food secure subjects.

Matching pictures and signs: An ERP study of the effects of iconic structural alignment in American sign language.

Event-related potentials (ERPs) were used to explore the effects of iconicity and structural visual alignment between a picture-prime and a sign-target in a picture-sign matching task in American Sign Language (ASL). Half the targets were iconic signs and were presented after a) a matching visually-aligned picture (e.g., the shape and location of the hands in the sign COW align with the depiction of a cow with visible horns), b) a matching visually-nonaligned picture (e.g., the cow's horns were not clearly shown), and c) a non-matching picture (e.g., a picture of a swing instead of a cow). The other half of the targets were filler signs. Trials in the matching condition were responded to faster than those in the non-matching condition and were associated with smaller N400 amplitudes in deaf ASL signers. These effects were also observed for hearing non-signers performing the same task with spoken-English targets. Trials where the picture-prime was aligned with the sign target were responded to faster than non-aligned trials and were associated with a reduced P3 amplitude rather than a reduced N400, suggesting that picture-sign alignment facilitated the decision process, rather than lexical access. These ERP and behavioral effects of alignment were found only for the ASL signers. The results indicate that iconicity effects on sign comprehension may reflect a task-dependent strategic use of iconicity, rather than facilitation of lexical access.

Picture-naming in American Sign Language: an electrophysiological study of the effects of iconicity and structured alignment.

A picture-naming task and ERPs were used to investigate effects of iconicity and visual alignment between signs and pictures in American Sign Language (ASL). For iconic signs, half the pictures visually overlapped with phonological features of the sign (e.g., the fingers of CAT align with a picture of a cat with prominent whiskers), while half did not (whiskers are not shown). Iconic signs were produced numerically faster than non-iconic signs and were associated with larger N400 amplitudes, akin to concreteness effects. Pictures aligned with iconic signs were named faster than non-aligned pictures, and there was a reduction in N400 amplitude. No behavioral effects were observed for the control group (English speakers). We conclude that sensory-motoric semantic features are represented more robustly for iconic than non-iconic signs (eliciting a concreteness-like N400 effect) and visual overlap between pictures and the phonological form of iconic signs facilitates lexical retrieval (eliciting a reduced N400).

Cystic fibrosis patients of minority race and ethnicity less likely eligible for CFTR modulators based on CFTR genotype.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are disease-modifying medications for cystic fibrosis (CF) and are shown to be efficacious for only specific CFTR mutations. CFTR mutation frequency varies by ancestry, which is different from but related to demographic racial and ethnic group. Eligibility for CFTR modulator therapy has not been previously reported by race and ethnicity. METHODS: We conducted a cross-sectional study of patients in the 2018 CF Foundation Patient Registry. We analyzed the percentage of patients in each US Census defined racial and ethnic group eligible for CFTR modulators based on CFTR mutations approved by the US FDA and then based on both mutations and FDA approval by age. We compared lung function based on CFTR modulator eligibility and prescription. FINDINGS: Based on CFTR mutations alone, 92.4% of non-Hispanic White patients, 69.7% of Black/African American patients, 75.6% of Hispanic patients, and 80.5% of other race patients eligible for CFTR modulators. For each CFTR modulator, Black/African American patients were least likely to have eligible mutations, and non-Hispanic White patients were most likely. There was no difference in the disparity between racial and/or ethnic groups with the addition of current FDA approval by age. The lowest pulmonary function in the cohort was seen in non-Hispanic White, Black/African American, and Hispanic patients not eligible for CFTR modulators. INTERPRETATION: Patients with CF from minority groups are less likely to be eligible for CFTR modulators. Because people with CF who are racial and ethnic minorities have increased disease severity and earlier mortality, this will further contribute to health disparities.

Early acquisition and conversion of Pseudomonas aeruginosa in Hispanic youth with cystic fibrosis in the United States.

