Exploring the Developmental Impact of Cystic Fibrosis on Lung Transplant Candidacy: Considerations for Adulthood.

J Clin Psychol Med Settings. 2021 Jan 29;:

Authors: Powell AL, Teh L, Patel A, Chernak Y

Abstract
The average life expectancy for cystic fibrosis (CF) has increased over the past four decades resulting in a higher rate of adult CF patients. Adults seeking lung transplant to address CF-related advanced lung disease (ALD) represent a small, yet growing, subset of lung transplant recipients. Psychosocial factors such as adherence to medical recommendations, self-management of medical care, and caregiver support have been identified as positive prognostic factors in lung transplant outcomes. These factors are also implicated in the pediatric chronic illness literature and are crucial as patients begin to transition to a more autonomous and independent role in their own health management. Adults with CF facing ALD must navigate through another transitional phase as lung transplant requires additional supports and new expectations. A case series is used to highlight specific psychosocial considerations in this population and to explore the seemingly dichotomous relationship between independent self-management and caregiver support.

PMID: 33515128 [PubMed - as supplied by publisher]

Serious infectious events and ibuprofen administration in pediatrics: a narrative review in the era of COVID-19 pandemic.

Ital J Pediatr. 2021 Jan 29;47(1):20

Authors: Quaglietta L, Martinelli M, Staiano A

Abstract
PURPOSE OF REVIEW: Despite its recognized efficacy and tolerability profile, during the last decade a rise of adverse events following ibuprofen administration in children has been reported, including a possible role in worsening the clinical course of infections. Our aim was to critically evaluate the safety of ibuprofen during the course of pediatric infectious disease in order to promote its appropriate use in children.
RECENT FINDINGS: Ibuprofen is associated with severe necrotizing soft tissue infections (NSTI) during chickenpox course. Pre-hospital use of ibuprofen seems to increase the risk of complicated pneumonia in children. Conflicting data have been published in septic children, while ibuprofen in the setting of Cystic Fibrosis (CF) exacerbations is safe and efficacious. No data is yet available for ibuprofen use during COVID-19 course. Ibuprofen should not be recommended for chickenpox management. Due to possible higher risks of complicated pneumonia, we suggest caution on its use in children with respiratory symptoms. While it remains unclear whether ibuprofen may have harmful effects during systemic bacterial infection, its administration is recommended in CF course. Despite the lack of data, it is seems cautious to prefer the use of paracetamol during COVID-19 acute respiratory distress syndrome in children.

PMID: 33514404 [PubMed - as supplied by publisher]

Lung Microbiome in Cystic Fibrosis.

Life (Basel). 2021 Jan 27;11(2):

Authors: Scialo F, Amato F, Cernera G, Gelzo M, Zarrilli F, Comegna M, Pastore L, Bianco A, Castaldo G

Abstract
The defective mucociliary clearance due to CFTR malfunctioning causes predisposition to the colonization of pathogens responsible for the recurrent inflammation and rapid deterioration of lung function in patients with cystic fibrosis (CF). This has also a profound effect on the lung microbiome composition, causing a progressive reduction in its diversity, which has become a common characteristic of patients affected by CF. Although we know that the lung microbiome plays an essential role in maintaining lung physiology, our comprehension of how the microbial components interact with each other and the lung, as well as how these interactions change during the disease's course, is still at an early stage. Many challenges exist and many questions still to be answered, but there is no doubt that manipulation of the lung microbiome could help to develop better therapies for people affected by CF.

PMID: 33513903 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model.

