Eur Respir Rev. 2021 Nov 30;30(162):200395. doi: 10.1183/16000617.0395-2020. Print 2021 Dec 31.

ABSTRACT

Cystic fibrosis, due to the absence or abnormal function of the cystic fibrosis transmembrane conductance regulator, is the most common life-limiting autosomal recessive genetic disorder among the Caucasian population. The lungs are particularly affected due to thick and tenacious mucus causing parenchymal anomalies ranging from bronchiectasis, progressive airflow limitation, respiratory infections, lung destruction and ultimately respiratory failure. Despite the remarkable advances in treatment that have greatly improved survival, most patients experience progressive exercise curtailment, with the consequence that a growing number of patients with cystic fibrosis will be referred for exercise-based evaluations in the forthcoming years. Cardiopulmonary exercise testing, in particular, is a useful tool to assess the mechanisms of exercise intolerance in individual patients that may have treatment and prognostic implications. In this review, we will focus on ventilatory efficiency and its clinical and prognostic value in adults with cystic fibrosis.

PMID:34853094 | DOI:10.1183/16000617.0395-2020

Pulmonology. 2021 Nov 15:S2531-0437(21)00205-1. doi: 10.1016/j.pulmoe.2021.10.006. Online ahead of print.

NO ABSTRACT

PMID:34852971 | DOI:10.1016/j.pulmoe.2021.10.006

Med Sci (Paris). 2021 Nov;37(11):993-1001. doi: 10.1051/medsci/2021164. Epub 2021 Dec 1.

ABSTRACT

Mycobacterium abscessus is an environmental fast-growing, non-tuberculous mycobacterium responsible for severe lung infections, especially in patients with underlying lung disorders such as cystic fibrosis. The standard chemotherapy combines a b-lactam (imipenem or cefoxitin), an aminoglycoside (amikacin) and a macrolide (clarithromycin or azithromycin). However, resistance of this bacterium to most antibiotic classes, including nearly all anti-tubercular drugs, leads frequently to treatment failure and considerably reduces the therapeutic arsenal available to the clinician. A comprehensive understanding of the innate and acquired resistance mechanisms is thus necessary to counteract M. abscessus lung infections.

PMID:34851275 | DOI:10.1051/medsci/2021164

Physiol Rep. 2021 Dec;9(23):e15128. doi: 10.14814/phy2.15128.

ABSTRACT

Micro- and macrovascular endothelial dysfunction in response to shear stress has been observed in cystic fibrosis (CF), and has been associated with inflammation and oxidative stress. We tested the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) regulates endothelial actin cytoskeleton dynamics and cellular alignment in response to flow. Human lung microvascular endothelial cells (HLMVEC) were cultured with either the CFTR inhibitor GlyH-101 (20 µM) or CFTRinh-172 (20 µM), tumor necrosis factor (TNF)-α (10 ng/ml) or a vehicle control (0.1% dimethyl sulfoxide) during 24 and 48 h of exposure to shear stress (11.1 dynes/cm2 ) or under static control conditions. Cellular morphology and filamentous actin (F-actin) were assessed using immunocytochemistry. [Nitrite] and endothelin-1 ([ET-1]) were determined in cell culture supernatant by ozone-based chemiluminescence and ELISA, respectively. Treatment of HLMVECs with both CFTR inhibitors prevented alignment of HLMVEC in the direction of flow after 24 and 48 h of shear stress, compared to vehicle control (both p < 0.05). Treatment with TNF-α significantly increased total F-actin after 24 h versus control (p < 0.05), an effect that was independent of shear stress. GlyH-101 significantly increased F-actin after 24 h of shear stress versus control (p < 0.05), with a significant (p < 0.05) reduction in cortical F-actin under both static and flow conditions. Shear stress decreased [ET-1] after 24 h (p < 0.05) and increased [nitrite] after 48 h (p < 0.05), but neither [nitrite] nor [ET-1] was affected by GlyH-101 (p > 0.05). CFTR appears to limit cytosolic actin polymerization, while maintaining a cortical rim actin distribution that is important for maintaining barrier integrity and promoting alignment with flow, without effects on endothelial nitrite or ET-1 production.

