Adult Care in Cystic Fibrosis.

Semin Respir Crit Care Med. 2019 Dec;40(6):857-868

Authors: Elborn JS

Abstract
Cystic fibrosis (CF) is now more common in adults than children in countries with well-developed health care systems. The number of adults continues to increase and will further increase if the new cystic fibrosis transmembrane conductance regulator (CFTR) modulators are disease modifying. Most of the complex morbidity and almost all the mortality of CF occur in adults and will increasingly follow this pattern even with new effective modulator therapies. Maintaining good quality of life including social functioning and maximizing survival for adults are the key priorities. This requires a highly knowledgeable and adaptable multidisciplinary team, which, though focused on maintaining lung health, requires an increasing range of other disciplines and specialties to maximize well-being. Changes in health care systems will require current models of care to adapt to provide care for the large number of adult patients. With increasing survival and age, many are likely to have both CF morbidities and additional diseases of aging. New models are needed for health care delivery for this expanding population with complex medical conditions.

PMID: 31887770 [PubMed - in process]

Organ Transplantation for Cystic Fibrosis.

Semin Respir Crit Care Med. 2019 Dec;40(6):842-856

Authors: Morrell MR, Kiel SC, Pilewski JM

Abstract
Cystic fibrosis (CF) remains the most common indication for lung transplantation in children and the third most common in adults and has the highest median survival posttransplant for all pretransplant diagnoses. Criteria for transplant in patients with CF vary widely among transplant centers and early referral to multiple centers may be needed to maximize opportunities for lung transplantation. Comorbidities unique to CF such as resistant and atypical pathogens like Burkholderia and Mycobacterium abscessus, and cirrhosis require special consideration for lung transplantation but should not be considered as absolute contraindications. For those patients who are listed for lung transplantation, mechanical support with extracorporeal membrane oxygenation and mechanical ventilation can be efficacious as bridges to lung transplantation in experienced centers with adequate resources. Liver and pancreas transplantations are also acceptable options for end-organ disease related to CF and can provide improvements in both quantity and quality of life.

PMID: 31887769 [PubMed - in process]

Microbiology of Cystic Fibrosis Airway Disease.

Semin Respir Crit Care Med. 2019 Dec;40(6):727-736

Authors: Blanchard AC, Waters VJ

Abstract
Although survival of individuals with cystic fibrosis (CF) has been continuously improving for the past 40 years, respiratory failure secondary to recurrent pulmonary infections remains the leading cause of mortality in this patient population. Certain pathogens such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and species of the Burkholderia cepacia complex continue to be associated with poorer clinical outcomes including accelerated lung function decline and increased mortality. In addition, other organisms such as anaerobes, viruses, and fungi are increasingly recognized as potential contributors to disease progression. Culture-independent molecular methods are also being used for diagnostic purposes and to examine the interaction of microorganisms in the CF airway. Given the importance of CF airway infections, ongoing initiatives to promote understanding of the epidemiology, clinical course, and treatment options for these infections are needed.

PMID: 31887768 [PubMed - in process]

Cystic Fibrosis: Advances in Understanding and Treatment.

Semin Respir Crit Care Med. 2019 Dec;40(6):699-700

Authors: Flume PA, Goss CH, VanDevanter D

PMID: 31887767 [PubMed - in process]

Generation and characterization of murine monoclonal antibodies against immunoreactive trypsinogen for newborn screening of cystic fibrosis.

