J Cyst Fibros. 2021 Dec 28:S1569-1993(21)02173-1. doi: 10.1016/j.jcf.2021.12.014. Online ahead of print.

ABSTRACT

BACKGROUND: There is a strong association between nutrition and long-term FEV1 in cystic fibrosis (CF), but studies have been driven by data from subjects with pancreatic insufficiency (PI-CF). We thus evaluated the association between body mass index (BMI) and FEV1 percent-predicted (FEV1pp) in children with pancreatic sufficiency (PS-CF) and contrasted it with the association in PI-CF.

METHODS: We utilized data from the CF Foundation Patient Registry. The cohort included children born 1995-2010, diagnosed <2 years of age, and who had annualized data on BMI percentile and FEV1pp at ages 6-16 years. Pancreatic status was defined based on pancreatic enzyme replacement therapy. The association between BMI and FEV1 was evaluated using linear and mixed-effects longitudinal regression.

RESULTS: There were 424 children with PS-CF and 7,849 with PI-CF. The association between BMI and FEV1 differed significantly by pancreatic status: each 10-pct higher BMI was associated with 2% [95%CI = 1.9-2.1] higher FEV1pp in PI-CF, compared to just 0.9% [0.5-1.3] in PS-CF (PINTERACTION < 0.001). Within the at-risk nutritional category (BMI <25pct), each 10-pct higher BMI was associated with 5% higher FEV1pp in PI-CF, but no significant increase in PS-CF. Moreover, in PS-CF, overweight/obesity (BMI ≥85pct) was associated with decreasing FEV1pp. In addition, FEV1pp decline through age 20 years in youth with PS-CF was modest (-0.6% per year) and independent of BMI (BMI*age PINTERACTION = 0.37).

CONCLUSIONS: In children with PS-CF, BMI remains an important determinant of lung function. However, it may be less critical to attain a BMI >50th percentile; and BMI ≥85th percentile may be detrimental.

PMID:34972650 | DOI:10.1016/j.jcf.2021.12.014

J Cyst Fibros. 2021 Dec 28:S1569-1993(21)02172-X. doi: 10.1016/j.jcf.2021.12.012. Online ahead of print.

ABSTRACT

BACKGROUND: Antisense oligonucleotide- based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to generate skipping over exon 23 of the CFTR transcript, to eliminate the W1282X nonsense mutation and avoid RNA degradation induced by the nonsense mediated mRNA decay mechanism, allowing production of partially active CFTR proteins lacking exon 23.

METHODS: ∼80 ASOs were screened in 16HBEge W1282X cells. ASO candidates showing significant exon skipping were assessed for their W1282X allele selectivity and the increase of CFTR protein maturation and function. The effect of a highly potent ASO candidates was further analyzed in well differentiated primary human nasal epithelial cells, derived from a W1282X homozygous patient.

RESULTS: ASO screening led to identification of several ASOs that significantly decrease the level of CFTR transcripts including exon 23. These ASOs resulted in significant levels of mature CFTR protein and together with modulators restore the channel function following free uptake into these cells. Importantly, a highly potent lead ASOs, efficiently delivered by free uptake, was able to increase the level of transcripts lacking exon 23 and restore the CFTR function in cells from a W1282X homozygote patient.

CONCLUSION: The highly efficient exon 23 skipping induced by free uptake of the lead ASO and the resulting levels of mature CFTR protein exhibiting channel function in the presence of modulators, demonstrate the ASO therapeutic potential benefit for CF patients carrying the W1282X mutation with the objective to advance the lead candidate SPL23-2 to proof-of-concept clinical study.

PMID:34972649 | DOI:10.1016/j.jcf.2021.12.012

J Vasc Interv Radiol. 2021 Dec 28:S1051-0443(21)01634-1. doi: 10.1016/j.jvir.2021.12.032. Online ahead of print.

NO ABSTRACT

PMID:34971724 | DOI:10.1016/j.jvir.2021.12.032

Cell Mol Life Sci. 2021 Dec 31. doi: 10.1007/s00018-021-04030-2. Online ahead of print.