Front Microbiol. 2020;11:620819

Authors: Cigana C, Castandet J, Sprynski N, Melessike M, Beyria L, Ranucci S, Alcalá-Franco B, Rossi A, Bragonzi A, Zalacain M, Everett M

Abstract
Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular location, its harmful degradative effects on host tissues and the immune system, and the potential to inhibit its activity using small molecule inhibitors. However, while the relevance of LasB in acute P. aeruginosa infection has been demonstrated, it is still unclear whether this elastase might also play a role in the early phase of chronic lung colonization. By analyzing clinical P. aeruginosa clonal isolates from a CF patient, we found that the isolate RP45, collected in the early phase of persistence, produces large amounts of active LasB, while its clonal variant RP73, collected after years of colonization, does not produce it. When a mouse model of persistent pneumonia was used, deletion of the lasB gene in RP45 resulted in a significant reduction in mean bacterial numbers and incidence of chronic lung colonization at Day 7 post-challenge compared to those mice infected with wild-type (wt) RP45. Furthermore, deletion of lasB in strain RP45 also resulted in an increase in immunomodulators associated with innate and adaptive immune responses in infected animals. In contrast, deletion of the lasB gene in RP73 did not affect the establishment of chronic infection. Overall, these results indicate that LasB contributes to the adaptation of P. aeruginosa to a persistent lifestyle. In addition, these findings support pharmacological inhibition of LasB as a potentially useful therapeutic intervention for P. aeruginosa-infected CF patients prior to the establishment of a chronic infection.

PMID: 33510733 [PubMed]

Screening of depression and anxiety in adolescents with cystic fibrosis and caregivers in Turkey by PHQ-9 and GAD-7 questionnaires.

Pediatr Pulmonol. 2021 Jan 29;:

Authors: Mursaloğlu HH, Yeğit CY, Ergenekon AP, Gökdemir Y, Eralp EE, Karakoç F, Nasr SZ, Karadağ BT

Abstract
BACKGROUND: Depression and anxiety symptoms in patients with cystic fibrosis (CF) and their caregivers are 2-3 times higher than in the normal population. This study aims to evaluate the frequency and severity of depression and anxiety symptoms and to determine possible risk factors in CF patients and their mother and/or fathers at Marmara University CF center.
METHODS: The study included 132 CF patients who were followed up at our CF center. Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Questionnaire (GAD-7) were used to screen depression and anxiety. The questionnaires were completed by 50 CF patients (aged 12 - 17 years) and 132 parents of patients (aged 0-17 years).
RESULTS: While moderate to severe depressive symptoms were seen in 26% of patients, 33.7% of mothers and 14.6% of fathers; moderate to severe anxiety were present in 18%, 21.8% and 8.5%, respectively. None of the demographic characteristics was identified as a predictor of depression or anxiety. GAD-7 scores have shown a higher prevalence of anxiety in mothers of patients with chronic methicillin-resistant Staphylococcus Aureus (p = 0.034). Additionally, hospitalization in the last 12 months was significantly correlated with higher PHQ-9 scores in fathers (p = 0.043). Analysis of patients' adherence to medical treatment and airway clearance showed higher depression and anxiety in mothers of the non-adherent group (p = 0.002).
CONCLUSION: Depression and anxiety were common in CF patients and their parents. These results illustrate the importance of depression/anxiety screening and psychosocial support for the CF patient and their parents. This article is protected by copyright. All rights reserved.

PMID: 33512091 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa colonization in cystic fibrosis: Impact on neutrophil functions and cytokine secretion capacity.

Pediatr Pulmonol. 2021 Jan 29;:

Authors: Aslanhan U, Cakir E, Ozyigit LP, Kucuksezer UC, Gelmez YM, Yuksel M, Deniz G, Aktas EC

