Arch Dis Child. 2022 Aug;107(8):739. doi: 10.1136/archdischild-2022-324569.

NO ABSTRACT

PMID:35853636 | DOI:10.1136/archdischild-2022-324569

Expert Rev Respir Med. 2022 Jul 19. doi: 10.1080/17476348.2022.2104249. Online ahead of print.

ABSTRACT

INTRODUCTION: Airway infection with pathogens and its associated pulmonary exacerbations (PEX) are the major causes of morbidity and premature death in cystic fibrosis (CF). Preventing or postponing chronic infections requires early diagnosis. However, limitations of conventional microbiology-based methods can hamper identification of exacerbations and specific pathogen detection. Analyzing volatile organic compounds (VOCs) in breath samples may be an interesting tool in this regard, as VOC-biomarkers can characterize specific airway infections in CF.

AREAS COVERED: We address the current achievements in VOC-analysis and discuss studies assessing VOC-biomarkers and fingerprints, i.e. a combination of multiple VOCs, in breath samples aiming at pathogen and PEX detection in people with CF (pwCF). We aim to provide bases for further research in this interesting field.

EXPERT OPINION: Overall, VOC-based analysis is a promising tool for diagnosis of infection and inflammation with potential to monitor disease progression in pwCF. Advantages over conventional diagnostic methods, including easy and non-invasive sampling procedures, may help to drive prompt, suitable therapeutic approaches in the future. Our review shall encourage further research, including validation of VOC-based methods. Specifically, longitudinal validation under standardized conditions is of interest in order to ensure repeatability and enable inclusion in CF diagnostic routine.

PMID:35853615 | DOI:10.1080/17476348.2022.2104249

J Microbiol Methods. 2022 Jul 16:106540. doi: 10.1016/j.mimet.2022.106540. Online ahead of print.

ABSTRACT

Next generation sequencing (NGS) has transformed our understanding of airway microbiology, however there are methodology limitations that require consideration. The presence of high concentrations of human DNA in clinical specimens can significantly impact sequencing of the microbiome, especially in low biomass samples. Here we compared three different methods (0.025% saponin, NEBNext Microbiome DNA enrichment kit, QIAamp DNA microbiome kit) for the reduction of human DNA from six CF sputum samples and determined the impact on the microbiome detected using 16S rRNA gene sequencing. Human DNA in undepleted CF sputum accounted for 94.3% of the total DNA. Saponin, the NEBNext kit and the QIAamp kit reduced human DNA levels by an average of 38.7%, 61.8% and 94.8%, respectively. None of the depletion methods reduced total bacterial DNA concentrations. QIAamp depletion did not influence taxa richness or alpha diversity however alterations to the core genera were noted following depletion. While all methods reduced human DNA in the CF sputum samples, the QIAamp DNA microbiome kit reduced Human DNA levels significantly while leaving bacterial DNA levels unchanged. Human DNA depletion in low biomass, human DNA-dense CF sputum samples is vital for improving bacterial resolution in the CF airway microbiome.

PMID:35853495 | DOI:10.1016/j.mimet.2022.106540

Drugs. 2022 Jul 19. doi: 10.1007/s40265-022-01745-9. Online ahead of print.

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation that ultimately leads to kidney failure in most patients. Approximately 10% of patients who receive kidney replacement therapy suffer from ADPKD. To date, a vasopressin V2 receptor antagonist (V2RA) is the only drug that has been proven to attenuate disease progression. However, aquaresis-related adverse events limit its widespread use. Data on the renoprotective effects of somatostatin analogues differ largely between studies and medications. This review discusses new drugs that are investigated in clinical trials to treat ADPKD, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators and micro RNA inhibitors, and drugs already marketed for other indications that are being investigated for off-label use in ADPKD, such as metformin. In addition, potential methods to improve the tolerability of V2RAs are discussed, as well as methods to select patients with (likely) rapid disease progression and issues regarding the translation of preclinical data into clinical practice. Since ADPKD is a complex disease with a high degree of interindividual heterogeneity, and the mechanisms involved in cyst growth also have important functions in various physiological processes, it may prove difficult to develop drugs that target cyst growth without causing major adverse events. This is especially important since long-standing treatment is necessary in this chronic disease. This review therefore also discusses approaches to targeted therapy to minimize systemic side effects. Hopefully, these developments will advance the treatment of ADPKD.

