Expression and Roles of Antimicrobial Peptides in Innate Defense of Airway Mucosa: Potential Implication in Cystic Fibrosis.

Front Immunol. 2020;11:1198

Authors: Geitani R, Moubareck CA, Xu Z, Karam Sarkis D, Touqui L

Abstract
The treatment of respiratory infections is associated with the dissemination of antibiotic resistance in the community and clinical settings. Development of new antibiotics is notoriously costly and slow; therefore, alternative strategies are needed. Antimicrobial peptides (AMPs), the central effector molecules of the immune system, are being considered as alternatives to conventional antibiotics. Most AMPs are epithelium-derived and play a key role in host defense at mucosal surfaces. They are classified on the basis of their structure and amino acid motifs. These peptides display a range of activities, including not only direct antimicrobial activity, but also immunomodulation and wound repair. In the lung, airway epithelial cells and neutrophils, in particular, contribute to AMP synthesis. The relevance of AMPs for host defense against infection has been demonstrated in animal models and is supported by observations in patient studies, showing altered expression and/or unfavorable circumstances for their action in a variety of lung diseases. Of note, AMPs are active against bacterial strains that are resistant to conventional antibiotics, including multidrug-resistant bacteria. Several strategies have been proposed to use these peptides in the treatment of infections, including direct administration of AMPs. In this review, we focus on studies related to direct bactericidal effects of AMPs and their potential clinical applications with a particular focus on cystic fibrosis.

PMID: 32695100 [PubMed - in process]

The Respiratory Microbiome in Cystic Fibrosis: Compartment Patterns and Clinical Relationships in Early Stage Disease.

Front Microbiol. 2020;11:1463

Authors: Garcia-Nuñez M, Garcia-Gonzalez M, Pomares X, Montón C, Millares L, Quero S, Prina E, Asensio O, Bosque M, Capilla S, Cuevas O, Monsó E

Abstract
We compared the bacterial microbiomes lodged in the bronchial tree, oropharynx and nose of patients with early stage cystic fibrosis (CF) not using chronic antibiotics, determining their relationships with lung function and exacerbation frequency. CF patients were enrolled in a cohort study during stability and were checked regularly over the following 9 months. Upper respiratory samples (sputum [S], oropharyngeal swab [OP] and nasal washing [N]) were collected at the first visit and every 3 months. 16S rRNA gene amplification and sequencing was performed and analyzed with QIIME. Seventeen CF patients were enrolled (16.6 SD 9.6 years). Alpha-diversity of bacterial communities between samples was significantly higher in S than in OP (Shannon index median 4.6 [IQR: 4.1-4.9] vs. 3.7 [IQR: 3-1-4.1], p = 0.003/Chao 1 richness estimator median 97.75 [IQR: 85.1-110.9] vs. 43.9 [IQR: 31.7-59.9], p = 0.003) and beta-diversity analysis also showed significant differences in the microbial composition of both respiratory compartments (Adonis test of Bray Curtis dissimilarity matrix, p = 0.001). Dominant taxa were found at baseline in five patients (29.4%), who showed lower forced expiratory volume in the first second (FEV1%, mean 74.8 [SD 19] vs. 97.2 [SD 17.8], p = 0.035, Student t test). The Staphylococcus genus had low RAs in most samples (median 0.26% [IQR 0.01-0.69%]), but patients with RA > 0.26% of Staphylococcus in bronchial secretions suffered more exacerbations during follow-up (median 2 [IQR 1-2.25] vs. 0 [0-1], p = 0.026. Mann-Whitney U test), due to S. aureus in more than a half of the cases, microorganism that often persists as bronchial colonized in these patients (9/10 [90%] vs. 2/7 [28.6%], p = 0.034, Fisher's exact test). In conclusion, the bronchial microbiome had significantly higher diversity than the microbial flora lodged in the oropharynx in early stage CF. Although the RA of the Staphylococcus genus was low in bronchial secretions and did not reach a dominance pattern, slight overrepresentations of this genus was associated with higher exacerbation frequencies in these patients.

PMID: 32695090 [PubMed]

Phase separation as a therapeutic target in tight junction-associated human diseases.