Abstract
BACKGROUND: Chronic colonisation with Pseudomonas (P.) aeruginosa worsens the prognosis of cystic fibrosis (CF) patients. This study aims to analyse the functional properties of neutrophils in CF patients with P. aeruginosa colonisation.
METHODS: Patients with CF (n=16) were grouped by positivity of P. aeruginosa in sputum culture, as positive (P.+) or negative (P.-), then compared with age and sex matched healthy controls (n=8). Adhesion molecules, apoptotic index, intracellular CAP-18, interleukin (IL)-8, and TNF-α levels of neutrophils, following P. aeruginosa and lipopolysaccharides (LPS) stimulation, were analysed by flow cytometry. IL-1β, IL-6, TNF-α and IL-17 plasma levels were determined by Luminex.
RESULTS: Patients with CF had increased phagocytosis of Escherichia coli and P. aeruginosa, upregulated oxidative burst and chemotaxis. Increased neutrophil apoptosis was noted in CF patients. In unstimulated conditions, higher levels of CD16+ TNF-α+ and CD16+ IL-8+ neutrophils were determined, whereas bacteria and LPS stimulation significantly decreased secretion of CAP-18 from CD16+ neutrophils of CF patients. Plasma levels of IL-1β, TNF-α and IL-17 in P.+ patients were higher than in P.- group.
CONCLUSION: Our findings confirm inadequate neutrophil defence towards pathogens in CF. A significant difference in migration, phagocytosis, oxidative burst, percentage of IL-8 producing neutrophils, IL-1β, TNF-α and IL-17 secretions were noted among CF patients according to their colonisation status, which might induce a further destructive effect on airways, resulting in an unfavourable prognosis for children with CF who also have colonisation. This article is protected by copyright. All rights reserved.

PMID: 33512090 [PubMed - as supplied by publisher]

Outcomes of Repeat Sweat Testing in Cystic Fibrosis Newborn Screen Positive Infants.

Pediatr Pulmonol. 2021 Jan 29;:

Authors: Bauer SE, Wesson M, Oles SK, Ren CL

Abstract
BACKGROUND: Infants with a positive cystic fibrosis (CF) newborn screen, only one identified CFTR mutation (NBS+/1mut), and an initial intermediate sweat chloride (30-59 mmol/L) should have repeat sweat chloride testing (SCT). However, the outcome of repeat SCT and the relationship between initial sweat Cl and subsequent CF diagnosis have not been reported.
OBJECTIVE: The objective of this study was to analyze the outcomes of repeat SCT and subsequent CF diagnosis in NBS+/1mut infants based on their initial sweat chloride concentration.
METHODS: We retrospectively identified all infants born in Indiana from 2007 through 2017 with NBS+/1mut and initial SCT in the intermediate range. For each infant, we recorded the initial and repeat SCT results and/or a final CF diagnosis.
RESULTS: From 2007 through 2017 there were 2,822 NBS+/1mut infants of which 2,613 (82%) had at least one SCT result. No infants with an initial SCT of 30-39 mmol/L were subsequently diagnosed with CF. Of the 31 infants with an initial SCT of 40-49 mmol/L, only 1 was subsequently diagnosed with CF. In contrast, 61% of those with SCTs of 50-59 mmol/L were later diagnosed with CF.
CONCLUSION: These results suggest that infants with a positive NBS for CF and 1 CFTR mutation whose initial sweat chloride concentration is 50-59 mmol/L need to be monitored more closely for CF with strong consideration for earlier repeat SCTs and immediate genotyping. This article is protected by copyright. All rights reserved.

PMID: 33512069 [PubMed - as supplied by publisher]

Personalized approaches to bronchiectasis.

Expert Rev Respir Med. 2021 Jan 29;:

Authors: Girón Moreno RM, Martínez-Vergara A, Martínez-García MÁ

Abstract
INTRODUCTION: Interest in bronchiectasis is increasing due to its rising prevalence, associated with ageing populations and the extended use of high-resolution chest tomography (HRCT), and the resulting high morbidity, mortality and demand for resources.
AREAS COVERED: This article provides an extensive review of bronchiectasis as a complex and heterogeneous disease, as well as examining the difficulty of establishing useful clinical phenotypes. In keeping with the aims of "precision medicine", we address the disease of bronchiectasis from three specific perspectives: severity, activity and impact. We used PubMed to search the literature for articles including the following key words: personalized medicine, bronchiectasis, biomarkers, phenotypes, precision medicine, treatable traits. We reviewed the most relevant articles published over the last 5 years.
EXPERT OPINION: : This article reflects on the usefulness of these three dimensions in "control panels" and clinical fingerprinting, as well as approaches to personalized medicine and the treatable features of bronchiectasis non-cystic fibrosis.