Anal Biochem. 2019 Dec 27;:113569

Authors: García GM, García de la Rosa I, Carballo SF, Castells Martínez EM, Stable Vernier IC, Quintana Guerra JM, Pérez LH, Delfino YL, Pérez Morás PL, Infante MP, Figueredo Lago JE, González Reyes EC

Abstract
Cystic fibrosis (CF) is a multisystem disorder that reduces quality of life and survival in affected individuals. In newborns, the release of pancreatic enzymes into the blood raises the levels of immunoreactive trypsinogen (IRT), the main marker for CF screening, which is detected in dried blood samples on filter paper by immunoenzymatic assays. In Cuba, CF has an estimated incidence of 1/9862 live births and should be included in the national basic newborn screening (NBS) panel given its benefits in terms of nutrition, lung function and survival. The Immunoassay Center develops and produces diagnostic kits allowing the establishment of large-scale NBS programs for inherited metabolic disorders in Cuba and other Latin American countries. IRT-specific monoclonal antibodies (MAbs) obtained at the Immunoassay Center are essential for developing an affordable immunoassay for IRT to support CF NBS in our low-income country. An immunization scheme with trypsinogen-1 originated two IgG1-producing murine hybridomas. 4C9C9 and 4C9E11 MAbs recognized different determinants on both trypsin-1 and trypsin-2 molecules. Both antibodies identified conformational epitopes on the molecule of trypsin-1 and of its zymogen. As 4C9E11 MAb cross-reacted with proteins structurally and functionally related to trypsinogen, it was used as revealing antibody in a sandwich-type UMELISA® assay for IRT determination with 4C9C9 MAb for capture. This combination, aside from detecting several commercially available trypsins, adequately quantified IRT from dried blood samples on filter paper of newborns. The evaluation of the assay's accuracy yielded percentage recoveries ranging 93.3-109.2% for commercial controls. The properties of the studied MAbs demonstrate their suitability for being used in a sandwich-type UMELISA® assay for the CF NBS in Cuba.

PMID: 31887264 [PubMed - as supplied by publisher]

Clinical relevance of Aspergillus fumigatus sensitization in cystic fibrosis.

Clin Exp Allergy. 2019 Dec 30;:

Authors: Eickmeier O, Zissler UM, Wittschorek J, Unger F, Schmitt-Grohé S, Schubert R, Herrmann E, Zielen S

Abstract
RATIONALE: The clinical relevance of sensitization to Aspergillus (A) fumigatus in cystic fibrosis (CF) is unclear. Some researchers propose that specific A. fumigatus IgE is an innocent bystander, whereas others describe it as the major cause of TH-2-driven asthma-like disease.
OBJECTIVES: Lung function parameters in mild CF patients may be different in patients with and without A. fumigatus sensitization. We aimed to ascertain whether allergen exposure to A. fumigatus by bronchial allergen provocation (BAP) induces TH-2 inflammation comparable to an asthma-like disease.
METHODS: A total of 35 patients, aged 14.8±8.5 years, and 20 healthy controls were investigated prospectively. The patients were divided into two groups: group 1 (n=18): specific (s)IgE negative, and group 2 (n=17): sIgE positive (≥ 0.7 KU/L) for A. fumigatus. Lung function, exhaled NO, and induced sputum were analyzed. All sensitized patients with an FEV1 > 75% (n=13) underwent BAP with A. fumigatus, and cell counts, and the expression of IL-5, IL-13, INF-γ, and IL-8 as well as transcription factors T-bet, GATA-3, and FoxP3, were measured.
RESULTS: Lung function parameters decreased significantly compared to controls, but not within the CF patient group. After BAP, 8 of 13 patients (61%) had a significant asthmatic response and increased eNO 24 hours later. In addition, marked TH-2-mediated inflammation involving eosinophils, IL-5, IL-13, and FoxP3 became apparent in induced sputum cells.
CONCLUSION: Our study demonstrated the clinical relevance of A. fumigatus for the majority of sensitized CF patients. A distinct IgE/TH-2-dominated inflammation was found in induced sputum after A. fumigatus exposure.

PMID: 31886564 [PubMed - as supplied by publisher]

Serum-Associated Antibiotic Tolerance in Pediatric Clinical Isolates of Pseudomonas aeruginosa.