Acta Pharmacol Sin. 2020 Jul 21;:

Authors: Sun S, Zhou J

Abstract
Tight junctions (TJs) play an important role in the maintenance of epithelial and endothelial barriers. Zonula occludens (ZO) proteins are scaffolding molecules essential for the formation of TJ complexes, and abnormalities in ZO proteins have been implicated in various TJ-associated human diseases such as tumor invasion and metastasis, and barrier dysfunction. Recent studies reveal that liquid-liquid phase separation of ZO proteins drives the polymerization of TJ proteins into a continuous belt, which then recruits various proteins to form the TJ complex to regulate selective paracellular permeability and signal transduction. Herein, we describe recent advances on how ZO phase separation contributes to TJ formation and discuss the potential of phase separation as a target for the treatment of TJ-associated diseases.

PMID: 32694756 [PubMed - as supplied by publisher]

Effect of highly effective modulator treatment on sinonasal symptoms in cystic fibrosis.

J Cyst Fibros. 2020 Jul 18;:

Authors: DiMango E, Overdevest J, Keating C, Francis SF, Dansky D, Gudis D

Abstract
BACKGROUND: Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator for cystic fibrosis (CF) patients homozygous or heterozygous for F508del. Effects of the drug on sinonasal symptoms have not been studied.
METHODS: Adult participants were prospectively evaluated at baseline and after three months of treatment using validated questionnaires assessing sinonasal symptoms (SNOT-22) and CF-related quality of life (CFQ-R).
RESULTS: Forty-three participants completed the study; 23 were taking other CF transmembrane conductance (CFTR) modulators at the time of study participation. There was a significant improvement in mean SNOT-22 from 34.8 (29.4-40, 95% confidence interval) to 24.4 (19.9-29.0) (p = 0.000003) and in the Respiratory domain of the CFQR from 60.6 (57.1-64.1) to 83.3 (79.4-87.2) (p = 0.0000002), both achieving a minimal clinically important difference. Patients previously taking CFTR modulators experienced a greater benefit in sinonasal and respiratory symptoms.
CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor is associated with significant improvement in sinonasal symptoms; previous use of CFTR modulators is associated with greater benefit.

PMID: 32694034 [PubMed - as supplied by publisher]

AcrAB-TolC Inhibition by Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Restores Antibiotic Activity in Vitro and in Vivo.

ACS Infect Dis. 2019 08 09;5(8):1446-1455

Authors: Sturge CR, Felder-Scott CF, Pifer R, Pybus C, Jain R, Geller BL, Greenberg DE

Abstract
Overexpression of bacterial efflux pumps is a driver of increasing antibiotic resistance in Gram-negative pathogens. The AcrAB-TolC efflux pump has been implicated in resistance to a number of important antibiotic classes including fluoroquinolones, macrolides, and β-lactams. Antisense technology, such as peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), can be utilized to inhibit expression of efflux pumps and restore susceptibility to antibiotics. Targeting of the AcrAB-TolC components with PPMOs revealed a sequence for acrA, which was the most effective at reducing antibiotic efflux. This acrA-PPMO enhances the antimicrobial effects of the levofloxacin and azithromycin in a panel of clinical Enterobacteriaceae strains. Additionally, acrA-PPMO enhanced azithromycin in vivo in a K. pneumoniae septicemia model. PPMOs targeting the homologous resistance-nodulation-division (RND)-efflux system in P. aeruginosa, MexAB-OprM, also enhanced potency to several classes of antibiotics in a panel of strains and in a cell culture infection model. These data suggest that PPMOs can be used as an adjuvant in antibiotic therapy to increase the efficacy or extend the spectrum of useful antibiotics against a variety of Gram-negative infections.

PMID: 31119935 [PubMed - indexed for MEDLINE]

Triaging Access to Critical Care Resources in Patients with Chronic Respiratory Diseases in the Event of a Major COVID-19Surge: Key highlights from the Canadian Thoracic Society (CTS) Position Statement.

Chest. 2020 Jul 18;:

Authors: Gupta S, Batt J, Bourbeau J, Chapman KR, Gershon A, Granton J, Hambly N, Hernandez P, Kolb M, Mehta S, Mielniczuk L, Provencher S, Stephenson AL, Swiston J, Tullis DE, Vozoris NT, Wald J, Weatherald J, Bhutani M

PMID: 32693101 [PubMed - as supplied by publisher]

Advances in anion transport and supramolecular medicinal chemistry.

Chem Soc Rev. 2020 Jul 21;:

Authors: Davis JT, Gale PA, Quesada R

Abstract
Advances in anion transport by synthetic supramolecular systems are discussed in this article. Developments in the design of discrete molecular carriers for anions and supramolecular anion channels are reviewed followed by an overview of the use of these systems in biological systems as putative treatments for diseases such as cystic fibrosis and cancer.

