Pediatr Pulmonol. 2022 May 2. doi: 10.1002/ppul.25941. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis-related liver disease (CFLD) is more prevalent in recent decades due to the increasing life expectancy of patients with cystic fibrosis (CF). There is paucity of population-level data on the impact of CFLD on hospital outcomes.

METHODS: We interrogated non-overlapping years (2003-2016) of the National Inpatient Sample and Kids' Inpatient Database to include all hospitalized patients <21 years of age with a primary diagnosis of CF within the United States. A concomitant diagnosis of cirrhosis, liver fibrosis, chronic liver disease, portal hypertension, hepatomegaly, splenomegaly, hypersplenism, and liver transplant status were considered as surrogates for the diagnosis of CFLD and compared to CF-related hospitalizations without these diagnoses (controls) for demographics, comorbid conditions, in-hospital mortality, length-of-stay, and hospital charges.

RESULTS: We evaluated 94,374 CF-related hospitalizations. The prevalence of CFLD was 5.8%. The prevalence increased from 3.1% (2003) to a peak of 7.3% (2014) with an overall increasing trend, P<0.001. Hospitalizations with CFLD had an increased prevalence of significant comorbidities: respiratory failure or lung transplant, pulmonary hypertension, diabetes mellitus, malnutrition, Clostridioides difficile infection, cholelithiasis, anemia, and need for parenteral nutrition, P<0.001. Multivariate regression models showed CFLD as independently associated with 2.1 (95% CI:1.5 to 2.8) times increased risk of inpatient mortality, contributed to 1.1 (95% CI:0.89 to 1.37) additional days of hospitalization, and incurring $14,852 (95% CI:12,204 to 17,501) excess hospital charges, P<0.001.

CONCLUSION: CFLD is associated with multiple comorbidities and is independently associated with increased risk of mortality and increased health care resource utilization in pediatric CF-related hospitalizations. This article is protected by copyright. All rights reserved.

PMID:35499220 | DOI:10.1002/ppul.25941

Clin Case Rep. 2022 Apr 26;10(4):e05782. doi: 10.1002/ccr3.5782. eCollection 2022 Apr.

ABSTRACT

Pulmonary infections represent the major causes of morbidity and mortality in cystic fibrosis (CF). Here, we report a 3-month-old infant with pancreatic insufficient CF was hospitalized with positive RT-PCR test for COVID-19. He was treated successfully. Hypertonic saline can be hypothesized as a treatment regimen against COVID-19 infection after further investigations.

PMID:35498345 | PMC:PMC9040559 | DOI:10.1002/ccr3.5782

Respir Med Case Rep. 2022 Apr 18;37:101652. doi: 10.1016/j.rmcr.2022.101652. eCollection 2022.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is a condition that most often occurs in patients with asthma or cystic fibrosis. The diagnosis is usually confirmed by the combination of clinical, radiographic, and immunologic criteria as there is not individual test to establish the diagnosis. We describe the case of a 64-year-old male with a prior medical history of moderate persistent asthma who presented with worsening cough and was found to have IgE positive for Aspergillus fumigatus with findings of diffuse bilateral pulmonary calcifications on HRCT.

PMID:35494552 | PMC:PMC9048082 | DOI:10.1016/j.rmcr.2022.101652

Sarcoidosis Vasc Diffuse Lung Dis. 2022;39(1):e2022002. doi: 10.36141/svdld.v39i1.11967. Epub 2022 Mar 31.

ABSTRACT

Cardiac sarcoidosis and cystic fibrosis (CF) are both rare conditions and their co-existence has not previously been noted in adults. For the first time we report a case of isolated cardiac sarcoidosis in a woman with CF, and discuss the possible combined aetiological factors. As the life expectancy of people with CF continues to increase, clinicians should be aware of the emergence of concomitant inflammatory conditions typically diagnosed in adulthood, and the diagnostic challenges this may present.

PMID:35494166 | PMC:PMC9007026 | DOI:10.36141/svdld.v39i1.11967

Front Cell Infect Microbiol. 2022 Apr 14;12:817315. doi: 10.3389/fcimb.2022.817315. eCollection 2022.