PMID:34851051 | DOI:10.14814/phy2.15128

Pediatr Pulmonol. 2021 Nov 30. doi: 10.1002/ppul.25779. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) related liver disease (CFLD) manifests as a wide spectrum of hepatobiliary disease and can progress to need liver transplantation. Elexacaftor/tezacaftor/ivacaftor (elx/tez/iva) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator which has superior efficacy compared to previously approved modulators. Use of elx/tez/iva, should be approached with caution in individuals with CFLD or following liver transplantation due to possible increases in LFTs and drug-drug interactions with several immunosuppressant medications.

OBJECTIVE: The purpose of this case series was to explore if the use of elx/tez/iva is safe and tolerable in patients with CF post-liver transplantation.

METHODS: A retrospective case series including patients prescribed elx/tez/iva following liver transplantation and an immunosuppressive regimen consisting of drug therapy metabolized by P-glycoprotein was completed.

RESULTS: Ten patients at six CF centers with a median age of 22.1 years (range 14-43.4 years) and median time from transplant of 6.9 years (range 0.6-22 years) were included. Most patients (8, 80%) received a reduced or full dose of elx/tez/iva for a mean duration of 10.4 months (range 7-12 months). Fluctuations in LFTs occurred in all patients (10, 100%) and led to therapy discontinuation in two patients (20%). Elx/tez/iva initiation resulted in elevations in tacrolimus trough concentration in 7 patients (70%). Most patients who tolerated elx/tez/iva had symptomatic and quality of life improvement, increased body-mass-index, and maintained or improved lung function.

CONCLUSION: Initiation of elx/tez/iva in patients with CF who received a liver transplantation may be safe with clinical benefits. This article is protected by copyright. All rights reserved.

PMID:34850610 | DOI:10.1002/ppul.25779

J Clin Endocrinol Metab. 2021 Nov 29:dgab857. doi: 10.1210/clinem/dgab857. Online ahead of print.

ABSTRACT

CONTEXT: The clinical utility and implications of continuous glucose monitoring (CGM) in cystic fibrosis (CF) are unclear.

OBJECTIVE: We examined the correlation between CGM measures and clinical outcomes in adults with CF, investigated the relationship between hemoglobin A1c (HbA1c) and CGM-derived average glucose (AG), and explored CGM measures that distinguish CFRD from normal and abnormal glucose tolerance.

DESIGN: Prospective observational study.

PARTICIPANTS: 77 adults with CF.

MAIN OUTCOMES: CGM and HbA1c measured at 2-3 time-points three months apart.

RESULTS: Thirty-one of the 77 participants met American Diabetes Association-recommended diagnostic criteria for CFRD by oral glucose tolerance testing and/or HbA1c. In all participants, CGM measures of hyperglycemia and glycemic variability correlated with nutritional status and pulmonary function. HbA1c was correlated with AG (R 2=0.71, p=<0.001), with no significant difference between this regression line and that previously established in type 1 and type 2 diabetes and healthy volunteers. Cutoffs of 17.5% time >140 mg/dL and 3.4% time >180 mg/dL had sensitivities of 87% and 90%, respectively, and specificities of 95%, for identifying CFRD. Area under the curve and percent of participants correctly classified with CFRD were higher for AG, standard deviation, % time >140, >180, and >250 mg/dL than HbA1c.

CONCLUSIONS: CGM measures of hyperglycemia and glycemic variability are superior to HbA1c in distinguishing those with and without CFRD. CGM-derived AG is strongly correlated with HbA1c in adults with CF, with a similar relationship to other diabetes populations. Future studies are needed to investigate CGM as a diagnostic and screening tool for CFRD.

PMID:34850006 | DOI:10.1210/clinem/dgab857

Clin Infect Dis. 2021 Nov 27:ciab982. doi: 10.1093/cid/ciab982. Online ahead of print.

ABSTRACT

INTRODUCTION: Currently, data on treatment, outcome, and prognostic factors in children with tuberculous meningitis (TBM) in Europe are limited. To date, most existing data on TBM originate from adult studies, or studies conducted in low-resource settings.

METHODS: Multicentre, retrospective study involving 27 paediatric healthcare institutions in nine European countries via an established paediatric TB research network, before and after the 2014 revision of WHO dosing recommendations.

RESULTS: Of 118 children, 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2 and 11 (9.3%) grade 3. Fifty-eight (49.1%) children received a standard four-drug treatment regimen; other commonly used drugs included streptomycin, prothionamide, and amikacin. Almost half of the patients (48.3%; 56/116) were admitted to intensive care unit, with a median stay of 10 (IQR 4.5-21.0) days. Of 104 children with complete outcome data, 9.6% (10/104) died, and only 47.1% (49/104) recovered fully. Main long-term sequelae included spasticity of one or more limbs and developmental delay both in 19.2% (20/104), and seizure disorder in 17.3% (18/104). Multivariate regression analyses identified microbiological confirmation of TBM, the need for neurosurgical intervention and mechanical ventilation as risk factors for unfavourable outcome.

