Pulmonary embolism in a young pregnant woman with COVID-19.

Thromb Res. 2020 Apr 20;191:36-37

Authors: Martinelli I, Ferrazzi E, Ciavarella A, Erra R, Iurlaro E, Ossola M, Lombardi A, Blasi F, Mosca F, Peyvandi F

PMID: 32371163 [PubMed - as supplied by publisher]

ACR Appropriateness Criteria® Hemoptysis.

J Am Coll Radiol. 2020 May;17(5S):S148-S159

Authors: Expert Panel on Thoracic Imaging, Olsen KM, Manouchehr-Pour S, Donnelly EF, Henry TS, Berry MF, Boiselle PM, Colletti PM, Harrison NE, Kuzniewski CT, Laroia AT, Maldonado F, Pinchot JW, Raptis CA, Shim K, Tong BC, Wu CC, Kanne JP

Abstract
Hemoptysis, the expectoration of blood, ranges in severity from nonmassive to massive. This publication reviews the literature on the imaging and treatment of hemoptysis. Based on the literature, the imaging recommendations for massive hemoptysis are both a chest radiograph and CT with contrast or CTA with contrast. Bronchial artery embolization is also recommended in the majority of cases. In nonmassive hemoptysis, both a chest radiograph and CT with contrast or CTA with contrast is recommended. Bronchial artery embolization is becoming more commonly utilized, typically in the setting of failed medical therapy. Recurrent hemoptysis, defined as hemoptysis that recurs following initially successful cessation of hemoptysis, is best reassessed with a chest radiograph and either CT with contrast or CTA with contrast. Bronchial artery embolization is increasingly becoming the treatment of choice in recurrent hemoptysis, with the exception of infectious causes such as in cystic fibrosis. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

PMID: 32370959 [PubMed - in process]

Long-term pulmonary function testing in pediatric bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

Pediatr Pulmonol. 2020 May 05;:

Authors: Walther S, Rettinger E, Maurer HM, Pommerening H, Jarisch A, Sörensen J, Schubert R, Berres M, Bader P, Zielen S, Jerkic SP

Abstract
RATIONALE: Bronchiolitis obliterans syndrome (BOS) is a severe, chronic inflammation of the airways leading to an obstruction of the bronchioles. So far, there are only a few studies looking at the long-term development of pulmonary impairment in children with BOS.
OBJECTIVE: The objective of this study was to investigate the incidence and long-term outcome of BOS in children who underwent allogeneic hematopoietic stem cell transplantation (HSCT).
METHODS: Medical charts of 526 children undergoing HSCT in Frankfurt/Main, Germany between 2000 and 2017 were analyzed retrospectively and as a result, 14 patients with BOS were identified. A total of 271 lung functions (spirometry and body plethysmography), 26 lung clearance indices (LCI), and 46 chest high-resolution computed tomography (HRCT) of these 14 patients with BOS were evaluated.
RESULTS: Fourteen patients suffered from BOS after HSCT (2.7%), whereby three distinctive patterns of lung function impairment were observed: three out of 14 patients showed a progressive lung function decline; two died and one received a lung transplant. In five out of 14 patients with BOS persisted with a severe obstructive and secondarily restrictive pattern in lung function (forced vital capacity [FVC] < 60%, forced expiratory volume in 1 second [FEV1] < 50%, and FEV1/FVC < 0.7) and increased LCI (11.67-20.9), six out of 14 patients recovered completely after moderate lung function impairment and signs of BOS on HRCT. Long-term FVC in absolute numbers was increased indicating that the children still have lung growth.
CONCLUSION: Our results showed that the incidence of BOS in children is low. BOS was associated with high mortality and may lead to persistent obstructive lung disease; although, lung growth continued to exist.

PMID: 32369682 [PubMed - as supplied by publisher]

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations.