ABSTRACT

Persons with cystic fibrosis (CF) frequently suffer from Pseudomonas aeruginosa and Aspergillus fumigatus co-infections. There is evidence that co-infections with these interacting pathogens cause airway inflammation and aggravate deterioration of lung function. We recently showed that P. aeruginosa laboratory isolates synergistically interact with the anti-fungal azole voriconazole (VCZ), inhibiting biofilm metabolism of several A. fumigatus laboratory strains. Interaction was usually mediated via pyoverdine, but also via pyocyanin or pyochelin. Here we used planktonic filtrates of 7 mucoid and 9 non-mucoid P. aeruginosa isolates from CF patients, as well as 8 isolates without CF origin, and found that all of these isolates interacted with VCZ synergistically at their IC50 as well as higher dilutions. CF mucoid isolates showed the weakest interactive effects. Four non-mucoid P. aeruginosa CF isolates produced no or very low levels of pyoverdine and did not reach an IC50 against forming A. fumigatus biofilm; interaction with VCZ still was synergistic. A VCZ-resistant A. fumigatus strain showed the same level of susceptibility for P. aeruginosa anti-fungal activity as a VCZ-susceptible reference strain. Filtrates of most Pseudomonas isolates were able to increase anti-fungal activity of VCZ on a susceptible A. fumigatus strain. This was also possible for the VCZ-resistant strain. In summary these data show that clinical P. aeruginosa isolates, at varying degrees, synergistically interact with VCZ, and that pyoverdine is not the only molecule responsible. These data also strengthen the idea that during co-infections of A. fumigatus and P. aeruginosa lower concentrations of VCZ might be sufficient to control fungal growth.

PMID:35493738 | PMC:PMC9047052 | DOI:10.3389/fcimb.2022.817315

Front Immunol. 2022 Apr 12;13:850416. doi: 10.3389/fimmu.2022.850416. eCollection 2022.

ABSTRACT

Neutrophil extracellular traps (NETs) are a recently described mechanism of neutrophils that play an important role in health and disease. NETs are an innate defense mechanism that participate in clearance of pathogens, but they may also cause collateral damage in unrelated host tissues. Neutrophil dysregulation and NETosis occur in multiple lung diseases, such as pathogen-induced acute lung injury, pneumonia, chronic obstructive pulmonary disease (COPD), severe asthma, cystic fibrosis, and recently, the novel coronavirus SARS-CoV-2. More recently, research into immunometabolism has surged due to the possibility of reprogramming metabolism in order to modulate immune functions. The present review analyzes the different metabolic pathways associated with NETs formation, and how these impact on pathologies of the airways.

PMID:35493475 | PMC:PMC9039247 | DOI:10.3389/fimmu.2022.850416

mBio. 2022 May 2:e0023522. doi: 10.1128/mbio.00235-22. Online ahead of print.

ABSTRACT

The oral microbiota is enormously diverse, with over 700 microbial species identified across individuals that play a vital role in the health of our mouth and our overall well-being. In addition, as oral diseases such as caries (cavities) and periodontitis (gum disease) are mediated through interspecies microbial interactions, this community serves as an important model system to study the complexity and dynamics of polymicrobial interactions. Here, we review historical and recent progress in our understanding of the oral microbiome, highlighting how oral microbiome research has significantly contributed to our understanding of microbial communities, with broad implications in polymicrobial diseases and across microbial community ecology. Further, we explore innovations and challenges associated with analyzing polymicrobial systems and suggest future directions of study. Finally, we provide a conceptual framework to systematically study microbial interactions within complex communities, not limited to the oral microbiota.

PMID:35491817 | DOI:10.1128/mbio.00235-22

J Cyst Fibros. 2022 Apr 28:S1569-1993(22)00105-9. doi: 10.1016/j.jcf.2022.04.017. Online ahead of print.

NO ABSTRACT

PMID:35491319 | DOI:10.1016/j.jcf.2022.04.017

Iran J Allergy Asthma Immunol. 2022 Apr 11;21(2):189-196. doi: 10.18502/ijaai.v21i2.9226.