PMID:35852784 | DOI:10.1007/s40265-022-01745-9

Pediatr Pulmonol. 2022 Jul 18. doi: 10.1002/ppul.26078. Online ahead of print.

ABSTRACT

OBJECTIVE: Elexacaftor/Tezacaftor/Ivacaftor (Kaftrio®) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator with the potential to improve exercise capacity. This case-series of 3 adolescents with CF aimed to investigate whether 6 weeks treatment with Kaftrio® could improve exercise capacity in CFTR modulator naive adolescents with CF.

METHODS: Three adolescents (14.0 ± 1.4 years) with CF (FEV1 % predicted: 62.5 ± 17.1; F508del/F508del genotype) completed an exhaustive maximal cardiopulmonary exercise test on a cycle ergometer to determine peak oxygen uptake ( V ̇ O2peak ) and measure changes in gas exchange and ventilation during exercise at 6 weeks. We also analysed wrist-worn device-based physical activity (PA) data in 2 of the 3 cases. Validated acceleration thresholds were used to quantify time spent in each PA intensity category.

RESULTS: Clinically meaningful improvements in V ̇ O2peak were observed in all 3 cases (+17.6%, +52.4% and +32.9%, respectively), with improvements greatest in those with more severe lung disease and lower fitness at baseline. Although lung function increased in all cases, inconsistent changes in markers of ventilatory and peripheral muscle efficiency likely suggest different mechanisms of improvement in this case group of adolescents with CF. Device-based analysis of PA was variable, with one case increasing and one case decreasing.

CONCLUSION: In this case-series we have observed, for the first time, improvements in exercise capacity following 6 weeks treatment with Kaftrio®. Improvements were greatest in the presence of more severe CF lung disease and lower aerobic fitness at baseline. The mechanism(s) responsible for these changes warrant further investigation in larger trials. This article is protected by copyright. All rights reserved.

PMID:35851858 | DOI:10.1002/ppul.26078

Chest. 2022 Jul 15:S0012-3692(22)01242-9. doi: 10.1016/j.chest.2022.07.004. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease, in which mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein result in a multisystem disease dominated by digestive and respiratory manifestations. In the mid-twentieth century, CF used to cause death within the first years of life. Over the past decades, advances in disease management, including systematic neonatal screening, multidisciplinary symptomatic CF care, lung transplantation and, more recently, highly effective CFTR modulators, have markedly transformed the prognosis of people with CF. In most countries with well-established CF care, adults now outnumber children and life expectancy is expected to increase further, narrowing the survival gap with the general population. However, marked differences in the prognosis of CF exist not only between high-income, low- and middle-income countries, but also among high-income countries, based on the presence and quality of a specialized CF care provision network. Current evidence suggests that differences in patient clinical status and survival could be attributable not only to intrinsic disease severity but also to disparities in access to high-quality specialized care. As CF is generally a progressive disease, adults with CF often show increased pulmonary severity and complications, and increased occurrence of comorbidities, highlighting the need for specialized adult CF centers. This article seeks to describe the evolution of CF demography over the past decades, predict future trends and anticipate the future of adult CF care provision.

PMID:35850286 | DOI:10.1016/j.chest.2022.07.004

Am J Respir Cell Mol Biol. 2022 Jul 18. doi: 10.1165/rcmb.2022-0172OC. Online ahead of print.