Cell Mol Life Sci. 2020 May 04;:

Authors: Lara-Reyna S, Holbrook J, Jarosz-Griffiths HH, Peckham D, McDermott MF

Abstract
Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating condition is associated with recurrent lower respiratory tract bacterial and viral infections, as well as inflammatory complications that may eventually lead to pulmonary failure. Immune cells play a crucial role in protecting the organs against opportunistic infections and also in the regulation of tissue homeostasis. Innate immune cells are generally affected by CFTR mutations in patients with CF, leading to dysregulation of several cellular signalling pathways that are in continuous use by these cells to elicit a proper immune response. There is substantial evidence to show that airway epithelial cells, neutrophils, monocytes and macrophages all contribute to the pathogenesis of CF, underlying the importance of the CFTR in innate immune responses. The goal of this review is to put into context the important role of the CFTR in different innate immune cells and how CFTR dysfunction contributes to the pathogenesis of CF, highlighting several signalling pathways that may be dysregulated in cells with CFTR mutations.

PMID: 32367193 [PubMed - as supplied by publisher]

Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach.

Genet Med. 2020 May 05;:

Authors: Westemeyer M, Saucier J, Wallace J, Prins SA, Shetty A, Malhotra M, Demko ZP, Eng CM, Weckstein L, Boostanfar R, Rabinowitz M, Benn P, Keen-Kim D, Billings P

Abstract
PURPOSE: To present results from a large cohort of individuals receiving expanded carrier screening (CS) in the United States.
METHODS: Single-gene disorder carrier status for 381,014 individuals was determined using next-generation sequencing (NGS) based CS for up to 274 genes. Detection rates were compared with literature-reported values derived from disease prevalence and carrier frequencies. Combined theoretical affected pregnancy rates for the 274 screened disorders were calculated.
RESULTS: For Ashkenazi Jewish (AJ) diseases, 81.6% (4434/5435) of carriers identified did not report AJ ancestry. For cystic fibrosis, 44.0% (6260/14,229) of carriers identified had a variant not on the standard genotyping panel. Individuals at risk of being a silent spinal muscular atrophy carrier, not detectable by standard screening, comprised 1/39 (8763/344,407) individuals. For fragile X syndrome, compared with standard premutation screening, AGG interruption analysis modified risk in 83.2% (1128/1356) premutation carriers. Assuming random pairing across the study population, approximately 1/175 pregnancies would be affected by a disorder in the 274-gene screening panel.
CONCLUSION: Compared with standard screening, NGS-based CS provides additional information that may impact reproductive choices. Pan-ethnic CS leads to substantially increased identification of at-risk couples. These data support offering NGS-based CS to all reproductive-aged women.

PMID: 32366966 [PubMed - as supplied by publisher]

Clinically relevant epithelial lining fluid concentrations of meropenem with ciprofloxacin provide synergistic killing and resistance suppression of hypermutable Pseudomonas aeruginosa in a dynamic biofilm model.

Antimicrob Agents Chemother. 2020 May 04;:

Authors: Bilal H, Bergen PJ, Tait JR, Wallis SC, Peleg AY, Roberts JA, Oliver A, Nation RL, Landersdorfer CB

Abstract
Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOΔmutS (MICciprofloxacin 0.25 mg/L, MICmeropenem 2 mg/L) and CW44 (MICciprofloxacin 0.5 mg/L, MICmeropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log10 CFU/mL) and biofilm (>8log10 CFU/cm2) bacteria at 120h (MICciprofloxacin up to 8 mg/L, MICmeropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ∼48h onwards and suppressed regrowth to ≤4log10 CFU/mL and ≤6log10 CFU/cm2 at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOΔmutS Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

PMID: 32366710 [PubMed - as supplied by publisher]

Achromobacter xylosoxidans cellular pathology is correlated with activation of a type III secretion system.

