A 16-year retrospective study on fungal prevalence and diversity in patients with Cystic Fibrosis- Candida dubliniensis was associated with a decline in lung function.

Int J Infect Dis. 2020 May 22;:

Authors: Shakirchi MA, Klingspor L, Bergman P, Hjelte L, de Monestrol I

Abstract
OBJECTIVES: To study the prevalence of fungal species in CF patients over a 16 years period, as well as the impact of C. albicans, C. dubliniensis and A. fumigatus on lung function.
METHODS: Observational single-center cohort study (2000-2015) including 133 CF patients (ages 6-66 years). Linear mixed models with autoregressive covariance matrix were used.
RESULTS: C. albicans was the most common fungus (prevalence 62%) followed by A. fumigatus (22%) and C. dubliniensis (11%). In the initial year of detection, there was no impact of C. albicans, C. dubliniensis or A. fumigatus on lung function. However, one and two years after detection of C. dubliniensis a reduction in ppFEV1 with 3.8%, p=0.022, (year 1) and with 4.1%, p=0.017 (year 2) compared to CF patients without these findings, was observed. Furthermore, patients with positive cultures for any of these fungal species for three consecutive years exhibited a decline in lung function (C. dubliniensis, 7.6% reduction in ppFEV1, p=0.001; A. fumigatus, 4.9%, p=0.007; C. albicans, 2.6%, p=0.014). The results were adjusted for age, CFTR genotype, chronic and intermittent P. aeruginosa colonization and numbers of intravenous antibiotic treatments per year. Persistence of C. dubliniensis for three consecutive years was correlated positively to age and ESR (both p=0.001).
CONCLUSIONS: CF patients who were cultured positive for C. dubliniensis, C. albicans or A. fumigatus in sputum exhibited a decline in ppFEV1 over time. The effect was most pronounced for C. dubliniensis.

PMID: 32450290 [PubMed - as supplied by publisher]

Females with cystic fibrosis have a larger decrease in sweat chloride in response to lumacaftor/ivacaftor compared to males.

J Cyst Fibros. 2020 May 21;:

Authors: Aalbers BL, Hofland RW, Bronsveld I, de Winter-de Groot KM, Arets HGM, de Kiviet AC, van Oirschot-van de Ven MMM, Kruijswijk MA, Schotman S, Michel S, van der Ent CK, Heijerman HGM

Abstract
AIM: To explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV1 or BMI response, using systematically collected real-life clinical data.
METHODS: 160 CF patients were identified who had used lumacaftor/ivacaftor for at least six months. Of these patients, age, sweat chloride levels, ppFEV1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations.
RESULTS: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m2, 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV1 change or BMI change at 6 months after start of therapy.
CONCLUSION: Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor. Sweat chloride response does not correlate with the responses in ppFEV1 and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments, and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators.

PMID: 32448708 [PubMed - as supplied by publisher]

The psycho-social effects of COVID-19 on Italian adolescents' attitudes and behaviors.

Ital J Pediatr. 2020 May 24;46(1):69

Authors: Buzzi C, Tucci M, Ciprandi R, Brambilla I, Caimmi S, Ciprandi G, Marseglia GL

Abstract
BACKGROUND: COVID-19 is an emerging issue that has significant consequences on psycho-social well-being.
METHODS: In this regard, a survey was conducted on a large group of adolescents in Italy. The survey investigated four items: concerns and fears, information on the pandemic, provisions of public authorities (e.g., lockdown), and impact on everyday life.
RESULTS: Adolescents actively participated in the survey. COVID-19 affected emotions and lifestyle. COVID-19 influenced relationships with peers and parents. There were regional differences.
CONCLUSIONS: The current research highlighted the remarkable, healthy, and certainly unexpected, emotional balance of the new generations in the face of a sudden, unpredictable phenomenon capable of jeopardizing life itself. While understanding the gravity of the phenomenon and willingly adapting to all the necessary precautions, the adolescents still seemed to express an excellent ability to manage situations of insecurity and to deal with unfavorable and adverse conditions by adapting to the new routine and finding alternative and innovative means of meeting their social and psychological needs.

PMID: 32448323 [PubMed - in process]

Italian pediatric respiratory society recommendations on pediatric pulmonary function testing during COVID-19 pandemic.