PMID: 33511899 [PubMed - as supplied by publisher]

Bitter taste receptor agonists regulate epithelial two-pore potassium channels via cAMP signaling.

Respir Res. 2021 Jan 28;22(1):31

Authors: Kohanski MA, Brown L, Orr M, Tan LH, Adappa ND, Palmer JN, Rubenstein RC, Cohen NA

Abstract
BACKGROUND: Epithelial solitary chemosensory cell (tuft cell) bitter taste signal transduction occurs through G protein coupled receptors and calcium-dependent signaling pathways. Type II taste cells, which utilize the same bitter taste signal transduction pathways, may also utilize cyclic adenosine monophosphate (cAMP) as an independent signaling messenger in addition to calcium.
METHODS: In this work we utilized specific pharmacologic inhibitors to interrogate the short circuit current (Isc) of polarized nasal epithelial cells mounted in Ussing chambers to assess the electrophysiologic changes associated with bitter agonist (denatonium) treatment. We also assessed release of human β-defensin-2 from polarized nasal epithelial cultures following treatment with denatonium benzoate and/or potassium channel inhibitors.
RESULTS: We demonstrate that the bitter taste receptor agonist, denatonium, decreases human respiratory epithelial two-pore potassium (K2P) current in polarized nasal epithelial cells mounted in Ussing chambers. Our data further suggest that this occurs via a cAMP-dependent signaling pathway. We also demonstrate that this decrease in potassium current lowers the threshold for denatonium to stimulate human β-defensin-2 release.
CONCLUSIONS: These data thus demonstrate that, in addition to taste transducing calcium-dependent signaling, bitter taste receptor agonists can also activate cAMP-dependent respiratory epithelial signaling pathways to modulate K2P currents. Bitter-agonist regulation of potassium currents may therefore serve as a means of rapid regional epithelial signaling, and further study of these pathways may provide new insights into regulation of mucosal ionic composition and innate mechanisms of epithelial defense.

PMID: 33509163 [PubMed - in process]

Soda stream modifies airway fluid.

J Physiol. 2020 10;598(19):4143-4144

Authors: Parker MD

PMID: 33211328 [PubMed - indexed for MEDLINE]

Thrombocytosis during Stable State Predicts Mortality in Bronchiectasis.

Ann Am Thorac Soc. 2021 Jan 28;:

Authors: Aliberti S, Sotgiu G, Gramegna A, McDonnell MJ, Polverino E, Torres A, Goeminne PC, Dimakou K, Shteinberg M, Sibila O, Conio V, Fardon TC, Rutherford R, Dore S, Saderi L, Faverio P, Amati F, Corsico AG, Blasi F, Chalmers JD

Abstract
RATIONALE: Although platelets are considered key inflammatory mediators in respiratory diseases, their role in bronchiectasis has not been fully explored.
OBJECTIVES: We hypothesized that thrombocytosis in stable state may be associated with bronchiectasis severity and worse clinical outcomes.
METHODS: Bronchiectasis patients have been enrolled from 10 centers in Europe and Israel, with platelet count recorded during stable state. Primary outcome was five-year all-cause mortality. Secondary outcomes included exacerbations, hospitalizations, and mortality at one, two and three-year follow-up. Analyses were conducted using logistic regression after adjustment for confounding variables.
RESULTS: Among the 1,771 patients (median age: 67 years; 63.4% females) included, 136 (7.7%) had thrombocytosis. Patients with thrombocytosis had a significant higher disease severity, worse quality of life, higher number of exacerbations and hospitalizations, and higher mortality rate at both three-year (23 [22.8%] vs. 83 [8.5%], respectively; p-value <0.01) and five-year (26 [35.1%] vs. 116 [15.9%], respectively; p-value <0.01) in comparison with those with normal platelet count. Thrombocytosis was significantly associated with hospitalizations due to severe exacerbations [OR (95% CI): 1.83 (1.20-2.79); p-value: 0.01] after one-year follow-up, as well as increased 3-year [OR (95% CI): 3.06 (1.74-5.39); p-value <0.01] and 5-year [OR (95% CI): 2.46 (1.39-4.37); p<0.01] mortality.
CONCLUSIONS: Platelets represent a cheap and easy to evaluate biomarker and the presence of thrombocytosis during stable state is associated with disease severity, hospitalizations due to exacerbations, poor quality of life and mortality in adults with bronchiectasis.