ABSTRACT

Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein lead to persistent lung bacterial infections, mainly due to Pseudomonas aeruginosa, causing loss of respiratory function and finally death of people affected by CF. Unfortunately, even in the era of CFTR modulation therapies, management of pulmonary infections in CF remains highly challenging especially for patients with advanced stages of lung disease. Recently, we identified antimicrobial peptides (AMPs), namely Esc peptides, with potent antipseudomonal activity. In this study, by means of electrophysiological techniques and computational studies we discovered their ability to increase the CFTR-controlled ion currents, by direct interaction with the F508del-CFTR mutant. Remarkably, this property was not explored previously with any AMPs or peptides in general. More interestingly, in contrast with clinically used CFTR modulators, Esc peptides would give particular benefit to CF patients by combining their capability to eradicate lung infections and to act as promoters of airway wound repair with their ability to ameliorate the activity of the channel with conductance defects. Overall, our findings not only highlighted Esc peptides as the first characterized AMPs with a novel property, that is the potentiator activity of CFTR, but also paved the avenue to investigate the functions of AMPs and/or other peptide molecules, for a new up-and-coming pharmacological approach to address CF lung disease.

PMID:34971429 | DOI:10.1007/s00018-021-04030-2

Pediatr Pulmonol. 2021 Dec 29. doi: 10.1002/ppul.25811. Online ahead of print.

ABSTRACT

INTRODUCTION: Despite emerging data that suggest a high frequency and severity of obstructive sleep apnea (OSA) among patients with cystic fibrosis (CF), few of them are referred for polysomnography. Little is known about which patients with CF are at increased risk for OSA and which sleep symptoms merit investigation.

METHODS: A single-center retrospective analysis of clinical and polysomnographic data from 1/1/2009-10/31/2020 in referred children and adults with CF.

RESULTS: Among 74 patients (42 children, 32 adults) with CF, 39 (53%) had OSA. No age or sex differences emerged in OSA frequency. Mean apnea-hypopnea index (AHI) was higher among overweight/obese adults (n=16) as compared to adults of normal weight or underweight (11.4 vs. 6.2; p=0.005). Adults with (n=10) vs. without a crowded oropharynx had 13.0 times greater odds of OSA (95%CI: 1.4, 121.4; p=0.02). Children with (n=24) vs. without tonsillar hypertrophy had a higher risk for OSA (OR=5.2; 95%CI: 1.4, 19.8; p=0.02), as did children with (n=10) vs. without symptomatic chronic sinusitis (OR=5.8; 95%CI: 1.1, 32.1; p=0.04). Neither snoring, excessive daytime sleepiness, nor lung disease severity were associated with OSA.

CONCLUSION: Key risk factors for OSA may differ between children and adults with CF: upper airway pathology appears important in children and overweight/obesity or a crowded oropharynx in adults. Given the lack of sensitivity of snoring, daytime sleepiness, and lung disease severity, detection of OSA may require a low threshold for polysomnographic assessment in this vulnerable population. This article is protected by copyright. All rights reserved.

PMID:34967157 | DOI:10.1002/ppul.25811

Pediatr Pulmonol. 2021 Dec 29. doi: 10.1002/ppul.25809. Online ahead of print.

ABSTRACT

Patients with cystic fibrosis (CF) are exposed to many drugs in their lifetime and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines that are available to guide dosing. Contemporary CF treatments are targeted to specific mutations in the CF transmembrane conductance regulator (CFTR) gene, and thus, require patients to have genetic testing prior to initiation of modulator therapy. However, aside from CFTR genetic testing, pharmacogenomic testing is not standard of care for CF patients. The aim of this study was to determine the number of non-CFTR modulator medications with CPIC guidelines that are prescribed to patient with CF. We identified all patients with a diagnosis of CF and queried our hospital electronic medical records (EMR) for all orders, including inpatient and prescriptions, for all drugs or drug classes that have CPIC actionable guidelines for drug-gene pairs that can be used to guide therapy. We identified 576 patients with a diagnosis of CF that were treated at our institution during this 16-year period between June 2005 - May 2021. Of these patients, 504 patients (87.5%) received at least one drug that could have been dosed according to CPIC guidelines if pharmacogenomic results would have been available. Patients with CF have a high utilization of drugs with CPIC guidelines, therefore preemptive pharmacogenomic testing should be considered in CF patients at the time of CFTR genetic testing. This article is protected by copyright. All rights reserved.

PMID:34967155 | DOI:10.1002/ppul.25809

Pediatr Pulmonol. 2021 Dec 29. doi: 10.1002/ppul.25810. Online ahead of print.