J Pediatric Infect Dis Soc. 2019 Dec 30;:

Authors: Morrison JM, Chojnacki M, Fadrowski JJ, Bauza C, Dunman PM, Dudas RA, Goldenberg NA, Berman DM

Abstract
BACKGROUND: When grown in human serum, laboratory isolates of Pseudomonas aeruginosa exhibit tolerance to antibiotics at inhibitory concentrations. This phenomenon, known as serum-associated antibiotic tolerance (SAT), could lead to clinical treatment failure of pseudomonal infections. Our purpose in this study was to determine the prevalence and clinical impact of SAT in Pseudomonas isolates in hospitalized children.
METHODS: The SAT phenotype was assessed in patients aged <18 years admitted with respiratory or blood cultures positive for P. aeruginosa. The SAT phenotype was a priori defined as a ≥2-log increase in colony-forming units when grown in human serum compared with Luria-Bertani medium in the presence of minocycline or tobramycin.
RESULTS: SAT was detected in 29 (64%) patients. Fourteen patients each (34%) had cystic fibrosis (CF) and tracheostomies. Patient demographics and comorbidities did not differ by SAT status. Among CF patients, SAT was associated with longer duration of intravenous antibiotics (10 days vs 5 days; P < .01).
CONCLUSIONS: This study establishes that SAT exists in P. aeruginosa from human serum and may be a novel factor that contributes to differences in clinical outcomes. Future research should investigate the mechanisms that contribute to SAT in order to identify novel targets for adjunctive antimicrobial therapies.

PMID: 31886511 [PubMed - as supplied by publisher]

Multi-use Hypertonic Saline Packets for Nebulization - A Threat for Patients with Cystic Fibrosis in India.

Indian Pediatr. 2019 Dec 15;56(12):1068-1069

Authors: Varkki S, Rose W

PMID: 31884452 [PubMed - in process]

The influence of CFTR complex alleles on precision therapy of cystic fibrosis.

J Cyst Fibros. 2019 Dec 25;:

Authors: Chevalier B, Hinzpeter A

Abstract
CFTR is an extensively studied gene and multiple sequence variants have been identified, many of which still need to be defined as neutral or disease causing. Complex alleles are defined when at least two variants are identified on the same allele. Each pathogenic variant can affect distinct steps of the CFTR biogenesis. As CFTR modulators are being developed to alleviate specific defects, pathogenic variants need to be characterized to propose adequate treatments. Conversely, cis-variants can affect treatment response when defects are additive or if they alter the binding or efficacy of the modulator. Hence, complex alleles increase the complexity of CFTR variant classification and need to be assigned as neutral, disease causing or modulating treatment efficacy. This review was based on a symposium session presented at the 16th ECFS Basic Science Conference, Dubrovnik, Croatia, 27 to 30 March, 2019.

PMID: 31883651 [PubMed - as supplied by publisher]

Genetic variants in acute, acute recurrent and chronic pancreatitis affect the progression of disease in children.

Pancreatology. 2019 Jun;19(4):535-540

Authors: Abu-El-Haija M, Valencia CA, Hornung L, Youssef N, Thompson T, Barasa NW, Wang X, Denson LA

Abstract
BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) is emerging in pediatrics. A subset of children with AP progresses to acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). The role of extensive gene testing in the progression has not been investigated previously. We have followed children enrolled in the registry and at our center for progression to ARP and CP after the first attack.
METHODS: This study utilizes an extensive gene sequencing panel as a platform to evaluate the role of genetics in first attack AP, and the progression over time, from first attack to ARP and CP in children.
RESULTS: Genes, with corresponding variants were involved in the 3 groups studied: AP, ARP and CP. We have shown that the presence of gene variants from the eight tested genes is enriched in the CP group compared to the AP and ARP groups. The presence of more than one gene was associated with CP (p = 0.01). SPINK1 mutation(s) was significantly associated with faster progression to ARP, (p = 0.04). Having a variant from CFTR, SPINK1 or PRSS1, was associated with the faster progression from AP to CP over time (p < 0.05).
CONCLUSIONS: This study shows that genetics have a significant role in progression to ARP and CP from the first attack of pancreatitis.