PMID: 33507847 [PubMed - as supplied by publisher]

[Novel therapies in respiratory management].

Rev Med Suisse. 2021 Jan 27;17(723):209-213

Authors: Schmit A, Guerreiro I, Plojoux J, Janssens JP, Adler D

Abstract
In this review of the recent medical literature, we have identified 4 topics of interest for the readers of Revue Médicale Suisse. Use of antifibrotic drugs in interstitial lung diseases will soon be extended to a phenotype labeled « progressive fibrosing interstitial lung disease » (PF-ILD). While awaiting for evidence-based treatment, consensual recommendations for a treatment algorithm in pulmonary sarcoidosis has been published. New guidance for non-invasive ventilation in COPD and obesity-hypoventilation syndrome are available in Switzerland and are in line with international recommendations. New treatments targeting CFTR protein activity have become available and could become a therapeutic option for up to 85% of cystic fibrosis patients in Switzerland.

PMID: 33507663 [PubMed - as supplied by publisher]

The effectiveness and value of novel treatments for cystic fibrosis.

J Manag Care Spec Pharm. 2021 Feb;27(2):276-280

Authors: Tice JA, Kuntz KM, Wherry K, Seidner M, Rind DM, Pearson SD

Abstract
DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Seidner, Rind, and Pearson are employed by ICER. Tice reports contracts to his institution, University of California, San Francisco, from ICER during the conduct of this study. Wherry has nothing to disclose.

PMID: 33506736 [PubMed - in process]

Cost-effectiveness of implementing routine hearing screening using a tablet audiometer for pediatric cystic fibrosis patients receiving high-dose IV aminoglycosides.

J Manag Care Spec Pharm. 2021 Feb;27(2):157-165

Authors: Huang SP, McKinzie CJ, Tak CR

Abstract
BACKGROUND: Cystic fibrosis (CF) patients who receive high-dose aminoglycosides can acquire inner ear damage and subsequent hearing loss. There is no current standard protocol for assessing ototoxicity in CF centers in the United States. OBJECTIVE: To evaluate the cost-effectiveness of a pharmacist-implemented routine hearing screening for ototoxicity among pediatric patients using a clinically validated tablet audiometer to allow for earlier detection of hearing loss in an exploratory analysis. METHODS: A Markov decision-analytic model was developed to assess the cost-effectiveness of implementing routine screening with monthly cycles over a 3-year time horizon. The model measured the difference in promptly detected hearing loss, delayed detected hearing loss, and undetected hearing loss, compared with current screening practices. Model inputs were obtained through a comprehensive literature review. Primary model outcomes included total health care costs and quality-adjusted life-years (QALYs) gained with a 3% yearly discount. One-way, two-way, and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. RESULTS: In a hypothetical cohort of 100 patients, routine screening using a tablet audiometer increased promptly detected hearing loss by 8 patients. There was an incremental gain of 3.2 QALYs at an increased cost of $333,826 compared with current screening practices. This resulted in an incremental cost-effectiveness ratio (ICER) of $103,771 per QALY. In the 1-way sensitivity analysis, the ICER ranged between $64,345 and $258,830 per QALY. CONCLUSIONS: Using a tablet audiometer for routine hearing screening appears to be a cost-effective option at a $150,000 per QALY willingness-to-pay threshold when only considering the immediate benefits gained. This analysis did not examine the long-term effects of early detection in language development for pediatric patients. DISCLOSURES: Huang reports funding from the University of North Carolina and GlaxoSmithKline Health Outcomes Fellowship. GlaxoSmithKline had no involvement in the study creation, analysis, or manuscript composition. The other authors have nothing to disclose.