Ital J Pediatr. 2020 May 24;46(1):68

Authors: Bignamini E, Cazzato S, Cutrera R, Ferrante G, La Grutta S, Licari A, Lombardi E, Midulla F, Piacentini G, Pifferi M, Santamaria F, Tancredi G, Turchetta A, Italian Pediatric Respiratory Society (IPRS) Committee Members

Abstract
BACKGROUND: Effective prevention and control strategies are mandatory to prevent SARS-CoV-2 infection.
MAIN TEXT: The Italian Pediatric Respiratory Society promotes a series of new recommendations that should be followed in pulmonary function testing laboratories during the COVID-19 pandemic.
CONCLUSION: Pulmonary function testing should be performed in children with chronic lung disease only if it is needed to guide management and limited to the necessary tests, namely spirometry. When performed, strict infection control measures should be followed due to the potential risk of transmitting SARS-CoV-2.

PMID: 32448282 [PubMed - in process]

The Aspergillus fumigatus secretome alters the proteome of Pseudomonas aeruginosa to stimulate bacterial growth: implications for co-infection .

Mol Cell Proteomics. 2020 May 23;:

Authors: Margalit A, Carolan JC, Shehan D, Kavanagh K

Abstract
Individuals with cystic fibrosis are susceptible to co-infection by Aspergillus fumigatus and Pseudomonas aeruginosa. Despite the persistence of A.  fumigatus in the cystic fibrosis lung P. aeruginosa eventually predominates as the primary pathogen. Several factors are likely to facilitate P. aeruginosa colonization in the airways, including alterations to the microbial environment. The cystic fibrosis airways are hypoxic, nitrate-rich environment, and the sputum has higher amino acid concentrations than normal. In this study, significant growth proliferation was observed in P. aeruginosa when the bacteria were exposed to A. fumigatus culture filtrates (CuF) containing a high nitrate content. Proteomic analysis of the A. fumigatus CuF identified a significant number of environment-altering proteases and peptidases. The molecular mechanisms promoting bacterial growth were investigated using Label-free quantitative (LFQ) proteomics to compare the proteome of P. aeruginosa grown in the A. fumigatus CuF and in CuF produced by a P. aeruginosa-A. fumigatus Co-culture, to that cultured in P. aeruginosa CuF. LFQ proteomics revealed distinct changes in the proteome of P. aeruginosa when cultured in the different CuF, including increases in the levels of proteins involved in denitrification, stress response, replication, amino acid metabolism and efflux pumps, and a downregulation of pathways involving ABC transporters. These findings offer novel insights into the complex dynamics that exist between P. aeruginosa and A. fumigatus. Understanding the molecular strategies that enable P. aeruginosa to predominate in an environment where A. fumigatus exists is important in the context of therapeutic development to target this pathogen.

PMID: 32447284 [PubMed - as supplied by publisher]

NICE guidance on diagnosis and management of cystic fibrosis.

Arch Dis Child Educ Pract Ed. 2020 May 23;:

Authors: Dayasiri K, Hull J, Rao S

PMID: 32447278 [PubMed - as supplied by publisher]

A systematic review of the effect of delayed appropriate antibiotic treatment on the outcomes of patients with severe bacterial infections.

Chest. 2020 May 21;:

Authors: Zasowski EJ, Bassetti M, Blasi F, Goossens H, Rello J, Sotgiu G, Tavoschi L, Arber MR, McCool R, Patterson JV, Longshaw CM, Lopes S, Manissero D, Nguyen ST, Tone K, Aliberti S

Abstract
BACKGROUND: Patients with severe bacterial infections often experience delay in receiving appropriate treatment. Consolidated evidence of the impact of delayed appropriate treatment is needed to guide treatment and improve outcomes.
RESEARCH QUESTION: What is the impact of delayed appropriate antibacterial therapy on clinical outcomes in patients with severe bacterial infections.
STUDY DESIGN: and Methods.Literature searches of MEDLINE and Embase, conducted on 24 July 2018, identified studies published after 2007 reporting the impact of delayed appropriate therapy on clinical outcomes for hospitalised adult patients with bacterial infections. Where appropriate, results were pooled and analysed with delayed therapy modeled three ways: delay versus no delay in receiving appropriate therapy; duration of delay; and inappropriate versus appropriate initial therapy. This paper reports meta-analyses on the effect of delay and duration of delay.
RESULTS: The eligibility criteria were met by 145 studies, of which 37 contributed data to analyses of effect of delay. Mortality was significantly lower in patients receiving appropriate therapy without delay compared with those experiencing delay (odds ratio [OR] 0.57 [95% CI, 0.45-0.72]). Mortality was also lower in the no delay group compared to the delay group in subgroups of studies reporting mortality at 20-30 days, during intensive care unit stay or in patients with bacteraemia (OR 0.57 [95% CI, 0.43-0.76]; OR 0.47 [95% CI, 0.27-0.80]; and OR 0.54 [95% CI, 0.40-0.75]). No difference was found in time to appropriate therapy between those who died and those who survived (P = .09), but heterogeneity between studies was high.
INTERPRETATION: Avoiding delayed appropriate therapy is essential to reduce mortality in patients with severe bacterial infections.