BACKGROUND: For unknown reasons, Hispanic patients with cystic fibrosis (CF) have more severe pulmonary disease than non-Hispanic white patients. In CF, the pulmonary pathogen Pseudomonas aeruginosa is associated with worse outcomes. We sought to determine if Hispanic patients with CF are at an increased risk of acquiring P. aeruginosa or acquire it earlier than non-Hispanic white patients. METHODS: This is a longitudinal study comparing the timing and risk of acquisition of different forms of P. aeruginosa between Hispanic and non-Hispanic white patients aged 0-21 years old with CF in the CF Foundation Patient Registry (CFFPR) in 2008-2013. The age at the initial acquisition of P. aeruginosa (initial acquisition, mucoid, chronic, multidrug-resistant) was summarized using Kaplan-Meier survival curves and analyzed using Cox proportional hazards regression models. RESULTS: Of 10,464 patients, 788 (7.5%) were Hispanic and 9,676 (92.5%) were non-Hispanic white. Hispanic patients acquired all forms of P. aeruginosa at a younger age than non-Hispanic white patients. Hispanic patients had a higher risk of acquiring P. aeruginosa than non-Hispanic white patients: the hazard ratio (HR) was 1.26 (95% CI 1.16-1.38, p<0.001) for initial P. aeruginosa, 1.59 (95% CI 1.43-1.77, p<0.001) for mucoid P. aeruginosa, 1.91 (95% CI 1.64-2.23, p<0.001) for multidrug-resistant P. aeruginosa, and 1.39 (95% CI 1.25-1.55, p<0.001) for chronic P. aeruginosa. CONCLUSIONS: Hispanic patients have an increased risk of acquiring P. aeruginosa and acquire it at an earlier age than non-Hispanic white patients in the United States. This may contribute to increased morbidity and mortality in Hispanic patients with CF.

Outcomes of Children With Cystic Fibrosis Admitted to PICUs.

OBJECTIVES: Data on outcomes of children with cystic fibrosis admitted to PICUs are limited and outdated. Prior studies cite PICU mortality rates ranging from 37.5% to 100%. Given the advances made in cystic fibrosis care, we expect outcomes for these patients to have changed significantly since last studied. We provide an updated report on PICU mortality and the factors associated with death among critically ill children with cystic fibrosis. DESIGN: Retrospective multicenter cohort analysis utilizing data from the Virtual Pediatric Systems database. SETTING: Data were collected from 135 PICUs from January 1, 2009, to June 20, 2018. PATIENTS: One-thousand six-hundred thirty-three children with cystic fibrosis accounting for 2,893 PICU admissions were studied. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality during PICU admission. Predictors included demographics, anthropometrics, diagnoses, clinical characteristics, and critical care interventions. Odds ratios of mortality were calculated in univariate and multivariable analyses to assess differences in mortality associated with predictor variables. Generalized estimating equation models were used to account for multiple admissions per patient. The overall PICU mortality rate was 6.6%. Factors associated with increased odds of mortality included hemoptysis/pulmonary hemorrhage, pneumothorax, gastrointestinal bleeding, bacterial/fungal infections, lower body mass index/malnutrition, and need for noninvasive or invasive respiratory support. Intubation/mechanical ventilation occurred in 26.4% of the 2,893 admissions and was associated with a 19.1% mortality rate. Of the nonsurvivors, 20.7% died without receiving mechanical ventilation. CONCLUSIONS: The mortality rate during PICU admissions for patients with cystic fibrosis is lower than has been reported in prior studies, both in the overall cohort and in the subset requiring invasive mechanical ventilation. These data provide updated insight into the prognosis for cystic fibrosis patients requiring critical care.

Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico.