PMID: 32692794 [PubMed - as supplied by publisher]

Rats Race to Keep Pace in the Growing CF Model Space.

Am J Respir Crit Care Med. 2020 Jul 21;:

Authors: Hisert KB

PMID: 32692578 [PubMed - as supplied by publisher]

A functional genomics approach to investigate the differentiation of iPSCs into lung epithelium at air-liquid interface.

J Cell Mol Med. 2020 Jul 21;:

Authors: Kerschner JL, Paranjapye A, Yin S, Skander DL, Bebek G, Leir SH, Harris A

Abstract
The availability of robust protocols to differentiate induced pluripotent stem cells (iPSCs) into many human cell lineages has transformed research into the origins of human disease. The efficacy of differentiating iPSCs into specific cellular models is influenced by many factors including both intrinsic and extrinsic features. Among the most challenging models is the generation of human bronchial epithelium at air-liquid interface (HBE-ALI), which is the gold standard for many studies of respiratory diseases including cystic fibrosis. Here, we perform open chromatin mapping by ATAC-seq and transcriptomics by RNA-seq in parallel, to define the functional genomics of key stages of the iPSC to HBE-ALI differentiation. Within open chromatin peaks, the overrepresented motifs include the architectural protein CTCF at all stages, while motifs for the FOXA pioneer and GATA factor families are seen more often at early stages, and those regulating key airway epithelial functions, such as EHF, are limited to later stages. The RNA-seq data illustrate dynamic pathways during the iPSC to HBE-ALI differentiation, and also the marked functional divergence of different iPSC lines at the ALI stages of differentiation. Moreover, a comparison of iPSC-derived and lung donor-derived HBE-ALI cultures reveals substantial differences between these models.

PMID: 32692488 [PubMed - as supplied by publisher]

Inhaled Liposomal Antimicrobial Delivery in Lung Infections.

Drugs. 2020 Jul 20;:

Authors: Bassetti M, Vena A, Russo A, Peghin M

Abstract
The management of difficult-to-treat acute and chronic respiratory infections (infections in cystic fibrosis, non-cystic fibrosis bronchiectasis, immunocompromised and mechanically ventilated patients) and difficult-to-treat pathogens (including multidrug-resistant strains) has become a challenge in clinical practice. The arsenal of conventional antibiotic drugs can be limited by tissue penetration, toxicities, or increasing antibiotic resistance. Inhaled antimicrobials are an interesting therapeutic approach for optimizing the management of respiratory infections. Due to extensive developments in liposome technology, a number of inhaled liposome-based antibiotic and antifungal formulations are available for human use and many products are undergoing clinical trials. Liposomes are biocompatible, biodegradable, and nontoxic vesicles able to encapsulate and carry antimicrobials, enhancing the therapeutic index of various agents and retention at the desired target within the lung. Liposomes reduce drug toxicity and improve tolerability, leading to better compliance and to decreased respiratory side effects. The aim of this article was to provide an up-to-date overview of nebulized liposomal antimicrobials for lung infections (with a special focus on liposomal amikacin, tobramycin, ciprofloxacin, and amphotericin B for inhalation), discussing the feasibility and therapeutic potential of these new strategies of preventing and treating bacteria, mycobacterial and fungal infections.

PMID: 32691293 [PubMed - as supplied by publisher]

Sweat chloride assay by inductively coupled plasma mass spectrometry: a confirmation test for cystic fibrosis diagnosis.

Anal Bioanal Chem. 2020 Jul 21;:

Authors: Marvelli A, Campi B, Mergni G, Di Cicco ME, Turini P, Scardina P, Zucchi R, Pifferi M, Taccetti G, Paolicchi A, la Marca G, Saba A