PMID: 32446623 [PubMed - as supplied by publisher]

Distal Intestinal Obstruction Syndrome resolved by dissolution with Coca-Cola® via colonoscopy in a cystic fibrosis patient.

J Cyst Fibros. 2020 May 20;:

Authors: Ferre-Aracil C, González-Haba M, Tormo-Lanseros B, Giménez-Alvira L, Jiménez-Garrido M

Abstract
We report the case of a 37 years old woman who presented to emergency department because of a 3 days history of abdominal disconfort and distension. After physical examination and a CT scan of the abdomen she was diagnosed of Distal Intestinal Obstruction Syndrome (DIOS) in the context of her underlying cystic fibrosis. Conservative management was attempted with no improvement. A colonoscopy was performed and thick solid feces were seen filling the cecum and right colon. An attempt to dissolve the impacted stool was made by instilling one liter of Diet Coca-Cola® through the working channel of the colonoscope. After that, the condition of the resolved in the following 24 h with no more interventions.

PMID: 32446590 [PubMed - as supplied by publisher]

50 Years Ago in TheJournalofPediatrics: Massive Hemoptysis in Patients with Cystic Fibrosis: When the Problem Is Solved with Prevention.

J Pediatr. 2020 Jun;221:131

Authors: Russi A

PMID: 32446471 [PubMed - as supplied by publisher]

Working towards consensus in the management of pediatric chronic rhinosinusitis in cystic fibrosis.

Int J Pediatr Otorhinolaryngol. 2020 May 05;135:110047

Authors: Jayawardena ADL, Fracchia MS, Bartley BL, Yonker LM, Lapey A, Virgin F, Hartnick CJ

Abstract
OBJECTIVE: The prevalence of chronic rhinosinusitis (CRS), defined by mucosal thickening on imaging, approaches 100% in the cystic fibrosis (CF) population. CRS is associated with significant morbidity in CF, including its ability to trigger pulmonary exacerbations. CRS in CF is typically managed by pediatricians, otolaryngologists and pulmonologists. This survey evaluates the variance in practice patterns of CRS in CF amongst specialists.
METHODS: This is a cross-sectional, electronic survey in which maximum variation purposive sampling was used by a multi-disciplinary group of pediatric, otolaryngology and pulmonology providers in order to select a survey population with expertise in CRS in CF patients. The survey was distributed to 381 practitioners from September to October 2019.
RESULTS: 175 participants responded (45% response rate). Ten (of 54) statements achieved 75% consensus agreement. Consensus statements included: The decision to pursue surgical intervention for CRS in CF is a multi-disciplinary approach (94%; n = 146); maximal medical management should include nasal saline irrigation (93%; n = 142), topical steroids (75%; n = 117), maximal medical management should not include intravenous steroids (79%; n = 122); image guidance in surgery is necessary for all surgery involving the frontal sinuses (77%; n = 43), and all revision surgery(80%, n = 45); the appropriate setting for sinus surgery in a CF patient varies depending on patient presentation (89%; n = 133); post-operative regimen should include nasal saline (93%; n = 137); but does depend on the severity of disease discovered intra-operatively (84%; n = 124); post-operative antibiotics should be guided by intra-operative culture data (82%; n = 121).
CONCLUSIONS: There is a great deal of variation amongst specialists in the treatment of CRS in CF, however 10 statements met consensus criteria and should be considered when forming clinical care guidelines in this population.

PMID: 32446041 [PubMed - as supplied by publisher]

An observational study of the lung clearance index throughout childhood in cystic fibrosis: Early years matter.