Infect Immun. 2020 May 04;:

Authors: Pickrum AM, DeLeon O, Dirck A, Tessmer MH, Riegert MO, Biller JA, Ledeboer NA, Kirby JR, Frank DW

Abstract
Achromobacter xylosoxidans is increasingly recognized as a colonizer of cystic fibrosis (CF) patients but the role that A. xylosoxidans plays in pathology remains unknown. This knowledge gap is largely due to the lack of model systems available to study the toxic potential of this bacterium. Recently, a phospholipase A2 (PLA2) encoded by a majority of A. xylosoxidans genomes, termed AxoU, was identified. Here we show that AxoU is a type III secretion system (T3SS) substrate that induces cytotoxicity to mammalian cells. A tissue culture model was developed showing that a subset of A. xylosoxidans isolates from CF patients induce cytotoxicity in macrophages, suggestive of a pathogenic or inflammatory role in the CF lung. In a toxic strain, cytotoxicity is correlated with transcriptional activation of axoU and T3SS genes, demonstrating that this model can be used as a tool to identify and track expression of virulence determinants produced by this poorly understood bacterium.

PMID: 32366575 [PubMed - as supplied by publisher]

PROCEEDINGS OF THE 17th ITALIAN CONVENTION OF FFC INVESTIGATORS IN CYSTIC FIBROSIS : VERONA 14th-16th NOVEMBER 2019 Every year, the Italian Cystic Fibrosis Research Foundation (FFC) brings together all its funded researchers from across Italy and beyond, in a Convention where results from FFC projects are shared and debated. These projects are either newly funded, on-going or recently concluded research. The Proceedings of the 17th Italian Convention of FFC Investigators in Cystic Fibrosis report the results of the concluded research projects. Correspondence: Dr. F. Malvezzi (flaminia.malvezzi@fibrosicisticaricerca.it).

BMC Pulm Med. 2020 May 04;20(Suppl 1):100

Authors:

PMID: 32366331 [PubMed - in process]

What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer?

Int J Mol Sci. 2020 Apr 29;21(9):

Authors: Amaral MD, Quaresma MC, Pankonien I

Abstract
One of the key features associated with the substantial increase in life expectancy for individuals with CF is an elevated predisposition to cancer, firmly established by recent studies involving large cohorts. With the recent advances in cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and the increased long-term survival rate of individuals with cystic fibrosis (CF), this is a novel challenge emerging at the forefront of this disease. However, the mechanisms linking dysfunctional CFTR to carcinogenesis have yet to be unravelled. Clues to this challenging open question emerge from key findings in an increasing number of studies showing that CFTR plays a role in fundamental cellular processes such as foetal development, epithelial differentiation/polarization, and regeneration, as well as in epithelial-mesenchymal transition (EMT). Here, we provide state-of-the-art descriptions on the moonlight roles of CFTR in these processes, highlighting how they can contribute to novel therapeutic strategies. However, such roles are still largely unknown, so we need rapid progress in the elucidation of the underlying mechanisms to find the answers and thus tailor the most appropriate therapeutic approaches.

PMID: 32365523 [PubMed - in process]

Sleep-disordered breathing and markers of morbidity in children and adolescents with cystic fibrosis.

Pediatr Pulmonol. 2020 May 04;:

Authors: Barbosa RRB, Liberato FMG, de Freitas Coelho P, Vidal PDR, de Carvalho RBCO, Donadio MVF