ABSTRACT

In cystic fibrosis (CF), reduced HCO3- secretion acidifies the airway surface liquid (ASL) and the acidic pH disrupts host defenses. Thus, understanding the control of ASL pH (pHASL) in CF may help identify novel targets and facilitate therapeutic development. In diverse epithelia, the with-no-lysine [K] (WNK) kinases coordinate HCO3- and Cl- transport, but their functions in airway epithelia are poorly understood. Here, we tested the hypothesis that WNK kinases regulate CF pHASL. In primary cultures of differentiated human airway epithelia, inhibiting WNK kinases acutely increased both CF and non-CF pHASL. This response was HCO3--dependent and involved downstream SPAK/ OSR1 kinases. Importantly, WNK inhibition enhanced key host defenses otherwise impaired in CF. Human airway epithelia expressed two WNK isoforms in secretory cells and ionocytes, and knockdown of either WNK1 or WNK2 increased CF pHASL. WNK inhibition decreased Cl- secretion and the response to bumetanide, an NKCC1 inhibitor. Surprisingly, bumetanide alone or basolateral Cl- substitution also alkalinized CF pHASL. These data suggest that WNK kinases influence the balance between transepithelial Cl- versus HCO3- secretion. Moreover, reducing basolateral Cl- entry may increase HCO3- secretion and raise pHASL, thereby improving CF host defenses.

PMID:35849656 | DOI:10.1165/rcmb.2022-0172OC

Curr Opin Infect Dis. 2022 Aug 1;35(4):346-352. doi: 10.1097/QCO.0000000000000847. Epub 2022 Jul 5.

ABSTRACT

PURPOSE OF REVIEW: We describe recent changes in care for people with cystic fibrosis (PwCF) that could impact infection prevention and control (IP&C) practices.

RECENT FINDINGS: Current IP&C guidelines primarily aim to prevent acquisition and transmission of pathogens in PwCF utilizing evidence-based recommendations for healthcare settings. Currently, highly effective modulator therapy (HEMT) is dramatically improving the clinical manifestations of cystic fibrosis and reducing pulmonary exacerbations and hospitalizations. Thus, it is feasible that long-term, sustained improvements in pulmonary manifestations of cystic fibrosis could favorably alter cystic fibrosis microbiology. The COVID-19 pandemic increased the use of virtual care, enabling PwCF to spend less time in healthcare settings and potentially reduce the risk of acquiring cystic fibrosis pathogens. The increasing use of whole genome sequencing (WGS) shows great promise in elucidating sources of cystic fibrosis pathogens, shared strains, and epidemic strains and ultimately could allow the cystic fibrosis community to monitor the safety of changed IP&C practices, if deemed appropriate. Finally, given the nonhealthcare environmental reservoirs for cystic fibrosis pathogens, practical guidance can inform PwCF and their families about potential risks and mitigation strategies.

SUMMARY: New developments in the treatment of PwCF, a shift toward virtual care delivery of care, and use of WGS could change future IP&C practices.

PMID:35849525 | DOI:10.1097/QCO.0000000000000847

J Pediatr Gastroenterol Nutr. 2022 Jul 18. doi: 10.1097/MPG.0000000000003566. Online ahead of print.

ABSTRACT

OBJECTIVES: Pediatric gastroenterologists are often consulted to perform diagnostic and therapeutic endoscopy in infants with gastrointestinal bleeding (GIB). The value of endoscopy and risk of complications in this population are not well characterized. We aimed to describe findings and outcomes of infants with GIB who undergo endoscopy.

METHODS: Retrospective, single-center, cohort study of hospitalized infants ≤ 12 months who underwent esophagogastroduodenoscopy (EGD) and/or colonoscopy/flexible sigmoidoscopy (COL) for GIB. CPT codes, ICD codes, and quality control logs identified infants.

RESULTS: Fifty-six infants were identified from 2008-2019 (51.8% female; mean age 161.6 days). Seven endoscopies identified sources of GIB: gastric ulcers, a duodenal ulcer, fundic angiodysplasia, esophageal varices, and an anastomotic ulcer. Three infants underwent therapeutic interventions of banding/sclerotherapy of esophageal varices and triamcinolone injection of an anastomotic ulcer. Six infants underwent abdominal surgery for GIB or suspected intestinal perforation after endoscopy, where a gastric perforation, jejunal perforation at an anastomotic stricture, necrotizing enterocolitis totalis with perforation, Meckel's diverticulum, and a duodenal ulcer were identified. No source of bleeding was identified surgically in one infant with GIB. Respiratory failure, use of vasopressors or octreotide, administration of blood products, and high BUN were associated with increased likelihood of requiring surgery (p<0.05 for all).