Eur Respir J. 2020 May 22;:

Authors: Davies G, Stanojevic S, Raywood E, Duncan JA, Stocks J, Lum S, Bush A, Viviani L, Wade A, Calder A, Owens CM, Goubau C, Carr SB, Bossley CJ, Pao C, Aurora P, London Cystic Fibrosis Collaboration

PMID: 32444409 [PubMed - as supplied by publisher]

Overcoming Immunological Challenges to Helper-Dependent Adenoviral Vector-Mediated Long-Term CFTR Expression in Mouse Airways.

Genes (Basel). 2020 May 18;11(5):

Authors: Cao H, Duan R, Hu J

Abstract
Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and CF patients require life-long treatment. Although CFTR modulators show a great potential for treating most CF patients, some individuals may not tolerate the treatment. In addition, there is no effective therapy for patients with some rare CFTR mutations, such as class I CF mutations, which lead to a lack of CFTR protein production. Therefore, other therapeutic strategies, such as gene therapy, have to be investigated. Currently, immune responses to gene therapy vectors and transgene products are a major obstacle to applying CF gene therapy to clinical applications. In this study, we examined the effects of cyclophosphamide on the modulation of host immune responses and for the improvement of the CFTR transgene expression in the repeated delivery of helper-dependent adenoviral (HD-Ad) vectors to mouse lungs. We have found that cyclophosphamide significantly decreased the expression of T cell genes, such as CD3 (cluster of differentiation 3) and CD4, and reduced their infiltration into mouse lung tissues. We have also found that the levels of the anti-adenoviral antibody and neutralizing activity as well as B-cell infiltration into the mouse lung tissues were significantly reduced with this treatment. Correspondingly, the expression of the human CFTR transgene has been significantly improved with cyclophosphamide administration compared to the group with no treatment. These data suggest that the sustained expression of the human CFTR transgene in mouse lungs through repeated vector delivery can be achieved by transient immunosuppression.

PMID: 32443586 [PubMed - as supplied by publisher]

Antifungal Activity of Antimicrobial Peptides and Proteins against Aspergillus fumigatus.

J Fungi (Basel). 2020 May 18;6(2):

Authors: Ballard E, Yucel R, Melchers WJG, Brown AJP, Verweij PE, Warris A

Abstract
Antimicrobial peptides and proteins (AMPs) provide an important line of defence against invading microorganisms. However, the activity of AMPs against the human fungal pathogen Aspergillus fumigatus remains poorly understood. Therefore, the aim of this study was to characterise the anti-Aspergillus activity of specific human AMPs, and to determine whether A. fumigatus can possess resistance to specific AMPs, as a result of in-host adaptation. AMPs were tested against a wide range of clinical isolates of various origins (including cystic fibrosis patients, as well as patients with chronic and acute aspergillosis). We also tested a series of isogenic A. fumigatus isolates obtained from a single patient over a period of 2 years. A range of environmental isolates, obtained from soil in Scotland, was also included. Firstly, the activity of specific peptides was assessed against hyphae using a measure of fungal metabolic activity. Secondly, the activity of specific peptides was assessed against germinating conidia, using imaging flow cytometry as a measure of hyphal growth. We showed that lysozyme and histones inhibited hyphal metabolic activity in all the A. fumigatus isolates tested in a dose-dependent fashion. In addition, imaging flow cytometry revealed that histones, β-defensin-1 and lactoferrin inhibited the germination of A. fumigatus conidia.

PMID: 32443413 [PubMed - as supplied by publisher]

Effectivity of Pancreatic Enzyme Replacement Therapy in Malnourished Children.