Abstract
The current guidelines for sweat chloride analysis identify the procedures for sweat collection, but not for chloride assay, which is usually performed by methods originally not aiming at the low concentrations of chloride found in sweat. To overcome this limitation, we set up, characterized, and adopted an original inductively coupled plasma mass spectrometry (ICP-MS) method for sweat chloride determination, which was designed for its easy use in a clinical laboratory. The method was linear in the range 8.5E-3 to 272.0E-3 mM, precision exhibited a relative standard deviation < 6%, and accuracy was in the range 99.7-103.8%. Limit of blank, limit of detection, and limit of quantitation were 2.1 mM, 3.2 mM, and 7.0 mM, respectively, which correspond to real concentrations injected into the mass spectrometer of 3.9E-3 mM for LOD and 8.5E-3 mM for LOQ. At first, the method was tested on 50 healthy volunteers who exhibited a mean chloride concentration of 15.7 mM (25-75th percentile 10.1-19.3 mM, range 2.8-37.4 mM); then, it was used to investigate two patients with suspected cystic fibrosis, who exhibited sweat chloride values of 65.6 mM and 81.2 mM, respectively. Moreover, the method was cross-validated by assaying 50 samples with chloride concentration values in the range 10-131 mM, by both ICP-MS and coulometric titration, which is the technology officially used in Tuscany for cystic fibrosis newborn screening. The reference analytical performances and the relatively low cost of ICP-MS, accompanied by the advantageous cost of a single sweat chloride assay, make this technology the best candidate to provide a top reference method for the quantification of chloride in sweat. The method that we propose was optimized and validated for sweat samples ≥ 75 mg, which is the minimum amount requested by the international protocols. However, the method sensitivity and, in addition, the possibility to reduce the sample dilution factor, make possible the quantification of chloride even in samples weighting < 75 mg that are discarded according to the current guidelines. Graphical abstract.

PMID: 32691087 [PubMed - as supplied by publisher]

Identification of the P. aeruginosa O17 and O15 O-Specific Antigen Biosynthesis Loci Reveals an ABC Transporter-Dependent Synthesis Pathway and Mechanisms of Genetic Diversity.

J Bacteriol. 2020 Jul 20;:

Authors: Huszczynski SM, Hao Y, Lam JS, Khursigara CM

Abstract
Many bacterial cell surface glycans, such as the O antigen component of lipopolysaccharide (LPS), are produced via the so-called Wzx/Wzy- or ABC-transporter-dependent pathways. O antigens are highly diverse polysaccharides that protect bacteria from their environment and engage in important host-pathogen interactions. The specific structure and composition of O antigens is the basis of classifying bacteria into O serotypes. In the opportunistic pathogen Pseudomonas aeruginosa, there are currently 20 known O-specific antigen (OSA) structures. The clusters of genes responsible for 18 of these O antigens have been identified, all of which follow the Wzx/Wzy-dependent pathway and are encoded at a common locus. In this study, we located the two unidentified O antigen biosynthesis clusters responsible for the synthesis of the O15 and the O17 OSA structures by analyzing published whole genome sequence data. Intriguingly, these clusters were found outside of the conserved OSA biosynthesis locus and were likely acquired through multiple horizontal gene transfer events. Based on data from knockout and overexpression studies, we determined that synthesis of these O antigens follows an ABC transporter-dependent rather than a Wzx/Wzy-dependent pathway. In addition, we collected evidence to show that the O15 and O17 polysaccharide chain lengths are regulated by molecular rulers with distinct and variable domain architectures. The findings in this report are critical to a comprehensive understanding of O antigen biosynthesis in P. aeruginosa and provide a framework for future studies.Importance: P. aeruginosa is a problematic opportunistic pathogen that causes diseases in those with compromised host defenses such as those suffering from cystic fibrosis. This bacterium produces a number of virulence factors, including a serotype-specific O antigen. Here, we identified and characterized the gene clusters that produce the O15 and O17 O antigens and show that they utilize a pathway for synthesis that is distinct from the 18 other known serotypes. We also provide evidence that these clusters have acquired mutations in specific biosynthesis genes and have undergone extensive horizontal gene transfer within the P. aeruginosa population. These findings expand on our understanding of O antigen biosynthesis in Gram negative bacteria and the mechanisms that drive O antigen diversity.

PMID: 32690555 [PubMed - as supplied by publisher]

Aspiration risk factors, microbiology and empiric antibiotics for patients hospitalized with community-acquired pneumonia.

Chest. 2020 Jul 17;:

Authors: Marin-Corral J, Pascual-Guardia S, Francesco A, Aliberti S, Masclans JR, Soni N, Rodriguez A, Sibila O, Sanz F, Sotgiu G, Anzueto A, Dimakou K, Petrino R, van de Garde E, Restrepo MI, GLIMP investigators