DISCUSSION: There was considerable heterogeneity in the use of TB drugs in this cohort. Despite few children presenting with advanced disease and the study being conducted in a high-resource setting, morbidity and mortality were high. Several risk factors for poor outcome were identified, which may aid prognostic predictions in children with TBM in the future.

PMID:34849642 | DOI:10.1093/cid/ciab982

J Clin Transl Endocrinol. 2021 Nov 17;26:100277. doi: 10.1016/j.jcte.2021.100277. eCollection 2021 Dec.

ABSTRACT

As females with cystic fibrosis (CF) increasingly reach their reproductive years, gynecologic issues have become an important area of clinical care and research. First, females with CF may have disease-specific gynecologic problems, including cyclic pulmonary symptoms, vaginal yeast infections, and urinary incontinence. Next, contraceptive methods are thought to be overall safe and effective, however further research is needed to confirm this and to understand the lower rates of uptake among females with CF compared to the general population. Further, females with CF have reduced fertility, although the etiology of this is unknown and under investigation. While assisted reproductive technologies may help achieve pregnancy, decision-making around parenthood remains complex. Finally, while patients and providers agree on the importance of sexual and reproductive health care, females with CF underutilize basic preventive services such as cervical cancer screening, and better approaches are needed to bridge the gap with gynecology. In this review, we discuss the current state of gynecologic care for females with CF, as well as clinical and research opportunities for improvement.

PMID:34849351 | PMC:PMC8607192 | DOI:10.1016/j.jcte.2021.100277

Respir Med Case Rep. 2021 Nov 9;34:101545. doi: 10.1016/j.rmcr.2021.101545. eCollection 2021.

ABSTRACT

Patients with cystic fibrosis (CF) are living longer due to advancements in treatment. We present a patient with CF in whom diagnoses of Human Immunodeficiency Virus (HIV) and severe pneumocystis pneumonia were delayed due to anchor bias. Our case highlights the importance of routine age-appropriate health screenings in patients with CF. In addition, we discuss the number of management challenges that may arise in patients with a dual diagnosis of CF and HIV.

PMID:34849336 | PMC:PMC8608600 | DOI:10.1016/j.rmcr.2021.101545

Pediatr Pulmonol. 2021 Nov 30. doi: 10.1002/ppul.25764. Online ahead of print.

NO ABSTRACT

PMID:34847286 | DOI:10.1002/ppul.25764

J Clin Invest. 2021 Nov 30:e144983. doi: 10.1172/JCI144983. Online ahead of print.

ABSTRACT

Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here we define a molecular pathway through which recombinant interleukin-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activates NADPH Oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1 dependent anti-inflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.

PMID:34847078 | DOI:10.1172/JCI144983

R I Med J (2013). 2021 Dec 1;104(10):53-55.

NO ABSTRACT

PMID:34846384

Microb Genom. 2021 Nov;7(11). doi: 10.1099/mgen.0.000708.

ABSTRACT

Mycobacterium abscessus comprises three subspecies: M. abscessus subsp. abscessus , M. abscessus subsp. bolletii , and M. abscessus subsp. massiliense. These closely related strains are typically multi-drug-resistant and can cause difficult-to-treat infections. Dominant clusters of isolates with increased pathogenic potential have been demonstrated in pulmonary infections in the global cystic fibrosis (CF) population. An investigation was performed on isolates cultured from an Asian, predominantly non-CF population to explore the phylogenomic relationships within our population and compare it to global M. abscessus isolates. Whole-genome-sequencing was performed on M. abscessus isolates between 2017 and 2019. Bioinformatic analysis was performed to determine multi-locus-sequence-type, to establish the phylogenetic relationships between isolates, and to identify virulence and resistance determinants in these isolates. A total of 210 isolates were included, of which 68.5 % (144/210) were respiratory samples. These isolates consisted of 140 (66.6 %) M. abscessus subsp. massiliense, 67 (31.9 %) M. abscessus subsp. abscessus, and three (1.4 %) M. abscessus subsp. bolletii. Dominant sequence-types in our population were similar to those of global CF isolates, but SNP differences in our population were comparatively wider despite the isolates being from the same geographical region. ESX (ESAT-6 secretory) cluster three appeared to occur most commonly in ST4 and ST6 M. abscessus subsp. massiliense, but other virulence factors did not demonstrate an association with isolate subspecies or sample source. We demonstrate that although similar predominant sequence-types are seen in our patient population, cross-transmission is absent. The risk of patient-to-patient transmission appears to be largely limited to the vulnerable CF population, indicating infection from environmental sources remains more common than human-to-human transmission. Resistance and virulence factors are largely consistent across the subspecies with the exception of clarithromycin susceptibility and ESX-3.