J Pediatr Gastroenterol Nutr. 2020 Jun;70(6):e114-e118

Authors: Güven B, Demir Mis M, Karaman K, Şahin Yaşar A

Abstract
OBJECTIVE: Malnutrition is commonly seen in children with exocrine pancreatic insufficiency (EPI). Pancreatic enzyme replacement therapy (PERT) is the mainstay treatment of acute malnutrition in children detected with a disease closely associated with EPI (eg, cystic fibrosis). The effectiveness of PERT in children with malnutrition without any chronic disease, however, remains unclear. The aim of this study was to investigate the effectiveness of PERT on weight gain and EPI in children classified as moderately and severely malnourished according to the World Health Organization (WHO) classification.
MATERIALS AND METHODS: The study included a total of 40 children aged 2-16 years who were classified as moderately and severely malnourished according to the WHO classification. The patients were randomly divided into 2 groups: PERT group (n = 20) received 2000 U lipase/kg/day (in 4 doses) in addition to hypercaloric enteral supplements and control group received hypercaloric enteral supplements only. In both groups, anthropometric measurements and the assessment of fecal elastase-1 (FE-1) levels were performed both at first admission and at the end of the 8-week treatment period.
RESULTS: On the basis of WHO classification, 10 (25%) children were classified as severely malnourished and 30 (75%) children as moderately malnourished. EPI was detected in all the patients, among whom 24 (60%) patients had severe EPI. At the end of the treatment, body weight, height, and body mass index (BMI) increased significantly in both groups compared to their pre-treatment values, whereas no significant difference was found with regard to waist circumference (WC) and FE-1 levels. Similarly, no significant difference was found between pre- and posttreatment measurements of PERT and control groups (P > 0.05) and between pre- and posttreatment measurements of patients with moderate and severe malnutrition (P > 0.05).
CONCLUSIONS: Malnutrition remains a serious public health problem, and thus, the development of novel treatment methods is highly essential. PERT is one of the most commonly considered alternatives, although there is little documentation of PERT in the literature. In the present study, although PERT resulted in higher weight gain, it established no significant difference between the 2 groups.

PMID: 32443036 [PubMed - as supplied by publisher]

Cystic Fibrosis-related Liver Disease is Associated With Increased Disease Burden and Endocrine Comorbidities.

J Pediatr Gastroenterol Nutr. 2020 Jun;70(6):796-800

Authors: Singh H, Coffey MJ, Ooi CY

Abstract
BACKGROUND: Cystic fibrosis-related liver disease (CFLD) is the leading nonpulmonary cause of mortality in cystic fibrosis (CF). We evaluated and compared the burden of disease and nonrespiratory comorbidities of those with severe CFLD and those without (noCFLD).
METHODS: A retrospective nationwide (Australia) longitudinal review (from 1998 to 2016) of severe CFLD patients compared with noCFLD controls (matched 1 : 1 for age, genotype, pancreatic insufficiency, and center).
RESULTS: One hundred sixty-six patients with severe CFLD and 166 with noCFLD were identified. Forced expiratory volume in 1 second percentage of predicted (FEV1%) was significantly lower in CFLD than noCFLD across all ages (estimate [SE] -6.05% [2.12]; P = 0.004). Median (IQR) hospitalizations per patient per year were higher in CFLD than noCFLD for: respiratory indications (0.6 [0.2-1.3] vs 0.4 [0.1-0.9]; P = 0.002); gastrointestinal indications (0.09 [0-0.2] vs 0 [0-0.05]; P < 0.001); and other indications (0.05 [0-0.2] vs 0 [0-0.1]; P = 0.03). In the CFLD cohort, there was increased use of nasogastric (12.6% vs 5.4%; OR 2.51 [95% CI 1.06-6.46]; P = 0.03) and gastrostomy nutritional supplementation (22.9% vs 13.2%; OR 1.93 [95% CI 1.05-3.63]; P = 0.03). Additionally, the CFLD cohort had a higher frequency of bone diseases, osteopenia (26.5% vs 16.8%; OR 1.77 [95%CI 1.01-3.15]; P = 0.04) and osteoporosis (16.2% vs 8.4%; OR 2.1 [95% CI 1.01-4.52]; P = 0.04), as well as CF-related diabetes (38.5% vs 19.2%; OR 2.61 [95% CI 1.55-4.47]; P = 0.001).
CONCLUSIONS: Patients with severe CFLD have greater disease burden, with higher number of hospitalizations (both respiratory and nonrespiratory indications), nutritional interventions, and are at higher risk of CF-related bone disease and diabetes.

PMID: 32443033 [PubMed - as supplied by publisher]

Clinical characteristics of rare CFTR mutations causing cystic fibrosis in Polish population.