Abstract
BACKGROUND: Aspiration community-acquired pneumonia (ACAP) and community-acquired pneumonia (CAP) in patients with aspiration risk factors (AspRFs) are infections associated with anaerobes, but limited evidence suggests their pathogenic role.
RESEARCH QUESTION: What are the aspiration risk factors, microbiology patterns, and empiric anti-anaerobic use in patients hospitalized with CAP?
STUDY DESIGN AND METHODS: This is a secondary analysis of GLIMP, an international, multicenter, point-prevalence study of adults hospitalized with CAP. Patients were stratified into three groups: 1) ACAP, 2) CAP/AspRF+ (CAP with AspRF) and 3) CAP/AspRF- (CAP without AspRF). Data on demographics, comorbidities, microbiological results, and anti-anaerobic antibiotics were analyzed in all groups. Patients were further stratified in severe and non-severe CAP groups.
RESULTS: We enrolled 2,606 patients with CAP, of which 193 (7.4%) had ACAP. Risk factors independently associated with ACAP were male, bedridden, underweight, a nursing home resident, and having a history of stroke, dementia, mental illness, and enteral tube feeding. Among non-ACAP patients, 1,709 (70.8%) had CAP/AspRF+ and 704 (29.2%) had CAP/AspRF-. Microbiology patterns including anaerobes were similar between CAP/AspRF-, CAP/AspRF+ and ACAP (0.0% vs. 1.03% vs. 1.64%). Patients with severe ACAP had higher rates of total Gram-negative bacteria (64.3% vs. 44.3% vs. 33.3%, p=0.021) and lower rates of total Gram-positive bacteria (7.1% vs. 38.1% vs. 50.0%, p<0.001) when compared to patients with severe CAP/AspRF+ and severe CAP/AspRF-, respectively. The majority of the patients (>50% in all groups) independent of AspRFs or ACAP received specific or broad-spectrum anti-anaerobic coverage antibiotics.
INTERPRETATION: Hospitalized patients with ACAP or CAP/AspRF+ had similar anaerobic flora compared to patients without aspiration risk factors. Gram-negative bacteria were more prevalent in patients with severe ACAP. Despite having similar microbiological flora between groups, a large proportion of CAP patients received anti-anaerobic antibiotic coverage.

PMID: 32687909 [PubMed - as supplied by publisher]

Mutations of the CFTR gene and novel variants in Turkish patients with cystic fibrosis: 24-years experience.

Clin Chim Acta. 2020 Jul 17;:

Authors: Dayangaç Erden D, Atalay M, Emiralioğlu N, Hızal M, Polat S, Özçelik U, Yalçın E, Doğru D, Yılmaz E, Kiper N

Abstract
BACKGROUND: Cystic fibrosis, the most prevalent autosomal recessive genetic disease, is caused by mutations in the CFTR gene. The spectrum and frequency of CFTR mutations in Turkish patients show heterogeneity.
METHODS: We investigated CFTR gene mutations in samples from 604 cystic fibrosis patients diagnosed at Hacettepe University, the largest referral CF center in Turkey, by different techniques such as strip assay and direct sequencing. We also analyzed the effects of novel variants and predicted pathogenicity by integrating information from different insilico tools.
RESULTS: We showed that mutation detection rate increased to 76.7% with direct sequencing of the coding region and exon/intron boundaries. Ten variants were described for the first time. All variants except T788R were reported as pathogenic.
CONCLUSION: Characterization of patients with CFTR mutations that occur at very low frequencies is necessary for mutation-based treatments. Population specific genetic screening panels should be designed since none of them are suitable for Turkish patients due to heterogeneous mutation distribution. The preliminary data obtained from in silico results of novel variants will pave the way for functional analysis by using samples obtained from patients. These observations will facilitate the discovery and development of new targeted and personalized therapies.

PMID: 32687833 [PubMed - as supplied by publisher]

An Overview of the Treatment of Less Common Non-Lactose Fermenting Gram Negative Bacteria.

Pharmacotherapy. 2020 Jul 20;:

Authors: Spencer HK, Spitznogle SL, Borjan J, Aitken SL

Abstract
Stenotrophomnas maltophilia, Burkholderia cepacia complex, Elizabethkingia spp., Chryseobacterium spp., Achromobacter spp., and Alcaligenes spp. are less-common non-lactose fermenting bacteria that have emerged as important opportunistic pathogens. Patients at the highest risk for these infections include the immunocompromised, those with cystic fibrosis, and the critically ill. These opportunistic pathogens are frequently drug resistant through the expression of β-lactamases, multidrug efflux pumps, aminoglycoside-modifying enzymes, and target site alterations discussed in detail throughout this review. As a result, treatment is extremely challenging. For each pathogen, this review will examine the epidemiology, mechanisms of resistance, and in vitro and in vivo data including that for novel β-lactam-β-lactamase inhibitors and cefiderocol. Treatment recommendations are provided based on the available literature.