ABSTRACT

INTRODUCTION: Temporal trends in CF survival from low-middle-income settings are poorly reported. We describe changes in CF survival after diagnosis over 40 years from a South African (SA) CF center.

METHODS: An observational cohort study of people diagnosed with CF from 1974 to 2019. Changes in age-specific mortality rates from the year 2000 (versus before 2000) were estimated using multivariable Poisson regression. Data were stratified by current age < or ≥ 10 years and models controlled for diagnosis age, sex, ethnicity, genotype, and P. aeruginosa (PA) infection. A second analysis explored association of mortality with weight and FEV1z-scores at age 5-8 years.

RESULTS: 288 people (52% male; 57% Caucasian; 44% p.Phe508del homozygous) were included (median diagnosis age 0.5 years: Q1,Q3: 0.2, 2.5); 100 (35%) died and 30 (10%) lost to follow-up. Among age >10 years, age-specific mortality from year 2000 was significantly lower (adjusted hazard ratio aHR: 0.14; 95% CI: 0.06,0.29; p<0.001), but not among age <10 years (aHR: 0.67; 95% CI: 0.28,1.64; p=0.383). In children <10 years, Caucasian ethnicity was associated with lower mortality (aHR 0.17; 95% CI 0.05,0.63), and longer times since first PA infection with higher mortality (aHR 1.31; 95% CI 1.01,1.68). Mortality was 7-fold higher if FEV1z was < -2.0 at age 5-8 years (aHR 7.64; 95% CI 2.58,22.59).

CONCLUSION: Overall, CF survival has significantly improved in SA from year 2000 in people older than 10 years. However, increased risk of mortality persists in young non-Caucasian children, and with FEV1z<-2.0 at age 5-8 years. This article is protected by copyright. All rights reserved.

PMID:34967140 | DOI:10.1002/ppul.25810

ACS Infect Dis. 2021 Dec 29. doi: 10.1021/acsinfecdis.1c00409. Online ahead of print.

ABSTRACT

The decreasing efficacy of existing antibiotics against pulmonary pathogens that affect cystic fibrosis (CF) patients calls for the development of novel antimicrobials. Iron uptake and metabolism are vital processes for bacteria, hence potential therapeutic targets. Gallium [Ga(III)] is a ferric iron-mimetic that inhibits bacterial growth by disrupting iron uptake and metabolism. In this work we evaluate the efficacy of three Ga(III) compounds, namely, Ga(NO3)3, (GaN), Ga(III)-maltolate (GaM), and Ga(III)-protoporphyrin IX (GaPPIX), against a collection of CF pathogens using both reference media and media mimicking biological fluids. All CF pathogens, except Streptococcus pneumoniae, were susceptible to at least one Ga(III) compound. Notably, Mycobacterium abscessus and Stenotrophomonas maltophilia were susceptible to all Ga(III) compounds. Achromobacter xylosoxidans, Burkholderia cepacia complex, and Pseudomonas aeruginosa were more susceptible to GaN and GaM, whereas Staphylococcus aureus and Haemophilus influenzae were more sensitive to GaPPIX. The results of this study support the development of Ga(III)-based therapy as a broad-spectrum strategy to treat CF lung infections.

PMID:34965085 | DOI:10.1021/acsinfecdis.1c00409

Monaldi Arch Chest Dis. 2021 Dec 28. doi: 10.4081/monaldi.2021.2047. Online ahead of print.

ABSTRACT

Six Minute Walk Test (6MWT) is a field exercise test widely used in clinical practice, both in adults and in pediatric patients. The primary aim of the study is to evaluate the physical performance of the subjects and compare them with the predicted Italian values. The secondary aim is to verify the possible relationship between the 6MWT distance (6MWD) and the clinical variables of the sample. Italian children between 6-11 years affected by CF were recruited from 9 regional centres for CF. Short questionnaire assessments about their health state and physical activity routine was administered. Anthropometric characteristics were measured before the test and, peripheral oxygen saturation (SpO2), heart and respiratory rate were measured before and after a 6-minute walk test. The tests were performed according to the American Thoracic Society (ATS) guidelines. 6MWD was compared with the predicted distance calculated by the reference equation for healthy subjects of the same age.A total of 132 children were recruited (70 male) and completed the assessment. The mean (±SD) for 6MWD was 557.4(±69.9), male = 551.4(±80.0), female = 560.4(±63.3), however the predicted distance mean was 605m. A total of 101(76.5%) subjects practice regular physical activity. A total of 31(23%) had a FEV1 lower than their Lower Limits of Normal (LLN). Functional performance on the 6MWT was poorer among the CF patients than among the predicted distance estimated with Italian values. The correlation with the amount of physical activity and 6MWD has been verified.