Abstract
BACKGROUND: Studies have shown that sleep disorders occur in cystic fibrosis (CF) patients and may be present before daytime clinical manifestations.
OBJECTIVES: To evaluate the presence of sleep disorders among children and adolescents with CF, attempting to identify associations with pulmonary function, nutritional status, days in hospital, and days taking antibiotics.
METHODS: Individuals with a diagnosis of CF aged between 6 and 18 years were included. Information on sociodemographic, clinical profile, history of hospitalizations, and use of antibiotics in the last year were collected. Spirometry, bioimpedance, and polysomnography were performed. The presence of nocturnal hypoxemia and obstructive sleep apnea syndrome (OSAS) were evaluated and participants divided according to their presence.
RESULTS: Thirty-one patients were included. The prevalence of OSAS was 32.3% and nocturnal hypoxemia was 29.0%. Average nocturnal peripheral oxyhemoglobin saturation (SpO2 ) correlated (P < .001) with forced vital capacity (r = .55) and forced expiratory volume in the first second (r = .62). The higher the percentage of total sleep time (TST) with SpO2 less than 90%, the lower the pulmonary function. Individuals with OSAS and nocturnal hypoxemia had lower spirometric values compared to patients without these disorders, but the nocturnal hypoxemia group also had lower Shwachman-Kulczycki score, longer hospitalization time and antibiotic use. TST with SpO2 less than 90% was associated with length of hospitalization (r2  = .53).
CONCLUSION: Children and adolescents with CF have sleep disorders, including OSAS (32.3%) and nocturnal hypoxemia (29%). Individuals with nocturnal hypoxemia presented lower lung function, worse clinical score, and higher morbidity. TST with SpO2 less than 90% was associated with length of hospitalization.

PMID: 32364318 [PubMed - as supplied by publisher]

Clinical features and accompanying findings of Pseudo-Bartter Syndrome in cystic fibrosis.

Pediatr Pulmonol. 2020 May 04;:

Authors: Sismanlar Eyuboglu T, Dogru D, Çakır E, Cobanoglu N, Pekcan S, Cinel G, Yalçın E, Kiper N, Sen V, Selimoglu Sen H, Ercan O, Keskin O, Bilgic Eltan S, Alshadfan L, Yazan H, Altıntas DU, Sasihuseyinoglu AS, Sapan N, Cekic S, Cokugraş H, Kılınc AA, Ramaslı Gursoy T, Aslan AT, Bingol A, Başaran AE, Ozdemir A, Kose M, Hangul M, Emiralioglu N, Tugcu G, Yuksel H, Yılmaz O, Orhan F, Gayretli Aydın ZG, Topal E, Tamay Z, Suleyman A, Can D, Bal CM, Caltepe G, Ozcelik U

Abstract
BACKGROUND: Pseudo-Bartter syndrome (PBS) is a rare complication of cystic fibrosis (CF) and there are limited data in the literature about it. We aimed to compare clinical features and accompanying findings of patients with PBS in a large patient population.
METHODS: The data were collected from the Cystic Fibrosis Registry of Turkey where 1170 CF patients were recorded in 2017. Clinical features, diagnostic test results, colonization status, complications, and genetic test results were compared in patients with and without PBS.
RESULTS: Totally 1170 patients were recorded into the registry in 2017 and 120 (10%) of them had PBS. The mean age of diagnosis and current age of patients were significantly younger and newborn screening positivity was lower in patients with PBS (P < .001). There were no differences between the groups in terms of colonization status, mean z-scores of weight, height, BMI, and mean FEV1 percentage. Types of genetic mutations did not differ between the two groups. Accompanying complications were more frequent in patients without PBS.
CONCLUSION: PBS was detected as the most common complication in the registry. It could be due to warm weather conditions of our country. It is usually seen in younger ages regardless of mutation phenotype and it could be a clue for early diagnosis of CF.

PMID: 32364312 [PubMed - as supplied by publisher]

Rare cause of upper bowel obstruction arising in a 17-year-old boy with cystic fibrosis: Superior mesenteric artery (Wilkie's) syndrome.

J Paediatr Child Health. 2020 May 04;:

Authors: Schwarz J, Sýkora J, Pomahačová R, Sýkorová A, Fremuth J, Šašek L, Vondráková R, Kreslová M

PMID: 32364286 [PubMed - as supplied by publisher]

Regulation of Cl- Electrolyte Permeability in Epithelia by Active Traditional Chinese Medicine.