PMID: 31088717 [PubMed - indexed for MEDLINE]

Prediction of peak oxygen uptake using the modified shuttle test - Methodological concerns and implications for clinical practice.

Pediatr Pulmonol. 2019 08;54(8):1104-1105

Authors: Williams CA, Barker AR, Tomlinson OW

PMID: 31001896 [PubMed - indexed for MEDLINE]

Prognostic ability of the distance-saturation product in the 6-minute walk test in patients with chronic obstructive pulmonary disease.

Clin Respir J. 2019 Dec 28;:

Authors: Gurbani N, Figueira Gonçalves JM, García Bello MÁ, García-Talavera I, Afonso Díaz A

Abstract
INTRODUCTION: The product (DSP) of the distance walked (meters) and minimum oxygen saturation obtained during the 6-minute walk test (6MWT) has been proposed as a predictor of mortality in idiopathic pulmonary fibrosis and in bronchiectasis not related to cystic fibrosis.
OBJECTIVE: The aim of this study was to determine the DSP's ability to predict mortality in patients with chronic obstructive pulmonary disease (COPD) at the outpatient level and compare it to the BODE index and meters walked in the 6MWT.
MATERIAL AND METHODS: Descriptive observational study in a cohort of patients with COPD being treated at outpatient pulmonology clinics. Each of the patients completed the 6MWT following ATS/ERS protocols and their BODE index and DSP were calculated.
RESULTS: 103 patients were included. The average length of follow-up was 36 months. Patients who died showed a lower number of meters walked in the 6MWT (p < 0.001), as well as a lower DSP (p < 0.001). A 6MWT < 334 meters, a DSP < 290 and a BODE ≥ 4 showed good prognostic ability at 3 years (AUC 71%, 69% and 70.4%, respectively). The 6MWT was superior to the BODE index in predicting mortality during the first year of follow-up (p = 0.023). We did not find any differences between DSP and meters walked in the 6MWT.
CONCLUSIONS: The DSP is a good predictor of mortality, although it does not offer a better prognostic ability than that of meters walked in the 6MWT.

PMID: 31883431 [PubMed - as supplied by publisher]

Epinephrine affects motility, and increases adhesion, biofilm and virulence of Pseudomonas aeruginosa H103.

Sci Rep. 2019 Dec 27;9(1):20203

Authors: Cambronel M, Tortuel D, Biaggini K, Maillot O, Taupin L, Réhel K, Rincé I, Muller C, Hardouin J, Feuilloley M, Rodrigues S, Connil N

Abstract
Microbial endocrinology has demonstrated for more than two decades, that eukaryotic substances (hormones, neurotransmitters, molecules of the immune system) can modulate the physiological behavior of bacteria. Among them, the hormones/neurotransmitters, epinephrine (Epi) and norepinephrine (NE), released in case of stress, physical effort or used in medical treatment, were shown to be able to modify biofilm formation in various bacterial species. In the present study, we have evaluated the effect of Epi on motility, adhesion, biofilm formation and virulence of Pseudomonas aeruginosa, a bacterium linked to many hospital-acquired infections, and responsible for chronic infection in immunocompromised patients including persons suffering from cystic fibrosis. The results showed that Epi increased adhesion and biofilm formation of P. aeruginosa, as well as its virulence towards the Galleria mellonella larvae in vivo model. Deciphering the sensor of this molecule in P. aeruginosa and the molecular mechanisms involved may help to find new strategies of treatment to fight against this bacterium.

PMID: 31882963 [PubMed - in process]

Dynamic, Simultaneous Concentration Mapping of Multiple MRI Contrast Agents with Dual Contrast - Magnetic Resonance Fingerprinting.