ABSTRACT

Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in white Caucasians. It affects many organs including the lung, pancreas, and liver. Whilst CF is a monogenic disease, several studies revealed a complex relationship between genotype and clinical phenotype of diseases. We examined the expression of human leukocyte antigen (HLA) class II alleles among Iranian CF patients with disease-related microbial infection. This study was conducted on 50 hospitalized CF patients (27 males, 23 females aged 15.5±6.5 years), and 50 healthy age- and gender-matched control subjects. 5ml whole blood was harvested and after isolation of genomic DNA, HLA-DRB1 subtypes were determined by single specific primer polymerase chain reaction methods. HLA-DRB1*10 was less frequent and HLA-DRB1*04 and HLA-DRB1*11 was the most frequent allele in CF patients, but none reached significance. HLA-DRB1*04 allele was frequently seen among16 CF patients with high serum IgE levels (430.25±219.7 IU/mL) and 27 CF patients that were positive for Pseudomonas aeruginosa colonization. A total of 31 CF patients had candida Albicans colonization in whom HLA-DRB1*11 was mostly seen. A total of 3 CF patients had allergic bronchopulmonary aspergillosis and two were diabetic. The DR4 and DR11 serotypes that recognize the HLA-DRB1*04 and HLA-DRB1*11 gene products respectively are not significantly enriched in the Iranian CF population. Further research should be conducted on DR4 and DR11 in CF patients to understand their possible role in infection and IgE expression.

PMID:35490272 | DOI:10.18502/ijaai.v21i2.9226

J Pediatr Surg. 2022 Apr 22:S0022-3468(22)00285-8. doi: 10.1016/j.jpedsurg.2022.04.013. Online ahead of print.

NO ABSTRACT

PMID:35490052 | DOI:10.1016/j.jpedsurg.2022.04.013

Lung India. 2022 May-Jun;39(3):274-278. doi: 10.4103/lungindia.lungindia_370_21.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) remains under-diagnosed in Pakistan. CF population has increased tendency for Pseudomonas aeruginosa (Pa) infection and it is one of the leading causes of mortality. Utilizing inhaled antibiotics (IAs) for the treatment of Pa infection has been well established in the literature. There is limited data available on CF in Pakistan, especially regarding the efficacy of IAs. The aim of this study is to investigate the role of IAs on Pa infection in children and adolescents with CF.

METHODOLOGY: CF patients enrolled between January 2012 and December 2019 were selected as part of this retrospective cohort study. CF patients from 2 to 18 years of age who cultured Pa on any respiratory sample and who had never been Pa-free in at least two sputum cultures in the previous 12 months were included. Patients were divided into an IA group and a noninhaled antibiotic (NIA) group based on the treatment they received. Follow-up was done between 3 and 6 months posttherapy on Pseudomonas growth in the sputum. The number of pulmonary exacerbations were documented for 6 months follow-up.

RESULTS: Eighty-one children with CF were enrolled during the study period, of which 39 were in the IA group and 42 were in the NIA group. There was no significant difference in their demographics and initial clinical characteristics. The mean pulmonary exacerbations after 6 months were lower in the IA group as compared to the NIA group (1.102 ± 0.50 vs. 2.45 ± 0.89: P = 0.001). Follow-up between 3 and 6 months showed greater Pseudomonas colonization in the IA group versus the NIA group (53.84% vs. 92.85%: P = 0.001).

CONCLUSION: IAs in combination with airway clearance therapy and oral or IV antibiotics are an effective regimen for children with CF.

PMID:35488686 | DOI:10.4103/lungindia.lungindia_370_21

Lung India. 2022 May-Jun;39(3):267-273. doi: 10.4103/lungindia.lungindia_284_21.

ABSTRACT

BACKGROUND: In childhood pneumonia, pediatric lung ultrasound (PLUS) is a very sensitive and specific diagnostic alternative to chest X-ray (CXR). However, there is a paucity of literature on this in India. We set out to compare the diagnostic accuracy of PLUS and CXR in hospitalized children with community-acquired pneumonia (CAP).

SETTING AND DESIGN: Prospective, observational study (June 2017-September 2019) at a tertiary care hospital.

METHODS: Hospitalized children of CAP (3 months-18 years) were included after taking informed, written consent. Hemodynamic instability, asthma, cystic fibrosis, congenital heart disease, immunodeficiency, and malignancy cases were excluded. CXR (frontal view) and PLUS were done within 6 h of each other and within 24 h of hospitalization. Statistical analysis was performed using SPSS software version 25.