PMID:34964575 | DOI:10.4081/monaldi.2021.2047

Monaldi Arch Chest Dis. 2021 Dec 28. doi: 10.4081/monaldi.2021.1984. Online ahead of print.

ABSTRACT

Dyspnea is a common symptom in Systemic Sclerosis (SSc) that considerably decreases patients' quality of life (QoL). Pulmonary Rehabilitation (PR) mitigates dyspnea impact on daily activities. The aim of this study is to evaluate the effect on respiratory disability of home-based PR in SSc patients with dyspnea. In this observational prospective monocentric study, we screened all dyspneic SSc consecutive patients attending the Rheumatological day hospital in the University hospital of Parma from January 2019 and June 2019. The aim of our study was to understand if a PR unsupervised home-based program could improve respiratory disability in this specific population. Dyspnea was evaluated with the self-administered questionnaires modified Medical Research Council (mMRC) and Saint George's Respiratory Questionnaire (SGRQ).Patients also filled in Short Form 36 (SF36) and the Modified-Health Assessment Questionnaire for SSc (HAQ-MOD). Health Professionals assessed and trained the patients and collected data before PR and at the end of the program. PR consisted in 5 weekly unsupervised sessions for 8 weeks. Wilcoxon test for paired data evaluated the changes after PR. p<0.05 was considered statistically significant. 46 SSc patients were included (43 female). Only 31 (29 female) performed PR as planned (Adherent Group-AG) while the others gave up within the first week (Non-Adherent Group-NAG). All SGRQ domains (Symptoms: from 30 to 18; p=0.0055; Activity: from 47 to 35, p=0.23; Impact from 29 to 25, p=0.044) and SGRQ total score (from 35 to 29; p=0.022) improved in AG. SGRQ scores did not change in NAG as well as SF36 and HAQ-MOD in both groups. The home-based PR program dramatically decreased the effect, frequency and severity of respiratory symptoms. Conversely, it slightly changed the activities causing breathlessness and dyspnea-related social functioning disturbances. PR appears to be a useful tool in treatment strategies aiming to achieve a QoL improvement in SSc patients.

PMID:34964573 | DOI:10.4081/monaldi.2021.1984

Pediatr Pulmonol. 2021 Dec 29. doi: 10.1002/ppul.25807. Online ahead of print.

ABSTRACT

Pediatric Pulmonology publishes original research, review articles, and case reports on topics related to a wide range of children's respiratory disorders. Here we review some of the most notable manuscripts published in 2020 in this journal on (1) children's interstitial lung disease (chILD), (2) congenital airway and lung anomalies, and (3) primary ciliary dyskinesia and other non-cystic fibrosis bronchiectasis. The papers reviewed are discussed in context with published works from other journals. This article is protected by copyright. All rights reserved.

PMID:34964566 | DOI:10.1002/ppul.25807

Pediatr Pulmonol. 2021 Dec 29. doi: 10.1002/ppul.25806. Online ahead of print.

ABSTRACT

INTRODUCTION: A risk associated with cystic fibrosis newborn screening (CFNBS) is parental misunderstanding of genetic information generated by the over 6,600 positive screens reported annually in the US. CFNBS algorithms incorporating DNA analysis can generate genetic information that requires clinical interpretation and has significance for the newborn, parents, and other relatives. Engagement between CF care centers and trained genetic counseling providers, such as licensed and/or certified genetic counselors (GCs), is variable and limited in providing information to CFNBS positive (CFNBS+) families.

METHODS: Using a modified Delphi process, a workgroup of CFNBS experts developed recommendations for engagement of genetic counseling services in CF care centers where CFNBS+ diagnostic evaluations are performed. Statements were assessed over three rounds of surveys, one face-to-face meeting, and through public feedback.

RESULTS: Seventeen statements achieved >80% consensus (range: 82-100%). The workgroup affirmed prior CFF policy statements recommending genetic counseling for parents of infants with CFNBS+. The remaining statements addressed infrastructure and logistics of genetic counseling services, including defining appropriate training for genetic counseling providers and counseling content, establishing a path to equal access to genetic counseling providers across CF care centers, and setting a standard for client-centered CFNBS genetic counseling that is respectful of diverse patient needs and autonomy.