Pediatr Pulmonol. 2020 May 22;:

Authors: Zybert K, Wozniacki L, Tomaszewska-Sobczyńska A, Wertheim-Tysarowska K, Czerska K, Ołtarzewski M, Sands D

Abstract
INTRODUCTION: More than 2000 mutations have been identified since the discovery of the CFTR gene in 1989. However, only 346 mutations have been classified as cystic fibrosis (CF)-causing mutations. Due to the increasing number of mutations and poor correlation between the genotype and phenotype, there is an urgent need to determine the mutations that are pathogenic, nonpathogenic, or lead to variable symptoms.
AIM: The aim of the study was to present the clinical characteristics of Polish patients with rare and novel CFTR mutations, with an attempt to determine the pathogenicity status of those variants.
MATERIALS AND METHODS: The group included 13 patients born between September 2006 and May 2019, who underwent CF newborn screening and in whom two CFTR mutations, including at least one rare or a novel mutation, were identified.
RESULTS: We identified 13 patients with mutations in both alleles of the CFTR gene, one of which was at least rare in Polish population (R289NfsX17, I618RfsX2, T682KfsX40, S1347PfsX13, W356X, E33X, dup.16,17A) or was a mutation of unknown clinical consequences (H199R, L468P, A1217E, Q359R, T1036I, W1282R). None of them were described in the CFTR2 database. In all examined patients, sweat tests were elevated. The diagnosed patients presented with a wide spectrum of clinical symptoms. Broad clinical characteristics and test results are presented.
CONCLUSION: Pathogenic mutations are H199R, L468P, A1217E, Q359R, T1036I, W1282R, R289NfsX17, I618RfsX2, T682KfsX40, S1347PfsX13, W356X, E33X, dup.16,17A. Every patient with a mutation of unknown clinical consequences in one CFTR allele requires attentive follow-up.

PMID: 32442342 [PubMed - as supplied by publisher]

The intestinal virome in children with cystic fibrosis differs from healthy controls.

PLoS One. 2020;15(5):e0233557

Authors: Coffey MJ, Low I, Stelzer-Braid S, Wemheuer B, Garg M, Thomas T, Jaffe A, Rawlinson WD, Ooi CY

Abstract
Intestinal bacterial dysbiosis is evident in children with cystic fibrosis (CF) and intestinal viruses may be contributory, given their influence on bacterial species diversity and biochemical cycles. We performed a prospective, case-control study on children with CF and age and gender matched healthy controls (HC), to investigate the composition and function of intestinal viral communities. Stool samples were enriched for viral DNA and RNA by viral extraction, random amplification and purification before sequencing (Illumina MiSeq). Taxonomic assignment of viruses was performed using Vipie. Functional annotation was performed using Virsorter. Inflammation was measured by calprotectin and M2-pyruvate kinase (M2-PK). Eight CF and eight HC subjects were included (50% male, mean age 6.9 ± 3.0 and 6.4 ± 5.3 years, respectively, p = 0.8). All CF subjects were pancreatic insufficient. Regarding the intestinal virome, no difference in Shannon index between CF and HC was identified. Taxonomy-based beta-diversity (presence-absence Bray-Curtis dissimilarity) was significantly different between CF and HC (R2 = 0.12, p = 0.001). Myoviridae, Faecalibacterium phage FP Taranis and unclassified Gokushovirinae were significantly decreased in CF compared with HC (q<0.05). In children with CF (compared to HC), the relative abundance of genes annotated to (i) a peptidoglycan-binding domain of the peptidoglycan hydrolases (COG3409) was significantly increased (q<0.05) and (ii) capsid protein (F protein) (PF02305.16) was significantly decreased (q<0.05). Picornavirales, Picornaviridae, and Enterovirus were found to positively correlate with weight and BMI (r = 0.84, q = 0.01). Single-stranded DNA viruses negatively correlated with M2-PK (r = -0.86, q = 0.048). Children with CF have an altered intestinal virome compared to well-matched HC, with both taxonomic and predicted functional changes. Further exploration of Faecalibacterium phages, Gokushovirinae and phage lysins are warranted. Intestinal viruses and their functions may have important clinical implications for intestinal inflammation and growth in children with CF, potentially providing novel therapeutic targets.

PMID: 32442222 [PubMed - as supplied by publisher]

Limitations of regional ventilation inhomogeneity indices in children with cystic fibrosis.