PMID:34845980 | DOI:10.1099/mgen.0.000708

Physiother Theory Pract. 2021 Nov 30:1-11. doi: 10.1080/09593985.2021.2005201. Online ahead of print.

ABSTRACT

BACKGROUND: Physical activity (PA) is a proven therapeutic tool to increase the quality of life and life expectancy in people with cystic fibrosis (pwCF). Despite this, the PA level of pwCF is lower than recommended.

OBJECTIVES: This study was conducted to identify the barriers to and facilitators of PA in adults with CF with heterogeneous severity.

METHODS: Twenty adults with CF (mean age = 33.3±11.7 years, mean FEV1% = 50.55±20.4%) were recruited from two specialized centers and interviewed about the factors that limit and facilitate their PA. The collected data were transcribed, coded and analyzed using deductive and inductive methods.

RESULTS: Barriers and facilitators were classified into physical, psychological and environmental dimensions. The main barriers were fatigue, breathing difficulties, lack of available facilities, negative perceptions of PA and perceived health risks. The most important facilitators were respiratory benefits, well-being, and social support.

CONCLUSION: Although some barriers and facilitators were similar to those found in children with CF or adults from other vulnerable populations, others were specific to adults with CF, such as the risk of cross-contamination and transplant preparation. The comprehensive study of the barriers and facilitators in adults will enhance PA counseling for pwCF and help improve their compliance with PA recommendations.

PMID:34845970 | DOI:10.1080/09593985.2021.2005201

BMJ Case Rep. 2021 Nov 29;14(11):e245971. doi: 10.1136/bcr-2021-245971.

ABSTRACT

Most patients with cystic fibrosis (CF) develop multisystemic clinical manifestations, the minority having mild or atypical symptoms. We describe an adolescent with chronic cough and purulent rhinorrhoea since the first year of life, with diagnoses of asthma, allergic rhinitis and chronic rhinosinusitis. Under therapy with long-acting bronchodilators, antihistamines, inhaled corticosteroids, antileukotrienes and several courses of empirical oral antibiotic therapy, there was no clinical improvement. There was no reference to gastrointestinal symptoms. Due to clinical worsening, extended investigations were initiated, which revealed Pseudomonas aeruginosa in sputum culture, sweat test with a positive result and heterozygosity for F508del and R334W mutations in genetic study which allowed to confirm the diagnosis of CF. In this case, heterozygosity with a class IV mutation can explain the atypical clinical presentation. It is very important to consider this diagnosis when chronic symptoms persist, despite optimised therapy for other respiratory pathologies and in case of isolation of atypical bacterial agents.

PMID:34844966 | DOI:10.1136/bcr-2021-245971

Pulmonology. 2021 Nov 26:S2531-0437(21)00204-X. doi: 10.1016/j.pulmoe.2021.10.005. Online ahead of print.

NO ABSTRACT

PMID:34844914 | DOI:10.1016/j.pulmoe.2021.10.005

Cochrane Database Syst Rev. 2021 Nov 29;11:CD013755. doi: 10.1002/14651858.CD013755.pub2.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is one of the most common life-shortening autosomal-recessive genetic conditions with around 100,000 people affected globally. CF mainly affects the respiratory system, but cystic fibrosis-related diabetes (CFRD) is a common extrapulmonary co-morbidity and causes excess morbidity and mortality in this population. Continuous glucose monitoring systems (CGMS) are a relatively new technology and, as yet, the impact of these on the monitoring and subsequent management of CFRD remains undetermined.

OBJECTIVES: To establish the impact of insulin therapy guided by continuous glucose monitoring compared to insulin therapy guided by other forms of glucose data collection on the lives of people with CFRD.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of latest search: 23 September 2021. We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 23 September 2021.