RESULTS: Out of 612 consecutive, hospitalized respiratory cases, 261 were recruited. CAP was diagnosed clinically in 148 (56.7%) patients [95 boys (64.19%), mean age in years ± SD: 4.31 ± 4.41]. Abnormal PLUS was present in 141 (95.27%) and abnormal CXR in 128 (86.48%) patients. In radiologically diagnosed pneumonia, PLUS was detected in 123 [123/128 (96.09%)] children, and when CXR was normal, PLUS was abnormal in 18 [18/20 (90%)]. PLUS showed a sensitivity of 95.27% (95%CI: 90.50-98.08) and a specificity of 92.90% (95%CI: 86.53-96.89). CXR showed a sensitivity of 86.49% (95%CI: 79.9-91.55) and a specificity of 90.27% (95%CI: 83.25-95.04).

CONCLUSIONS: PLUS is a sensitive, specific test and can be considered as the preferred investigation before CXR in children hospitalized with CAP.

PMID:35488685 | DOI:10.4103/lungindia.lungindia_284_21

Nat Commun. 2022 Apr 29;13(1):2344. doi: 10.1038/s41467-022-29935-9.

ABSTRACT

Approximately 10% of cystic fibrosis patients harbor nonsense mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which can generate nonsense codons in the CFTR mRNA and subsequently activate the nonsense-mediated decay (NMD) pathway resulting in rapid mRNA degradation. However, it is not known which NMD branches govern the decay of CFTR mRNAs containing nonsense codons. Here we utilize antisense oligonucleotides targeting NMD factors to evaluate the regulation of nonsense codon-containing CFTR mRNAs by the NMD pathway. We observe that CFTR mRNAs with nonsense codons G542X, R1162X, and W1282X, but not Y122X, require UPF2 and UPF3 for NMD. Furthermore, we demonstrate that all evaluated CFTR mRNAs harboring nonsense codons are degraded by the SMG6-mediated endonucleolytic pathway rather than the SMG5-SMG7-mediated exonucleolytic pathway. Finally, we show that upregulation of all evaluated CFTR mRNAs with nonsense codons by NMD pathway inhibition improves outcomes of translational readthrough therapy.

PMID:35487895 | DOI:10.1038/s41467-022-29935-9

Trends Microbiol. 2022 Apr 26:S0966-842X(22)00085-3. doi: 10.1016/j.tim.2022.03.009. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease that affects almost 100 000 people worldwide. CF patients suffer from chronic bacterial airway infections that are often polymicrobial and are the leading cause of mortality. Interactions between pathogens modulate expression of genes responsible for virulence and antibiotic resistance. One of the ways bacteria can interact is through contact-dependent systems, which secrete antibacterial proteins (effectors) that confer advantages to cells that harbor them. Here, we highlight recent work that describes effectors used by Gram-negative CF pathogens to eliminate competitor bacteria. Understanding the mechanisms of secreted effectors may lead to novel insights into the ecology of bacteria that colonize respiratory tracts and could also pave the way for the design of new therapeutics.

PMID:35487848 | DOI:10.1016/j.tim.2022.03.009

J Breath Res. 2022 Apr 29. doi: 10.1088/1752-7163/ac6bb6. Online ahead of print.

ABSTRACT

Pulmonary infections caused by mycobacteria cause significant mortality and morbidity in the human population. Diagnosing mycobacterial infections is challenging. An infection can lead to active disease or remain indolent with little clinical consequence. In patients with pulmonary non-tuberculosis Mycobacteria (PNTM) identification of infection and diagnosis of disease can take months to years. Our previous studies showed the potential diagnostic power of volatile molecules in the exhaled breath samples to detect active pulmonary Mycobacterium tuberculosis infection. Herein, we demonstrate the ability to detect the disease status of PNTM in the breath of persons with cystic fibrosis (PwCF). We putatively identified 17 volatile molecules that could discriminate between active-NTM disease (n=6), indolent patients (n=3), and those patients who have never cultured an NTM (n=2). The results suggest that further confirmation of the breath biomarkers as a non-invasive and culture-independent tool for diagnosis of NTM disease in a larger cohort of PwCF is warranted.

PMID:35487186 | DOI:10.1088/1752-7163/ac6bb6

Am J Respir Cell Mol Biol. 2022 Apr 29. doi: 10.1165/rcmb.2021-0359OC. Online ahead of print.