Pediatr Pulmonol. 2020 May 22;:

Authors: Verger N, Arigliani M, Raywood E, Duncan J, Negreskul Y, Bush A, Aurora P, London Cystic Fibrosis Collaboration

Abstract
BACKGROUND: Scond is a Multiple Breath Washout (MBW) index that measures convection-dependent ventilation inhomogeneity (CDI) arising within conductive airways, but the calculation method is unreliable in subjects with advanced cystic fibrosis (CF) lung disease. A new CDI index, Scond *, has been proposed for use in adults with CF and moderate to severe ventilation inhomogeneity. We aimed to evaluate the most appropriate CDI index in children and adolescents with CF and various degrees of inhomogeneity, and from that the most appropriate diffusion-convection-interaction index (Sacin or Sacin *).
METHODS: Scond , Sacin and the alternative indices, Scond *, and Sacin * were retrospectively calculated in subjects with CF aged 3-18 years and age-matched controls, who underwent SF6 MBW between 2003-2015. The upper limit of normal (ULN) was based on 95th percentile of the control population.
RESULTS: 127 subjects with CF (44% male, mean age±SD 7.5y±4.9) and 94 controls (53% male, 7.9y±5.1) were included in the final analysis. All measures of ventilation inhomogeneity were significantly higher in children with CF. As predicted, Scond reached a maximum value at LCI values of approximately 9. In subjects with LCI≥9 Scond * showed good correlation with Lung Clearance Index (LCI), whilst Scond had no relationship with LCI (Spearman rank correlation Scond */LCI 0.49, p<0.01; Scond /LCI -0.068, p=0.46). In subjects with mild disease (LCI<9) Scond was more frequently abnormal than Scond * (37% vs 16%, p=0.01).
CONCLUSIONS: Scond and Sacin are sensitive indices of early regional inhomogeneity, but are of no value when LCI≥9. In these subjects, Scond * & Sacin * are potential alternatives. This article is protected by copyright. All rights reserved.

PMID: 32441886 [PubMed - as supplied by publisher]

The Pediatric Sinus Staging System: A Computed Tomography-Based Approach to Grading Pediatric Sinus Disease.

Laryngoscope. 2020 May 22;:

Authors: Melder K, Shaffer A, Govil N, Stapleton A

Abstract
OBJECTIVES/HYPOTHESIS: Pediatric chronic rhinosinusitis (CRS) is a prevalent disease with few objective measurements available to predict which patients will require surgical intervention. The Lund-Mackay (LM) score for computed tomography (CT) scans is one objective data point available for the adult population; however, a dedicated scoring system in the pediatric population has not been popularized. We present a Pediatric Sinus Staging System (PSSS) that considers both opacification and the varying developmental stages of each sinus.
STUDY DESIGN: Retrospective chart review.
METHODS: We analyzed CT scans of pediatric patients with a diagnosis of CRS. Both LM and PSSS scores were calculated for each scan. Groups were formed based on treatment outcomes and included patients who were treated successfully with medical therapy and/or adenoidectomy (med/adenoid), patients who required functional endoscopic sinus surgery (FESS), and patients who required revision FESS.
RESULTS: Overall, 76 patient scans were reviewed. PSSS values were significantly less than LM for the control group (P = .001) and significantly higher for patients with cystic fibrosis (P = .027) and with CRS with polyps (P = .001). The ideal cutoff for PSSS to distinguish between med/adenoid and single FESS treatment with a sensitivity 90.6% and specificity of 50.0% was ≥2.
CONCLUSIONS: The PSSS gives a more descriptive score by accounting for the opacification and pneumatization of each sinus. Our current results show similar values between PSSS and LM scores, which suggests internal validity. In addition, a PSSS score of ≥2 may help physicians better counsel families on the likelihood of requiring FESS. Further investigation is needed to fully validate the PSSS.
LEVEL OF EVIDENCE: 3b Laryngoscope, 2020.

PMID: 32441813 [PubMed - as supplied by publisher]

Correctors modify the bicarbonate permeability of F508del-CFTR.

Sci Rep. 2020 May 21;10(1):8440

Authors: Fiore M, Picco C, Moran O

Abstract
One of the most common mutations in Cystic Fibrosis (CF) patients is the deletion of the amino acid phenylalanine at position 508. This mutation causes both the protein trafficking defect and an early degradation. Over time, small molecules, called correctors, capable of increasing the amount of mutated channel in the plasma membrane and causing an increase in its transport activity have been developed. This study shows that incubating in vitro cells permanently transfected with the mutated channel with the correctors VX809, VX661 and Corr4a, and the combination of VX809 and Corr4a, a recovery of anion transport activity is observed. Interestingly, the permeability of bicarbonate increases in the cells containing corrected p.F508del CFTR channels is greater than the increase of the halide permeability. These different increases of the permeability of bicarbonate and halides are consistent with the concept that the structural conformation of the pore of the corrector-rescued p.F508del channels would be different than the normal wild type CFTR protein.

PMID: 32439937 [PubMed - in process]