SELECTION CRITERIA: Randomised controlled studies comparing insulin regimens led by data from CGMS (including real-time or retrospective data, or both) with insulin regimens guided by abnormal blood glucose measurements collected through other means of glycaemic data collection in people with CFRD. Studies with a cross-over design, even with a washout period between intervention arms, are not eligible for inclusion due to the potential long-term impact of each of the interventions and the potential to compromise the outcomes of the second intervention.

DATA COLLECTION AND ANALYSIS: No studies were included in the review, meaning that no data were available to be collected for analysis.

MAIN RESULTS: Review authors screened 14 studies at the full-text stage against the review's inclusion criteria. Consequently, seven were excluded due to the study type being ineligible (not randomised), two studies were excluded due to their cross-over design, and two studies was excluded since the intervention used was not eligible and one was a literature review. One study in participants hospitalised for a pulmonary exacerbation is ongoing. Investigators are comparing insulin dosing via insulin pump with blood sugar monitoring by a CGMS to conventional diabetes management with daily insulin injections (or on an insulin pump if already on an insulin pump in the outpatient setting) and capillary blood glucose monitoring. The participants in the control arm will wear a blinded continuous glucose monitoring system for outcome assessment. In addition to this, one further study is still awaiting classification, and will be screened to determine whether it is eligible for inclusion, or is to be excluded, in an update of this review.

AUTHORS' CONCLUSIONS: No studies were included in the review, indicating that there is currently insufficient evidence to determine the impact of insulin therapy guided by CGMS compared to insulin therapy guided by other forms of glucose data collection on the lives of people with CFRD, nor on potential adverse effects of continuous glucose monitoring in this context. Randomised controlled studies are needed to generate evidence on the efficacy and safety of continuous glucose monitoring in people with CFRD. There is one relevant ongoing study that may be eligible for inclusion in a future update of this Cochrane Review, and whose results may help answer the review question.

PMID:34844283 | DOI:10.1002/14651858.CD013755.pub2

Lancet Respir Med. 2021 Nov 26:S2213-2600(21)00355-6. doi: 10.1016/S2213-2600(21)00355-6. Online ahead of print.

ABSTRACT

BACKGROUND: Spirometric restriction, defined as a reduced forced vital capacity (FVC) with a preserved FEV1/FVC ratio, is associated with increased respiratory and non-respiratory comorbidities and all-cause mortality in adulthood. Little is known about the early origins of this condition. We sought to identify early-life risk factors for spirometric restriction in adult life.

METHODS: In this longitudinal, multicohort, population-based study, we used data from the Tucson Children's Respiratory Study (TCRS), which recruited 1246 healthy infants at birth between April 1980, and October 1984, in Tucson, AZ, USA. Questionnaires were answered by the primary caregiver at enrolment, immediately after the child's birth, and multiple follow-up questionnaires were completed through childhood and adulthood. At the age of 22, 26, 32, and 36 years, lung function was measured with spirometry. At each survey, three mutually exclusive spirometric patterns were defined: (1) normal (FEV1/FVC ≥10th percentile and FVC ≥10th percentile); (2) restrictive (FEV1/FVC ≥10th percentile and FVC <10th percentile); and (3) obstructive (FEV1/FVC <10th percentile, independent of FVC). Data on demographic features and parental health factors were collected from questionnaires; pregnancy and perinatal data (including nutritional problems) and birth measurements were obtained from medical records; and weight, height, and body-mass index (BMI) during childhood (age 6-16 years) were measured by study nurses. The associations between early-life risk factors and spirometric patterns were assessed by multivariate multinomial logistic regression analysis, adjusted for survey year, sex, and race-ethnicity. Significant risk factors were further tested for replication in the Swedish Child (Barn), Allergy, Milieu, Stockholm, Epidemiological (BAMSE; n=1817; spirometry surveys were done at age 24 years) survey and the UK Manchester Asthma and Allergy Study (MAAS; n=411; spirometry surveys were done at age 18 years) birth cohorts, and fixed-effect meta-analyses of relative risk ratios (RRRs) from multinomial logistic regression models were done to generate a pooled estimate of the effect across the three cohorts. Measurements of body composition (MAAS; n=365) and total lung capacity (TCRS; n=173 and MAAS; n=407) were also available for a subset of participants.