CONCLUSIONS: Implementation of client-centered genetic counseling for CFNBS+ families in CF care centers by providers with expertise in both CF and genetic counseling will require efforts to further define core concepts, enhance education of providers, and develop opportunities for access via telemedicine. This article is protected by copyright. All rights reserved.

PMID:34964558 | DOI:10.1002/ppul.25806

Pediatr Pulmonol. 2021 Dec 29. doi: 10.1002/ppul.25804. Online ahead of print.

ABSTRACT

AIM: To report on the clinical, laboratory and radiological findings of adolescents who presented during the SARS-CoV-2 surge with symptoms of COVID-19, did not test positive for the infection and were diagnosed with e-cigarette and vaping product use associated lung injury (EVALI).

METHODS: A retrospective review of 12 cases of EVALI admitted to the Bristol Meyers Squibb Children's Hospital between February 2020 and June 2020 was conducted.

RESULTS: The ages of the patients ranged from 14 to 19 years. There were 6 males and 6 females. Three patients had a past history of anxiety, depression or other psychiatric/mental health disorder, nine had prolonged coagulation profile (PT,PTT and/or INR) and eleven had elevated inflammatory markers. Eight needed respiratory support. All 12 were negative for SARS-CoV-2 PCR. Four were tested for IgG Antibodies and were negative. As these cases were admitted to rule out COVID infection, initial treatment included hydroxychloroquine. Steroids were started only after SARS-CoV-2 PCR was shown to be negative. Urine THC was positive in all cases. CXR and CT findings showed ground glass opacities.

CONCLUSIONS: Clinical and radiological features are similar in both EVALI and SARS-CoV-2 infection. Inflammatory markers are elevated in both conditions. A detailed social and substance use history in patients presenting with "typical" COVID pneumonia like illness is important. EVALI should be ruled in early to start the appropriate treatment. Given the ongoing pandemic, pediatricians and other health care providers need to be aware of other conditions that can masquerade as SARS-CoV-2. This article is protected by copyright. All rights reserved.

PMID:34964550 | DOI:10.1002/ppul.25804

Paediatr Anaesth. 2021 Dec 28. doi: 10.1111/pan.14384. Online ahead of print.

ABSTRACT

Cystic Fibrosis is a multi-systemic disease of impaired sodium and chloride transport across epithelial surfaces. Cystic fibrosis is one of the most common autosomal recessive diseases amongst Caucasian children. However, recent epidemiologic studies suggest that the disease in Hispanic, African American, and Asian American populations may be more common than previously recognized. The phenotypic expression is characterized by the constellation of pulmonary, pancreatic, hepatobiliary, and gastrointestinal dysfunction. Progressive obstructive lung disease is the hallmark of cystic fibrosis, and end-stage respiratory failure is the primary cause of morbidity and mortality. The most significant advance in the care has been the development of Cystic Fibrosis modulators, a class of drugs that restore cystic fibrosis transmembrane conductance regulator folding, intracellular processing, or function. Improved diagnostic abilities, a multidisciplinary approach to medical management, and the use of cystic fibrosis modulators have led to improvement in the quality of life and life expectancy. These patients undergo range of procedures such as nasal polypectomy, placement of gastrostomy tubes, vascular access device placement, transbronchial lung biopsies, and other thoracic surgeries. The anesthetic care of children with advanced cystic fibrosis disease is complex. Preoperative optimization can help improve postoperative outcomes. Strategies for pain control should rely on non-opiate, multimodal adjuncts, and regional or neuraxial techniques. Unfortunately for some children, a progressive respiratory disease often leads to end-stage respiratory failure and lung transplant surgery remains the only viable treatment option. Widespread use of lung transplant surgery as a treatment option is severely constraint by donor organ availability. Primary graft dysfunction is the most common cause of early death and can be seen within 48 hours of surgery. Median long-term survival after lung transplant remains modest. Chronic lung allograft dysfunction, opportunistic infections, and post-transplant lymphoproliferative disorder are the most common causes of morbidity and mortality amongst long-term survivors.

PMID:34963200 | DOI:10.1111/pan.14384

J Cyst Fibros. 2021 Dec 24:S1569-1993(21)02168-8. doi: 10.1016/j.jcf.2021.12.009. Online ahead of print.