CONCLUSION: There was limited utility to performing endoscopy in infants ≤ 12 months old with clinical GIB. Endoscopy in these sick infants carries risk, and three infants in this series presented with a GI perforation shortly after the procedure. These limitations and risks should influence clinical decision-making regarding endoscopy in infants with GIB.

PMID:35848737 | DOI:10.1097/MPG.0000000000003566

Am J Rhinol Allergy. 2022 Jul 17:19458924221111830. doi: 10.1177/19458924221111830. Online ahead of print.

ABSTRACT

BACKGROUND: Nasal mucus is proving to be a useful means by which to study the pathogenesis of chronic rhinosinusitis (CRS). Given the increase in publications examining nasal mucus and the lack of a review on this topic, we will focus on this noninvasive approach to studying CRS. Particular attention will be drawn towards inflammatory cytokines and biomarkers and their influence on disease severity.

METHODS: A literature review of papers published in English pertaining to nasal mucus was performed using the PubMed database. The search utilized combinations of the following keywords: sinusitis, polyps, sample collection, nasal mucus, or nasal secretion. Studies solely on acute or bacterial sinusitis, allergic rhinitis, or cystic fibrosis were not included.

RESULTS: A wide variety of materials and methods have been used to collect nasal mucus. Numerous assay types have been performed with the most common being ELISA, cytometric bead array, and proteomics. Most studies have focused on examining the levels of Th1/Th2 cytokines along with chemokines associated with type 2 immunity. Other factors identified include growth factors, senescence-associated proteins, complement, and antimicrobial defenses have also been identified. Nasal mucus cytokines have proven useful in cluster analysis and predicting postoperative improvement in Sino-nasal Outcome Test (SNOT-22) scores. One limitation of the use of nasal mucus is that some studies have suggested that nasal mucus does not always reflect the tissue microenvironment.

CONCLUSIONS: Nasal mucus represents a critical tool by which to examine the sinonasal microenvironment in a noninvasive manner. Unlike studies of tissue, it can be utilized in both surgically and medically managed patients and avoids the trauma of biopsies. However, studies are still needed to determine the most effective method for nasal mucus collection. Studies should also take care to confirm that nasal mucus markers do, in fact, reflect the levels of the product studied in the tissue.

PMID:35848564 | DOI:10.1177/19458924221111830

J Pediatr Pharmacol Ther. 2022;27(5):407-408. doi: 10.5863/1551-6776-27.5.407. Epub 2022 Jul 6.

NO ABSTRACT

PMID:35845564 | PMC:PMC9268107 | DOI:10.5863/1551-6776-27.5.407

J Pediatr Pharmacol Ther. 2022;27(5):463-466. doi: 10.5863/1551-6776-27.5.463. Epub 2022 Jul 6.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionized care for patients with cystic fibrosis (CF). The triple combination product elexacaftor/tezacaftor/ivacaftor is a highly effective CFTR modulator that is generally well tolerated. However, in clinical trials of pediatric and adult patients, 4% to 12% developed rash after initiation of therapy. Few reports have described approaches to management of this adverse effect. In this report, we describe 2 children with CF who developed a pruritic, maculopapular rash after initiating elexacaftor/tezacaftor/ivacaftor. These patients were successfully rechallenged after rash resolution with a practical titration schedule.

PMID:35845562 | PMC:PMC9268115 | DOI:10.5863/1551-6776-27.5.463

J Pediatr Pharmacol Ther. 2022;27(5):467-469. doi: 10.5863/1551-6776-27.5.467. Epub 2022 Jul 6.