PMID: 33506732 [PubMed - in process]

CFTR modulators: transformative therapies for cystic fibrosis.

J Manag Care Spec Pharm. 2021 Feb;27(2):281-284

Authors: Dwight M, Marshall B

Abstract
DISCLOSURES: No funding contributed to the writing of this commentary. Both authors are employed by the Cystic Fibrosis Foundation. The Cystic Fibrosis Foundation has entered into therapeutic development award agreements and licensing agreements to assist with the development of CFTR modulators that may result in intellectual property rights, royalties, and other forms of consideration provided to CFF. Some of these agreements are subject to confidentiality restrictions and, thus, CFF cannot comment on them.

PMID: 33506726 [PubMed - in process]

Early Diagnosis and Intervention in Cystic Fibrosis: Imagining the Unimaginable.

Front Pediatr. 2020;8:608821

Authors: Coverstone AM, Ferkol TW

Abstract
Cystic fibrosis is the most common life-shortening genetic disease affecting Caucasians, clinically manifested by fat malabsorption, poor growth and nutrition, and recurrent sinopulmonary infections. Newborn screening programs for cystic fibrosis are now implemented throughout the United States and in many nations worldwide. Early diagnosis and interventions have led to improved clinical outcomes for people with cystic fibrosis. Newer cystic fibrosis transmembrane conductance regulator potentiators and correctors with mutation-specific effects have increasingly been used in children, and these agents are revolutionizing care. Indeed, it is possible that highly effective modulator therapy used early in life could profoundly affect the trajectory of cystic fibrosis lung disease, and primary prevention may be achievable.

PMID: 33505947 [PubMed]

Overcoming Challenges to Make Bacteriophage Therapy Standard Clinical Treatment Practice for Cystic Fibrosis.

Front Microbiol. 2020;11:593988

Authors: Ng RN, Tai AS, Chang BJ, Stick SM, Kicic A

Abstract
Individuals with cystic fibrosis (CF) are given antimicrobials as prophylaxis against bacterial lung infection, which contributes to the growing emergence of multidrug resistant (MDR) pathogens isolated. Pathogens such as Pseudomonas aeruginosa that are commonly isolated from individuals with CF are armed with an arsenal of protective and virulence mechanisms, complicating eradication and treatment strategies. While translation of phage therapy into standard care for CF has been explored, challenges such as the lack of an appropriate animal model demonstrating safety in vivo exist. In this review, we have discussed and provided some insights in the use of primary airway epithelial cells to represent the mucoenvironment of the CF lungs to demonstrate safety and efficacy of phage therapy. The combination of phage therapy and antimicrobials is gaining attention and has the potential to delay the onset of MDR infections. It is evident that efforts to translate phage therapy into standard clinical practice have gained traction in the past 5 years. Ultimately, collaboration, transparency in data publications and standardized policies are needed for clinical translation.

PMID: 33505366 [PubMed]

Recognition of Diagnostic Gaps for Laboratory Diagnosis of Fungal Diseases: Expert Opinion from the Fungal Diagnostics Laboratories Consortium (FDLC).

J Clin Microbiol. 2021 Jan 27;:

Authors: Zhang SX, Babady NE, Hanson KE, Harrington AT, Larkin PMK, Leal SM, Luethy PM, Martin IW, Pancholi P, Procop GW, Riedel S, Seyedmousavi S, Sullivan KV, Walsh TJ, Lockhart SR, Fungal Diagnostics Laboratories Consortium (FDLC)