Curr Drug Targets. 2020 May 03;:

Authors: Chen L, Ding Y, Hou Y, Liu Y, Nie H

Abstract
The epithelial layer, lining the inner surface of the mammalian alveolar, kidney, brain and colon, is a typical electrolyte transporting tissue. Large quantities of salt and fluid are actively moved from the mucosal side toward the blood vessel. Transepithelial salt reabsorption in epithelial tissues plays an important role in maintaining fluid homeostasis. In absorptive epithelium, fluid and salt flux is controlled by the machinery mainly composed of epithelial sodium channel, cystic fibrosis transmembrane conductance regulator, Na+ -K+ - 2Clcotransporter, Na+ /H+ exchanger, and Na+ /K+ -ATPase. Dysregulation of salt permeability across epithelium contributes to the pathogenesis of organ edema. In numerous ion transporters, epithelial Cltransportation plays an important role in water secretion across epithelial tissues and regulation of body fluid content. Many traditional Chinese medicines treat the diarrhea by regulating the Clelectrolyte transport. We systematically summarized the recent progress regarding the traditional Chinese medicine on Clelectrolyte transport in the intestinal epithelial tissues. The pharmaceutical relevance of developing advanced strategies to mitigate edematous disorders is also implicated. In conclusion, the crosstalk between Clelectrolyte transport and active traditional Chinese medicine monomers may lead to the development of new strategies for diarrhea by manipulating the function and expression of ion channels.

PMID: 32364074 [PubMed - as supplied by publisher]

What it takes to implement regular longitudinal multiple breath washout tests in infants with cystic fibrosis.

J Cyst Fibros. 2020 Apr 30;:

Authors: Schmidt MN, Sandvik RM, Voldby C, Buchvald FF, Jørgensen MN, Gustafsson P, Skov M, Nielsen KG

PMID: 32362559 [PubMed - as supplied by publisher]

Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of anti-infective therapy (SITA) and the Italian Society of Pulmonology (SIP).

Clin Microbiol Infect. 2020 Apr 29;:

Authors: Bassetti M, Giacobbe DR, Aliberti S, Barisione E, Centanni S, De Rosa FG, Di Marco F, Gori A, Granata G, Mikulska M, Petrosillo N, Richeldi L, Santus P, Tascini C, Vena A, Viale P, Blasi F, Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP)

Abstract
BACKGROUND: SARS-CoV-2 is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries.
OBJECTIVES: To narratively summarize the available literature on the management of COVID-19, in the attempt to combine current evidence and frontline opinions and provide balanced answers to pressing clinical questions.
SOURCES: Inductive PubMed search for publications relevant to the topic.
CONTENT: The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, plus a conclusive statement for each answer.
IMPLICATIONS: Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, being not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled in randomized clinical trials (RCT). Access to well-designed RCT should be expanded as much as possible, being the most secure way to change for the better our approach to COVID-19 patients.

PMID: 32360444 [PubMed - as supplied by publisher]

The relationship between the structure and toxicity of aminoglycoside antibiotics.

Bioorg Med Chem Lett. 2020 Apr 25;:127218

Authors: Jospe-Kaufman M, Siomin L, Fridman M

Abstract
Aminoglycoside antibiotics, used to treat persistent gram-negative infections, tuberculosis, and life-threatening infections in neonates and patients with cystic fibrosis, can infer acute kidney injury and irreversible hearing loss. The full repertoire of cellular targets and processes leading to the toxicity of aminoglycosides is not fully resolved, making it challenging to devise rational directions to circumvent their adverse effects. As a result, there has been very limited effort to rationally address the issue of aminoglycoside-induced toxicity. Here we provide an overview of the reported effects of aminoglycosides on cells of the inner ear and on kidney tubular epithelial cells. We describe selected examples for structure-toxicity relationships established by evaluation of both natural and semisynthetic aminoglycosides. The various assays and models used to evaluate these antibiotics and recent progress in development of safer aminoglycoside antibiotics are discussed.

PMID: 32360102 [PubMed - as supplied by publisher]

Cystic fibrosis 2019: Year in review.