ABSTRACT

Adverse reactions, including severe cutaneous reactions, to cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been described in the literature. Herein we present a drug eruption in response to elexacaftor/tezcaftor/ivacaftor (brand name, Trikafta) in a 7-year-old male with cystic fibrosis, followed by desensitization and successful continuation. A review of the literature outlining similar cases is provided. Attempting to mitigate and manage drug reactions to CFTR modulators is essential because they represent vital and irreplaceable therapies for individuals with cystic fibrosis (CF).

PMID:35845559 | PMC:PMC9268110 | DOI:10.5863/1551-6776-27.5.467

Front Pediatr. 2022 Jun 29;10:937250. doi: 10.3389/fped.2022.937250. eCollection 2022.

ABSTRACT

BACKGROUND AND AIM: Cystic fibrosis (CF) is a genetic disease that is difficult to treat and caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Small molecules have been used to treat the symptom caused by CFTR mutations by restoring CFTR protein function. However, the data on children with CF are scarce. This meta-analysis aimed to evaluate the effectiveness and safety of this therapy in children diagnosed with CF.

MATERIALS AND METHODS: Relevant studies were identified through searching medical databases before April 1, 2022. The primary outcomes of ppFEV1, lung clearance index2.5 (LCI2.5), sweat chloride concentration (SwCI), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) score were pooled and analyzed. The secondary outcomes were nutritional status (weight, BMI, stature, and their z-score) and adverse events under therapy.

RESULTS: A total of twelve studies were included. Compared with the placebo group, the pooled outcome of the ppFEV1, LCI2.5, SwCI, and CFQ-R score were improved by 7.91 {[95% confidence interval (CI), 3.71-12.12], -1.00 (95% CI, -1.38 to -0.63), -35.22 (95% CI, -55.51 to -14.92), and 4.45 (95% CI, 2.31-6.59), respectively}. Compared with the placebo group, the pooled result of the change in weight was improved by 1.53 (95% CI, 0.42-2.63). All the aforementioned results were also improved in single-arm studies. No clear differences in adverse events were found between CFTR modulator therapy and the placebo group.

CONCLUSION: CFTR modulators could improve multiaspect function in children with CF and result in comparable adverse events.

PMID:35844763 | PMC:PMC9276987 | DOI:10.3389/fped.2022.937250

Front Immunol. 2022 Jul 1;13:931524. doi: 10.3389/fimmu.2022.931524. eCollection 2022.

ABSTRACT

Lung transplantation is the definitive therapy for patients living with end-stage lung disease. Despite significant progress made in the field, graft survival remains the lowest of all solid organ transplants. Additionally, the lung has among the lowest of organ utilization rates-among eligible donors, only 22% of lungs from multi-organ donors were transplanted in 2019. Novel strategies are needed to rehabilitate marginal organs and improve graft survival. Gene therapy is one promising strategy in optimizing donor allografts. Over-expression or inhibition of specific genes can be achieved to target various pathways of graft injury, including ischemic-reperfusion injuries, humoral or cellular rejection, and chronic lung allograft dysfunction. Experiments in animal models have historically utilized adenovirus-based vectors and the majority of literature in lung transplantation has focused on overexpression of IL-10. Although several strategies were shown to prevent rejection and prolong graft survival in preclinical models, none have led to clinical translation. The past decade has seen a renaissance in the field of gene therapy and two AAV-based in vivo gene therapies are now FDA-approved for clinical use. Concurrently, normothermic ex vivo machine perfusion technology has emerged as an alternative to traditional static cold storage. This preservation method keeps organs physiologically active during storage and thus potentially offers a platform for gene therapy. This review will explore the advantages and disadvantages of various gene therapy modalities, review various candidate genes implicated in various stages of allograft injury and summarize the recent efforts in optimizing donor lungs using gene therapy.

PMID:35844566 | PMC:PMC9283701 | DOI:10.3389/fimmu.2022.931524

Immunol Lett. 2022 Jul 14:S0165-2478(22)00104-3. doi: 10.1016/j.imlet.2022.07.005. Online ahead of print.