Sci Rep. 2019 Dec 27;9(1):19888

Authors: Anderson CE, Johansen M, Erokwu BO, Hu H, Gu Y, Zhang Y, Kavran M, Vincent J, Drumm ML, Griswold MA, Steinmetz NF, Li M, Clark H, Darrah RJ, Yu X, Brady-Kalnay SM, Flask CA

Abstract
Synchronous assessment of multiple MRI contrast agents in a single scanning session would provide a new "multi-color" imaging capability similar to fluorescence imaging but with high spatiotemporal resolution and unlimited imaging depth. This multi-agent MRI technology would enable a whole new class of basic science and clinical MRI experiments that simultaneously explore multiple physiologic/molecular events in vivo. Unfortunately, conventional MRI acquisition techniques are only capable of detecting and quantifying one paramagnetic MRI contrast agent at a time. Herein, the Dual Contrast - Magnetic Resonance Fingerprinting (DC-MRF) methodology was extended for in vivo application and evaluated by simultaneously and dynamically mapping the intra-tumoral concentration of two MRI contrast agents (Gd-BOPTA and Dy-DOTA-azide) in a mouse glioma model. Co-registered gadolinium and dysprosium concentration maps were generated with sub-millimeter spatial resolution and acquired dynamically with just over 2-minute temporal resolution. Mean tumor Gd and Dy concentration measurements from both single agent and dual agent DC-MRF studies demonstrated significant correlations with ex vivo mass spectrometry elemental analyses. This initial in vivo study demonstrates the potential for DC-MRF to provide a useful dual-agent MRI platform.

PMID: 31882792 [PubMed - in process]

CFTR transmembrane segments are impaired in their conformational adaptability by a pathogenic loop mutation and dynamically stabilized by Lumacaftor.

J Biol Chem. 2019 Dec 27;:

Authors: Krainer G, Schenkel M, Hartmann A, Ravamehr-Lake D, Deber CM, Schlierf M

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel protein that is defective in individuals with cystic fibrosis (CF). To advance the rational design of CF therapies, it is important to elucidate how mutational defects in CFTR lead to its impairment and how pharmacological compounds interact with and alter CFTR. Here, using a helical-hairpin construct derived from CFTR's transmembrane (TM) helices 3 and 4 (TM3/4) and their intervening loop, we investigated the structural effects of a patient-derived CF-phenotypic mutation, E217G, located in the loop region of CFTR's membrane-spanning domain. Employing a single-molecule FRET assay to probe the folding status of reconstituted hairpins in lipid bilayers, we found that the E217G hairpin exhibits an altered adaptive packing behavior stemming from an additional GXXXG helix-helix interaction motif created in the mutant hairpin. This observation suggested that the misfolding and functional defects caused by the E217G mutation arise from an impaired conformational adaptability of TM helical segments in CFTR. Addition of the small-molecule corrector Lumacaftor exerts a helix stabilization effect not only on the E217G mutant hairpin, but also on WT TM3/4 and other mutations in the hairpin. This finding suggests a general mode of action for Lumacaftor through which this corrector efficiently improves maturation of various CFTR mutants.

PMID: 31882543 [PubMed - as supplied by publisher]

Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions.

Proc Natl Acad Sci U S A. 2019 Dec 27;:

Authors: Miller AC, Comellas AP, Hornick DB, Stoltz DA, Cavanaugh JE, Gerke AK, Welsh MJ, Zabner J, Polgreen PM

Abstract
Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions.

PMID: 31882447 [PubMed - as supplied by publisher]

Multidisciplinary Care for Cystic Fibrosis Liver Disease: Where Does the Adult Hepatologist Fit In?

Clin Liver Dis (Hoboken). 2019 Nov;14(5):187-190

Authors: Ayoub F, Li H, Blay C, Trillo-Alvarez C, Lascano J, Morelli G

PMID: 31879562 [PubMed]

A Peculiar Case of Pneumonia due to Mycoplasma pneumoniae in a Child with Cystic Fibrosis and Sensibilization to Aspergillus fumigatus.