ABSTRACT

BACKGROUND: This study was performed to describe the natural history of CF lung disease in young children over an 18 month period to assess the use of CT scanning as an outcome measure for intervention trials.

METHODS: Chest CT scans were obtained at baseline and after 18 months in 42 two- to six-year-old children with CF. CT scans were scored by 2 experienced radiologists for the presence and severity of bronchiectasis, mucous plugging, and air trapping.

RESULTS: Mean age at baseline 3.5 (1.3) (mean, sd) years. One or more findings of CF lung disease was seen on the first CT in 27 (64%) and at 18 months in 30 (75%). From baseline to 18 months bronchiectasis, mucous plugging, and air trapping increased from 50% to 53%, 14% to 28%, and 48% to 58% respectively. There was marked variability in the rate of progression, with subjects commonly showing improvement in lung disease. Bronchiectasis worsened in 14 (33%) and improved in 13 (31%). Single subjects with F508del/class III and F508del/class V demonstrated greater worsening and improvement respectively than F508del homozygous and class I genotypes.

CONCLUSIONS: The natural history of CF lung disease over 18 months varies widely between subjects. Factors including genotype may affect natural history as well as the effectiveness of mediators and could be an important confounder if not recognized. These findings suggest that the use of CT scanning as an outcome surrogate for CF lung disease in young children may be more challenging than has been previously recognized.

PMID:34961706 | DOI:10.1016/j.jcf.2021.12.009

J Cyst Fibros. 2021 Dec 24:S1569-1993(21)02167-6. doi: 10.1016/j.jcf.2021.10.013. Online ahead of print.

ABSTRACT

BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects.

METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks).

RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group.

CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.

PMID:34961705 | DOI:10.1016/j.jcf.2021.10.013

Nutrients. 2021 Dec 20;13(12):4554. doi: 10.3390/nu13124554.

ABSTRACT

Fat-soluble vitamin deficiency remains a challenge in cystic fibrosis (CF), chronic pancreatitis, and biliary atresia. Liposomes and cyclodextrins can enhance their bioavailability, thus this multi-center randomized placebo-controlled trial compared three-month supplementation of fat-soluble vitamins in the form of liposomes or cyclodextrins to medium-chain triglycerides (MCT) in pancreatic-insufficient CF patients. The daily doses were as follows: 2000 IU of retinyl palmitate, 4000 IU of vitamin D3, 200 IU of RRR-α-tocopherol, and 200 µg of vitamin K2 as menaquinone-7, with vitamin E given in soybean oil instead of liposomes. All participants received 4 mg of β-carotene and 1.07 mg of vitamin K1 to ensure compliance with the guidelines. The primary outcome was the change from the baseline of all-trans-retinol and 25-hydroxyvitamin D3 concentrations and the percentage of undercarboxylated osteocalcin. Out of 75 randomized patients (n = 28 liposomes, n = 22 cyclodextrins, and n = 25 MCT), 67 completed the trial (89%; n = 26 liposomes, n = 18 cyclodextrins, and n = 23 MCT) and had a median age of 22 years (IQR 19-28), body mass index of 20.6 kg/m2 [18.4-22.0], and forced expiratory volume in 1 s of 65% (44-84%). The liposomal formulation of vitamin A was associated with the improved evolution of serum all-trans-retinol compared to the control (median +1.7 ng/mL (IQR -44.3-86.1) vs. -38.8 ng/mL (-71.2-6.8), p = 0.028). Cyclodextrins enhanced the bioavailability of vitamin D3 (+9.0 ng/mL (1.0-17.0) vs. +3.0 ng/mL (-4.0-7.0), p = 0.012) and vitamin E (+4.34 µg/mL (0.33-6.52) vs. -0.34 µg/mL (-1.71-2.15), p = 0.010). Liposomes may augment the bioavailability of vitamin A and cyclodextrins may strengthen the supplementation of vitamins D3 and E relative to MCT in pancreatic-insufficient CF but further studies are required to assess liposomal vitamin E (German Clinical Trial Register number DRKS00014295, funded from EU and Norsa Pharma).

PMID:34960106 | DOI:10.3390/nu13124554

Nutrients. 2021 Dec 10;13(12):4414. doi: 10.3390/nu13124414.