BACKGROUND: In cystic fibrosis (CF), the spectrum and frequency of CFTR variants differ by geography and race/ethnicity. CFTR variants in White patients are well-described compared with Latino patients. No studies of CFTR variants have been done in patients with CF in the Dominican Republic or Puerto Rico. METHODS: CFTR was sequenced in 61 Dominican Republican patients and 21 Puerto Rican patients with CF and greater than ​​​​60 mmol/L sweat chloride. The spectrum of CFTR variants was identified and the proportion of patients with 0, 1, or 2 CFTR variants identified was determined. The functional effects of identified CFTR variants were investigated using clinical annotation databases and computational prediction tools. RESULTS: Our study found 10% of Dominican patients had two CFTR variants identified compared with 81% of Puerto Rican patients. No CFTR variants were identified in 69% of Dominican patients and 10% of Puerto Rican patients. In Dominican patients, there were 19 identified CFTR variants, accounting for 25 out of 122 disease alleles (20%). In Puerto Rican patients, there were 16 identified CFTR variants, accounting for 36 out of 42 disease alleles (86%) in Puerto Rican patients. Thirty CFTR variants were identified overall. The most frequent variants for Dominican patients were p.Phe508del and p.Ala559Thr and for Puerto Rican patients were p.Phe508del, p.Arg1066Cys, p.Arg334Trp, and p.I507del. CONCLUSIONS: In this first description of the CFTR variants in patients with CF from the Dominican Republic and Puerto Rico, there was a low detection rate of two CFTR variants after full sequencing with the majority of patients from the Dominican Republic without identified variants.

The demographics of adverse outcomes in cystic fibrosis.

Understanding variability in cystic fibrosis (CF) health outcomes requires an understanding of factors that go far beyond Cystic Fibrosis Transmembrane Receptor (CFTR) function caused by different gene mutations. Social and environmental factors that influence health have a significant influence on the trajectory of health in CF and in other chronic diseases. In this article, we review demographic factors associated with poorer health outcomes in CF, known and postulated biological mechanisms of these outcomes, and interventions that healthcare teams can implement that may reduce outcome disparities.

Regional variations in longitudinal pulmonary function: A comparison of Hispanic and non-Hispanic subjects with cystic fibrosis in the United States.

BACKGROUND: Hispanic subjects with cystic fibrosis (CF) have increased morbidity and mortality than non-Hispanic white subjects. The ethnic disparity in mortality varies by region. Factors influencing pulmonary function vary by both ethnicity and region. OBJECTIVE: To determine if the ethnic difference in pulmonary function varies by region. METHODS: This retrospective cohort study compared differences in longitudinal pulmonary function (percent-predicted forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1 ], forced expiratory flow at 25% to 75% [FEF25-75 ], FEV1 /FVC, and FEV1 decline) between Hispanic and non-Hispanic white subjects with CF by Census region of the United States (West, South, Midwest, and Northeast). Subjects were of ages 6 to 25 years and in the CF Foundation Patient Registry from 2008 to 2013. We used linear mixed effects models with subject-specific slopes and intercepts, adjusting for 14 demographic and clinical variables. RESULTS: Of 14 932 subjects, 1433 (9.6%) were Hispanic and 13 499 (90.4%) were non-Hispanic white. Hispanic subjects' FEV1 was 9.0% (8.3%-9.8%) lower than non-Hispanic white subjects in the West, while Hispanic subjects' FEV1 was only 4.0% (3.0%-5.0%) lower in the Midwest, 4.4% (3.1%-5.7%) lower in the Northeast, and 4.4% (3.2%-5.5%) lower in the South. Similarly, FVC and FEF25-75 were lower among Hispanic subjects compared to non-Hispanic white subjects in all US regions, with the biggest differences in the West. Only in the West was FEV1 /FVC significantly lower in Hispanic subjects (-0.019; -0.022 to -0.015). FEV1 decline was not significantly different between ethnicities in any region. CONCLUSIONS: In CF, Hispanic subjects have lower pulmonary function than non-Hispanic white subjects in all geographic regions with the largest difference in occurring in the West.

A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma.

Short-acting ß2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10-8). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.