FINDINGS: Of 1246 healthy infants included in TCRS, for the present study we included data for 652 participants who had at least one set of spirometry data, contributing up to 1668 observations. In the TCRS cohort, results from the multivariate models showed that maternal nutritional problems during pregnancy (RRR 2·48 [95% CI 1·30-4·76]; p=0·0062), being born small for gestational age (birthweight <10th percentile; 3·26 [1·34-7·93]; p=0·0093), and being underweight in childhood (BMI-for-age <5th percentile; 3·54 [1·35-9·26]; p=0·010) were independent predictors of spirometric restriction in adult life. Associations between being small for gestational age (p=0·0028) and underweight in childhood (p<0·0001) with adult spirometric restriction were supported by the results of meta-analysis of data from all three cohorts. In the MAAS cohort, having a low lean BMI (ie, <10th percentile) at age 11 years predicted adult (age 18 years) spirometric restriction (RRR 3·66 [1·48-9·02]; p=0·0048). These associations of spirometric restriction with small for gestational age, childhood underweight, and low lean BMI in childhood were verified in participants with spirometric restriction who had diminished total lung capacity, indicating that these factors specifically increase the risk of lung restriction.

INTERPRETATION: Poor growth and nutritional deficits in utero and throughout childhood precede and predict the development of spirometric restriction in adult life. Strategies to improve prenatal and childhood growth trajectories could help to prevent spirometric restriction and its associated morbidity and mortality burden.

FUNDING: National Institutes of Health.

PMID:34843665 | DOI:10.1016/S2213-2600(21)00355-6

Int J Neonatal Screen. 2021 Nov 2;7(4):73. doi: 10.3390/ijns7040073.

ABSTRACT

Newborn screening (NBS) for Cystic Fibrosis (CF) is associated with improved outcomes. All US states screen for CF; however, CF NBS algorithms have high false positive (FP) rates. In New York State (NYS), the positive predictive value of CF NBS improved from 3.7% to 25.2% following the implementation of a three-tier IRT-DNA-SEQ approach using commercially available tests. Here we describe a modification of the NYS CF NBS algorithm via transition to a new custom next-generation sequencing (NGS) platform for more comprehensive cystic fibrosis transmembrane conductance regulator (CFTR) gene analysis. After full gene sequencing, a tiered strategy is used to first analyze only a specific panel of 338 clinically relevant CFTR variants (second-tier), followed by unblinding of all sequence variants and bioinformatic assessment of deletions/duplications in a subset of samples requiring third-tier analysis. We demonstrate the analytical and clinical validity of the assay and the feasibility of use in the NBS setting. The custom assay has streamlined our molecular workflow, increased throughput, and allows for bioinformatic customization of second-tier variant panel content. NBS aims to identify those infants with the highest disease risk. Technological molecular improvements can be applied to NBS algorithms to reduce the burden of FP referrals without loss of sensitivity.

PMID:34842611 | DOI:10.3390/ijns7040073

Pediatr Pulmonol. 2021 Nov 29. doi: 10.1002/ppul.25778. Online ahead of print.

ABSTRACT

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in our country on January 1st, 2015, based on immunoreactive trypsinogen tests (IRT/IRT). Here, we aimed to evaluate the diagnoses of patients and follow-up process within the first 5 years of NBS from a tertiary care center.

METHODS: This retrospective cohort study was conducted on patients who were admitted to our pediatric pulmonology department for sweat test (ST) via NBS. Patients with CF with negative NBS results and those with CF with positive NBS and joined our follow-up were also investigated. Clinical outcome measures were compared between patients with CF with positive and negative NBS.

RESULTS: Six hundred sixty infants who were referred for ST via NBS were included. Across the entire study population(n=683), 11.4% of patients had CF (14.1% of had negative NBS in this CF group). The sensitivity of NBS was found as 84.9% and the positive predictive value (PPV) was 9.4%. The median age at diagnosis was older (p<0.001), reluctance for feeding and Pseudobartter syndrome (PBS) were significantly higher at presentation in the negative NBS group. There was no statistically significant difference between the groups regarding weight-for-age (p=0.899) and height-for-age (p=0.491) in the first two years' follow-ups.

CONCLUSIONS: Our findings showed the low sensitivity and PPV of NBS; therefore, further studies based on all patients in our country are necessary for new cut-off values. PBS and reluctance for feeding should be alarm symptoms for CF even if the infants had negative NBS. Additionally, later diagnosis of patients who had negative NBS did not affect the nutritional outcomes; we need large-scale prospective studies to optimize nutritional benefits for all infants diagnosed via NBS. This article is protected by copyright. All rights reserved.

PMID:34842364 | DOI:10.1002/ppul.25778