ABSTRACT

Efferocytosis is imperative to maintain lung homeostasis and control inflammation. Populations of lung macrophages are the main efferocytes in this tissue, responsible for controlling immune responses and avoiding unrestrained inflammation and autoimmunity through the expression of a plethora of receptors that recognize multiple 'eat me' signals on apoptotic cells. Efferocytosis is essentially anti-inflammatory and tolerogenic. However, in some situations, apoptotic cells phagocytosis can elicit inflammatory and immunogenic immune responses. Here, we summarized the current knowledge of the mechanisms of efferocytosis, and how any abnormality in this process may have an important contribution to the lung pathophysiology of many chronic inflammatory lung diseases such as asthma, acute lung injury, chronic obstructive pulmonary disease, and cystic fibrosis. Further, we consider the consequences of the dual role of efferocytosis on the susceptibility or resistance to pulmonary microbial infections. Understanding how efferocytosis works in different contexts will be useful to the development of new and more effective strategies to control the diversity of lung diseases.

PMID:35843361 | DOI:10.1016/j.imlet.2022.07.005

Stem Cell Res. 2022 Jul 7;63:102854. doi: 10.1016/j.scr.2022.102854. Online ahead of print.

ABSTRACT

Skin fibroblasts obtained from a 20-year-old woman with clinically manifested and genetically proven (F508del/CFTRdele2.3) cystic fibrosis were successfully transformed into induced pluripotent stem cells (iPSCs) by using Sendai virus-based reprogramming vectors including the four Yamanaka factors, OCT3/4, SOX2, KLF4, and c-MYC. The iPSCs showed a normal karyotype, expressed pluripotency markers and exhibited the potential to differentiate into three germ layers in spontaneous differentiation assay. This iPSC line may be used for development of a personalized treatment including genome editing, disease modelling, cell differentiation and organoid formation, pharmacological investigations and drug screening.

PMID:35843019 | DOI:10.1016/j.scr.2022.102854

J Cyst Fibros. 2022 Jul 13:S1569-1993(22)00622-1. doi: 10.1016/j.jcf.2022.07.004. Online ahead of print.

ABSTRACT

The Dutch CF Foundation (NCFS) developed a quality improvement program, to assess and improve quality of care in all CF centers in The Netherlands. Criteria to assess quality of care from the patient perspective were defined, and quality of care was assessed by patients via online surveys and site visits. Recommendations were addressed to all centers to improve quality of care. Most recommendations were related to communicational issues. All centers were given the quality mark of the patient organisation, although two of them needed extra time to meet the lower limit of the core set of criteria. After two years, over 75 % of the recommendations given to the centers were fully or partly implemented, showing a high efficacy of the program.

PMID:35842291 | DOI:10.1016/j.jcf.2022.07.004

J Cyst Fibros. 2022 Jul 12:S1569-1993(22)00598-7. doi: 10.1016/j.jcf.2022.06.011. Online ahead of print.

ABSTRACT

The triple combination of Elexacaftor-Tezacaftor-Ivacaftor (ELX-TEZ-IVA) has been shown to markedly improve lung function in persons with cystic fibrosis (pwCF). An important adverse effect of the drug is rash, which was reported in clinical trials and highlighted in case reports. Our report demonstrates a similar adverse event with the drug in one of our patients with spontaneous resolution of the rash not necessitating cessation of treatment or desensitization to the drug as were done in other cases. We highlight through our report the heterogeneity of the clinical presentation of the rash when on triple therapy and the need for further studies to understand the immunological mechanism of this adverse event.

PMID:35840534 | DOI:10.1016/j.jcf.2022.06.011

J Allergy Clin Immunol. 2022 Jul 12:S0091-6749(22)00913-7. doi: 10.1016/j.jaci.2022.07.002. Online ahead of print.

NO ABSTRACT

PMID:35839844 | DOI:10.1016/j.jaci.2022.07.002