Abstract
Fungal infections are a rising threat to our immunocompromised patient population as well as other non-immunocompromised patients with various medical conditions. However, little progress has been made in the past decade to improve fungal diagnostics. To jointly address this diagnostic challenge, the Fungal Diagnostics Laboratory Consortium (FDLC) was recently created. The FDLC consists of 26 laboratories from the United States and Canada that routinely provide fungal diagnostic services for patient care. A survey of fungal diagnostic capacity among the 26 members of the FDLC was recently completed, identifying the following diagnostic gaps: lack of molecular detection of mucormycosis; lack of an optimal diagnostic algorithm incorporating fungal biomarkers and molecular tools for early and accurate diagnosis of Pneumocystis pneumonia, aspergillosis, candidemia, and endemic mycoses; lack of a standardized molecular approach to identify fungal pathogens directly in formalin-fixed paraffin-embedded tissues; lack of robust databases to enhance mold identification with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; suboptimal diagnostic approaches for mold blood cultures, tissue culture processing for Mucorales, and fungal respiratory cultures for cystic fibrosis patients; inadequate capacity for fungal point-of-care testing, to detect and identify new, emerging or under-recognized, rare or uncommon fungal pathogens, and performance of antifungal susceptibility testing. In this commentary, the FDLC delineates the most pressing unmet diagnostic needs and provides expert opinion on how to fulfill them. Most importantly, the FDLC provides a robust laboratory network to tackle these diagnostic gaps and ultimately to improve and enhance the clinical laboratory's capability to rapidly and accurately diagnose fungal infections.

PMID: 33504591 [PubMed - as supplied by publisher]

Quantitative Evaluation of CFTR Pre-mRNA Splicing Dependent on the (TG)mTn Poly-Variant Tract.

Diagnostics (Basel). 2021 Jan 25;11(2):

Authors: Sterrantino M, Fuso A, Pierandrei S, Bruno SM, Testino G, Cimino G, Angeloni A, Lucarelli M

Abstract
Genetic analysis in cystic fibrosis (CF) is a difficult task. Within the many causes of variability and uncertainty, a major determinant is poor knowledge of the functional effect of most DNA variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. In turn, knowledge of the effect of a CFTR variant has dramatic diagnostic, prognostic and, in the era of CF precision medicine, also therapeutic consequences. One of the most challenging CFTR variants is the (TG)mTn haplotype, which has variable functional effect and controversial clinical consequences. The exact quantification of the anomalous splicing of CFTR exon 10 (in the HGVS name; exon 9 in the legacy name) and, consequently, of the residual wild-type functional CFTR mRNA, should be mandatory in clinical assessment of patients with potentially pathological haplotype of this tract. Here, we present a real time-based assay for the quantification of the proportion of exon 10+/exon 10- CFTR mRNA, starting from nasal brushing. Our assay proved rapid, economic and easy to perform. Specific primers used for this assay are either disclosed or commercially available, allowing any laboratory to easily perform it. A simplified analysis of the data is provided, facilitating the interpretation of the results. This method helps to enhance the comprehension of the genotype-phenotype relationship in CF and CFTR-related disorders (CFTR-RD), crucial for the diagnosis, prognosis and personalized therapy of CF.

PMID: 33504063 [PubMed]

Extracellular vesicles promote transkingdom nutrient transfer during viral-bacterial co-infection.

Cell Rep. 2021 Jan 26;34(4):108672

Authors: Hendricks MR, Lane S, Melvin JA, Ouyang Y, Stolz DB, Williams JV, Sadovsky Y, Bomberger JM

Abstract
Extracellular vesicles (EVs) are increasingly appreciated as a mechanism of communication among cells that contribute to many physiological processes. Although EVs can promote either antiviral or proviral effects during viral infections, the role of EVs in virus-associated polymicrobial infections remains poorly defined. We report that EVs secreted from airway epithelial cells during respiratory viral infection promote secondary bacterial growth, including biofilm biogenesis, by Pseudomonas aeruginosa. Respiratory syncytial virus (RSV) increases the release of the host iron-binding protein transferrin on the extravesicular face of EVs, which interact with P. aeruginosa biofilms to transfer the nutrient iron and promote bacterial biofilm growth. Vesicular delivery of iron by transferrin more efficiently promotes P. aeruginosa biofilm growth than soluble holo-transferrin delivered alone. Our findings indicate that EVs are a nutrient source for secondary bacterial infections in the airways during viral infection and offer evidence of transkingdom communication in the setting of polymicrobial infections.

PMID: 33503419 [PubMed - as supplied by publisher]