PMID: 32687670 [PubMed - as supplied by publisher]

The impact of ivacaftor on sinonasal pathology in S1251N-mediated cystic fibrosis patients.

PLoS One. 2020;15(7):e0235638

Authors: Gostelie R, Stegeman I, Berkers G, Bittermann J, Ligtenberg-van der Drift I, Kipshagen PV, de Winter-de Groot K, Speleman L

Abstract
IMPORTANCE: Sinonasal symptoms in patients suffering from cystic fibrosis can negatively influence the quality of life and sinuses can be a niche for pathogens causing infection and inflammation leading to a decrease of lung function. Ivacaftor, a potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator protein, has shown improvement in pulmonary function in cystic fibrosis patients with different forms of class III gating mutations. However, the effects of ivacaftor on sinonasal pathology have hardly been studied.
OBJECTIVE: To determine the impact of ivacaftor therapy on sinonasal pathology in patients with cystic fibrosis with an S1251N mutation.
DESIGN: Prospective observational mono-center cohort study, between June 2015 and December 2016.
SETTING: A tertiary referral center in Utrecht, The Netherlands.
PARTICIPANTS: Eight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated.
EXPOSURES: Ivacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy.
MAIN OUTCOMES AND MEASURES: Primary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment.
RESULTS: Computed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor.
CONCLUSION AND RELEVANCE: Ivacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation.

PMID: 32687499 [PubMed - as supplied by publisher]

Membrane Lipids and CFTR: The Ying/Yang of Efficient Ceramide Metabolism.

Am J Respir Crit Care Med. 2020 Jul 20;:

Authors: Bonfield TL

PMID: 32687399 [PubMed - as supplied by publisher]

Comparison of Organoid Swelling and in vivoBiomarkers of CFTR Function to Determine Effects of Lumacaftor-ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation.

Am J Respir Crit Care Med. 2020 Jul 20;:

Authors: Graeber SY, van Mourik P, Vonk AM, Kruisselbrink E, Hirtz S, van der Ent CK, Mall MA, Beekman JM

PMID: 32687398 [PubMed - as supplied by publisher]

Epidemiology and Persistence of Rhinovirus in Pediatric Lung Transplantation.

Transpl Infect Dis. 2020 Jul 19;:e13422

Authors: Ammerman E, Sweet SC, Storch GA, Buller RS, Mason S, Conrad C, Hayes D, Faro A, Goldfarb SB, Melicoff E, Schecter M, Visner G, Heeger PS, Mohanakumar T, N W, Danziger-Isakov L

Abstract
BACKGROUND: Infection with rhinovirus (HRV) occurs following pediatric lung transplantation. Prospective studies documenting frequencies, persistence, and progression of HRV in this at-risk population are lacking.
METHODS: In the Clinical Trials in Organ Transplant in Children prospective observational study, we followed 61 lung transplant recipients for 2 years. We quantified molecular subtypes of HRV in serially collected nasopharyngeal (NP) and bronchoalveolar lavage (BAL) samples and correlated them with clinical characteristics.
RESULTS: We identified 135 community acquired respiratory infections (CARV) from 397 BAL and 480 NP samples. We detected 93 HRV events in 42 (68.8%) patients, 22 of which (23.4%) were symptomatic. HRV events were contiguous with different genotypes identified in 23 cases but symptoms were not preferentially associated with any particular species. Nine (9.7%) HRV events persisted over multiple successive samples for a median of 36 days (range 18 - 408 days). Three persistent HRV were symptomatic. When we serially measured forced expiratory volume in one second (FEV1) in 23 subjects with events, we did not observe significant decreases in lung function over 12 months post-HRV.
CONCLUSION: In conjunction with our previous reports, our prospectively collected data indicate that molecularly heterogeneous HRV infections occur commonly following pediatric lung transplantation, but these infections do not negatively impact clinical outcomes.

PMID: 32686323 [PubMed - as supplied by publisher]

High-Dose Inhaled Nitric Oxide as Adjunct Therapy in Cystic Fibrosis Targeting Burkholderia multivorans.

Case Rep Pediatr. 2020;2020:1536714

Authors: Bartley BL, Gardner KJ, Spina S, Hurley BP, Campeau D, Berra L, Yonker LM, Carroll RW

Abstract
Background: Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. The gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers.
Conclusions: High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans.

PMID: 32685229 [PubMed]