Pathogens. 2019 Dec 22;9(1):

Authors: Peccini L, Pennoni S, Mencarini V, Saponara M, Palladino N, Principi N, Pennoni G, Esposito S

Abstract
Aspergillus fumigatus plays a major role in pulmonary exacerbations in patients with cystic fibrosis. The most common A. fumigatus diseases are those based on immune-mediated response to A. fumigatus antigens; including allergic bronchopulmonary aspergillosis (ABPA). In this condition; the presence of A. fumigatus in the lower respiratory tract triggers an IgE-mediated hypersensitivity response that causes airway inflammation; bronchospasms; and bronchiectasis. This case report describes a ten-year-old male patient suffering from cystic fibrosis (CF) in whom the diagnosis of ABPA occurred in association with pneumonia due to Mycoplasma pneumoniae more than two weeks after hospitalization. This case is a good example of how difficult the identification of ABPA in CF patients can be and highlights that ABPA can occur in association with co-infections due to other pathogens. In order to avoid the risk of a late ABPA diagnosis, it is imperative that the diagnostic criteria guidelines are reviewed and standardized.

PMID: 31877884 [PubMed]

Prenatal Diagnosis of Cystic Fibrosis and Hemophilia: Incidental Findings and Weak Points.

Diagnostics (Basel). 2019 Dec 21;10(1):

Authors: Comegna M, Maruotti GM, Sarno L, Cernera G, Gelzo M, Guida M, Zullo F, Zarrilli F, Castaldo G

Abstract
Because of the progression of genetics and genomics, the demand for prenatal diagnosis (PD) for inherited genetic diseases has increased. However, several incidental findings may emerge during PD, like misattributed paternity, the evidence of disease in a parent, and the possible misinterpretation of the results because of complex alleles or de novo mutations that have several implications. In a retrospective observational study on all the couples referred to our Medical School (1993-2018) for PD of genetic inherited diseases (n = 1502), we selected the cases of PD for cystic fibrosis (CF, n = 239) and hemophilia A and B (HA, HB, n = 47), revising all incidental findings previously mentioned. We found one case in which a technical error led to PD of carrier in two siblings that were born affected by CF, four cases of misattributed paternity, eight cases of asymptomatic parents revealed as affected by CF transmembrane regulator (CFTR)-related disorders, a case of a novel complex allele that could have caused the diagnosis of CF in a carrier fetus, and a case of a de novo mutation in a mother (already a carrier) that caused hemophilia in a child that PD had revealed as healthy. We present these conditions as clinical cases and discuss the technical, clinical, ethical, and legal aspects to be considered.

PMID: 31877800 [PubMed]

Molecular modeling assisted identification and biological evaluation of potent cathepsin S inhibitors.

J Mol Graph Model. 2019 Dec 12;96:107512

Authors: Ahmad S, Bhagwati S, Kumar S, Banerjee D, Siddiqi MI

Abstract
Cathepsin S (CatS) is one of the cysteinyl cathepsins widely studied for its clinical significance and found to be a promising therapeutic target for several diseases; to name a few is arthritis, allergic inflammation, cancer, diabetes, obesity, and cystic fibrosis. Elevated CatS level is a contributing factor for related disorders, and therefore among different strategies to regulate the activity of CatS, one is to design a quality inhibitor. Earlier, we have demonstrated a highly selective CatS inhibitor, RO5444101 interacts primarily with the S2 pocket of the protein which is structurally unique in contrast to other variants of cathepsin. However, the molecular properties of RO5444101 can question its efficacy at the clinical level. In the present study, we have implemented a series of molecular modeling methods to screen the Maybridge library considering the pharmacophoric features of RO5444101 and other relevant inhibitors of CatS. Based on the priority list, eight hits were subjected to biological evaluation. Subsequently, KM07987 was found to be most potent, with the IC50 of <5 μM. Molecular dynamics simulations also relate to our experimental findings and propose the importance of CatS's S2 pocket, which primarily interacts with the inhibitors. Based on the S2 pocket interactions, structural modifications of the promising hits can further be translated into novel scaffolds for improved inhibition of CatS.

PMID: 31881466 [PubMed - as supplied by publisher]