Paediatr Respir Rev. 2020 Apr 09;:

Authors: Doull I

Abstract
The evidence base for modulator therapies in cystic fibrosis (CF) has continued to expand, and it is likely that up to 90% of people with CF could benefit. Worldwide there are however marked inequalities of access to basic CF care and modulator therapies. For infants and young children there is now an evidence base for inhaled hypertonic saline. There is increasing evidence that structural lung disease in CF is not due purely to infection and that mucus retention and inflammation are also key, and further evidence of the value of azithromycin in those chronically infected with Pseudomonas aeruginosa. Finally, exercise is good for you, but airway clearance is better for mucus clearance.

PMID: 32359945 [PubMed - as supplied by publisher]

Inhaled mannitol for cystic fibrosis.

Cochrane Database Syst Rev. 2020 May 01;5:CD008649

Authors: Nevitt SJ, Thornton J, Murray CS, Dwyer T

Abstract
BACKGROUND: Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review.
OBJECTIVES: To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences. Date of last search: 12 December 2019.
SELECTION CRITERIA: All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment.
DATA COLLECTION AND ANALYSIS: Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE.
MAIN RESULTS: Six studies (reported in 36 unique publications) were included with a total of 784 participants. Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population. Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole. While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies. Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality. For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF. For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations. In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa).
AUTHORS' CONCLUSIONS: There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa. The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.

PMID: 32358807 [PubMed - as supplied by publisher]

The true panel of cystic fibrosis mutations in the Sicilian population.

BMC Med Genet. 2020 May 01;21(1):89

Authors: Chamayou S, Sicali M, Lombardo D, Maglia E, Liprino A, Cardea C, Fichera M, Venti E, Guglielmino A

Abstract
BACKGROUND: The aim was to establish the true risk of having an affected child with Cystic Fibrosis (CF) in the Sicilian infertile population.
METHODS: A longitudinal CFTR screening of 1279 Sicilian infertile patients for all CFTR mutations sequencing the entire gene by Next Generation Sequencing (NGS) was performed from patient's blood.
RESULTS: One patient out of 16 was a carrier of a CFTR mutation. Twenty-four mutations were found. Theoretically one couple out of 256 was at risk of CF transmission.
CONCLUSIONS: The risk of CF transmission is unexpectedly high in Sicily and with a high heterogeneity. Sequencing an entire and long gene such as CFTR makes accessible the true panel of mutations in a specific population and helps better to understand the true risk of having an affected child.

PMID: 32357917 [PubMed - as supplied by publisher]

Staphylococcus aureus Pathogenicity in Cystic Fibrosis Patients-Results from an Observational Prospective Multicenter Study Concerning Virulence Genes, Phylogeny, and Gene Plasticity.

Toxins (Basel). 2020 Apr 26;12(5):

Authors: Lange J, Heidenreich K, Higelin K, Dyck K, Marx V, Reichel C, Wamel WV, Reijer MD, Görlich D, Kahl BC

Abstract
Staphylococcus aureus and cystic fibrosis (CF) are closely interlinked. To date, however, the impact of S. aureus culture in CF airways on lung function and disease progression has only been elucidated to a limited degree. This analysis aims to identify bacterial factors associated to clinical deterioration. Data were collected during an observational prospective multi-center study following 195 patients from 17 centers. The average follow-up time was 80 weeks. S. aureus isolates (n = 3180) were scanned for the presence of 25 virulence genes and agr-types using single and multiplex PCR. The presence of specific virulence genes was not associated to clinical deterioration. For the agr-types 1 and 4, however, a link to the subjects' clinical status became evident. Furthermore, a significant longitudinal decrease in the virulence gene quantity was observed. Analyses of the plasticity of the virulence genes revealed significantly increased plasticity rates in the presence of environmental stress. The results suggest that the phylogenetic background defines S. aureus pathogenicity rather than specific virulence genes. The longitudinal loss of virulence genes most likely reflects the adaptation process directed towards a persistent and colonizing rather than infecting lifestyle.

PMID: 32357453 [PubMed - as supplied by publisher]