ABSTRACT

Poor linear growth is common in children with cystic fibrosis (CF) and predicts pulmonary status and mortality. Growth impairment develops in infancy, prior to pulmonary decline and despite aggressive nutritional measures. We hypothesized that growth restriction during early childhood in CF is associated with reduced adult height. We used the Cystic Fibrosis Foundation (CFF) patient registry to identify CF adults between 2011 and 2015 (ages 18-19 y, n = 3655) and had height for age (HFA) records between ages 2 and 4 y. We found that only 26% CF adults were ≥median HFA and 25% were <10th percentile. Between 2 and 4 years, those with height < 10th percentile had increased odds of being <10th percentile in adulthood compared to children ≥ 10th percentile (OR = 7.7). Of HFA measured between the 10th and 25th percentiles at ages 2-4, 58% were <25th percentile as adults. Only 13% between the 10th and 25th percentile HFA at age 2-4 years were >50th percentile as adults. Maximum height between ages 2 and 4 highly correlated with adult height. These results demonstrate that low early childhood CF height correlates with height in adulthood. Since linear growth correlates with lung growth, identifying both risk factors and interventions for growth failure (nutritional support, confounders of clinical care, and potential endocrine involvement) could lead to improved overall health.

PMID:34959966 | DOI:10.3390/nu13124414

Nutrients. 2021 Dec 9;13(12):4413. doi: 10.3390/nu13124413.

ABSTRACT

INTRODUCTION: In recent years, guidelines for vitamin D supplementation have been updated and prophylactic recommended doses have been increased in patients with cystic fibrosis (CF).

OBJECTIVE: To evaluate safety and efficacy of these new recommendations.

RESULTS: Two cohorts of pancreatic insufficient CF patients were compared before (cohort 1: 179 patients) and after (cohort 2: 71 patients) American CF Foundation and European CF Society recommendations were published. Cohort 2 patients received higher Vitamin D doses: 1509 (1306-1711 95% CI) vs 1084 (983-1184 95% CI) IU/Day (p < 0.001), had higher 25 OH vitamin D levels: 30.6 (27.9-33.26 95% CI) vs. 27.4 (25.9-28.8 95% CI) ng/mL (p = 0.028), and had a lower prevalence of insufficient vitamin D levels (<30 ng/mL): 48% vs 65% (p = 0.011). Adjusted by confounding factors, patients in cohort 1 had a higher risk of vitamin D insufficiency: OR 2.23 (1.09-4.57 95% CI) (p = 0.028).

CONCLUSION: After the implementation of new guidelines, CF patients received higher doses of vitamin D and a risk of vitamin D insufficiency decreased. Despite this, almost a third of CF patients still do not reach sufficient serum calcidiol levels.

PMID:34959965 | DOI:10.3390/nu13124413

Pharmaceuticals (Basel). 2021 Dec 12;14(12):1296. doi: 10.3390/ph14121296.

ABSTRACT

Cystic fibrosis (CF) is caused by different mutations related to the cystic fibrosis transmembrane regulator protein (CFTR), with F508del being the most common. Pioneering the development of CFTR modulators, thanks to the development of effective correctors or potentiators, more recent studies deeply encouraged the administration of triple combination therapeutics. However, combinations of molecules interacting with other proteins involved in functionality of the CFTR channel recently arose as a promising approach to address a large rescue of F508del-CFTR. In this context, the design of compounds properly targeting the molecular chaperone Hsp70, such as the allosteric inhibitor MKT-077, proved to be effective for the development of indirect CFTR modulators, endowed with ability to amplify the accumulation of the rescued protein. Herein we performed structure-based studies of a number of allosteric HSP70 inhibitors, considering the recent X-ray crystallographic structure of the human enzyme. This allowed us to point out the main interaction supporting the binding mode of MKT-077, as well as of the related analogues. In particular, cation-π and π-π stacking with the conserve residue Tyr175 deeply stabilized inhibitor binding at the HSP70 cavity. Molecular docking studies had been followed by QSAR analysis and then by virtual screening of aminoaryl thiazoles (I-IIIa) as putative HSP70 inhibitors. Their effectiveness as CFTR modulators has been verified by biological assays, in combination with VX-809, whose positive results confirmed the reliability of the whole applied computational method. Along with this, the "in-silico" prediction of absorption, distribution, metabolism, and excretion (ADME) properties highlighted, once more, that AATs may represent a chemical class to be further investigated for the rational design of novel combination of compounds for CF treatment.

PMID:34959696 | DOI:10.3390/ph14121296