ABSTRACT

The dynamics describing the vicious cycle characteristic of CF lung disease, initiated by stagnant mucus and perpetuated by infection and inflammation, remain unclear. Here we determine the effect of the CF airway milieu, with persistent muco-obstruction, resident pathogens, and inflammation, on the mucin quantity/quality that govern lung disease pathogenesis/progression. The concentrations of MUC5AC and MUC5B, were measured and characterized in sputum samples from CF (N=44) and healthy (N=29) subjects with respect to their macromolecular properties, degree of proteolysis, and glycomics diversity. These parameters were related to quantitative microbiome and clinical data. MUC5AC, and MUC5B concentrations were elevated, 30- and 8-fold respectively, in CF as compared to control sputum. Mucin parameters did not correlate with hypertonic saline, inhaled corticosteroids or antibiotics use. No differences in mucin parameters were detected at baseline vs during exacerbations. Mucin concentrations significantly correlated with the age and sputum human neutrophil elastase (HNE) activity. Although significantly more proteolytic cleavages were detected in CF mucins, their macromolecular properties, e.g., size and molecular weight, were not significantly different than controls likely reflecting the role of S-S bonds in maintaining multimeric structures. No evidence of giant mucin macromolecule reflecting oxidative stress-induced cross-linking was found. Mucin glycomic analysis revealed significantly more sialylated glycans in CF and the total abundance of non-sulfated O-glycans was correlated with the relative abundance of pathogens. Collectively, the interaction of mucins, pathogens, epithelium, and inflammatory cells promotes proteomic and glycomic changes that reflects a persistent muco-obstructive, infectious, and inflammatory state.

PMID:35486871 | DOI:10.1165/rcmb.2021-0359OC

Am J Respir Cell Mol Biol. 2022 May;66(5):577-579. doi: 10.1165/rcmb.2021-0404LE.

NO ABSTRACT

PMID:35486077 | DOI:10.1165/rcmb.2021-0404LE

Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221089467. doi: 10.1177/17534666221089467.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease that involves the cells that produce mucus and sweat, affecting many organs, especially the lungs. Positive expiratory pressure (PEP) devices generate a pressure opposite to that exerted by the airways during expiration, thus improving mucociliary clearance.

OBJECTIVES: To evaluate the efficacy of PEP devices as a resource to facilitate the mucus removal and other outcomes in people with CF, as well as the possible adverse effects derived from their use.

MATERIAL AND METHOD: A systematic review and meta-analysis was conducted according to PRISMA standards. The descriptors were 'cystic fibrosis', 'PEP', and 'physiotherapy and/or physical therapy'. The search was performed in four databases: PubMed, PEDro, and Web of Science and Scopus, in July 2021. The inclusion criteria were randomized controlled trials (RCTs) over the last 10 years. The methodological quality of the studies was analyzed and meta-analysis was performed with Review Manager software.

RESULTS: Ten RCTs met the objectives and criteria, with a total of 274 participants. The trials score a moderate methodological quality on the PEDro scale. No clear results were obtained on whether PEP provides better lung function than other breathing techniques (such as airway clearance); but it does achieve a higher rate of lung clearance than physical exercise.

CONCLUSIONS: PEP is more effective than usual care or no intervention, although there is not enough evidence to confirm that PEP achieves improvements in forced expiratory volume in the first second (FEV1) compared with other techniques. It is a safe technique, without adverse effects.

PMID:35485916 | DOI:10.1177/17534666221089467

J Paediatr Child Health. 2022 Apr 29. doi: 10.1111/jpc.16003. Online ahead of print.

NO ABSTRACT

PMID:35485426 | DOI:10.1111/jpc.16003

Pediatr Pulmonol. 2022 Apr 29. doi: 10.1002/ppul.25946. Online ahead of print.

ABSTRACT

This pilot study successfully implemented a standardized protocol for tablet-based ototoxicity screening in pediatric CF patients exposed to aminoglycosides. Further studies are needed to assess the impact of implementation in a larger number of patients, as well as to determine barriers that may exist at centers with variation in available resources. This method of ototoxicity screening represents an accessible alternative to traditional audiology testing, and given the continued improvements in expected life span for PwCF, it is imperative that patients have regular access to this type of screening to allow for early identification of medication-related toxicities. This article is protected by copyright. All rights reserved.

PMID:35485261 | DOI:10.1002/ppul.25946