HGG Adv. 2022 Oct 20;4(1):100156. doi: 10.1016/j.xhgg.2022.100156. eCollection 2023 Jan 12.

ABSTRACT

Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. We sequenced 477 individuals with cystic fibrosis (CF) using linked-read sequencing, which display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, demonstrating its utility for understanding complex CF alleles. These are visualized in a Web app, CFTbaRcodes, that enables interactive exploration of CFTR haplotypes present in this cohort. We perform fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus, an intestinal obstruction at birth associated with more severe CF outcomes and pancreatic disease. A 20-kb deletion polymorphism and a PRSS2 missense variant p.Thr8Ile (rs62473563) are shown to independently contribute to meconium ileus risk (p = 0.0028, p = 0.011, respectively) and are PRSS2 pancreas eQTLs (p = 9.5 × 10-7 and p = 1.4 × 10-4, respectively), suggesting the mechanism by which these polymorphisms contribute to CF. The phase information from linked reads provides a putative causal explanation for variation at a CF-relevant locus, which also has implications for the genetic basis of non-CF pancreatitis, to which this locus has been reported to contribute.

PMID:36386424 | PMC:PMC9647008 | DOI:10.1016/j.xhgg.2022.100156

Respir Med Case Rep. 2022 Nov 8;40:101778. doi: 10.1016/j.rmcr.2022.101778. eCollection 2022.

ABSTRACT

The introduction and rapid uptake of CFTR modulator therapy, in addition to other treatments, has significantly increased life expectancy in CF and provided more women the opportunity to consider and successfully be managed throughout pregnancy. There is however limited evidence to guide patient management and enable informed decision making. Here we report the experience to date from a large multidisciplinary Cystic Fibrosis quaternary referral center in managing patients on CFTR modulators in the peri- and post-partum periods. While women in this case series were advised to discontinue CFTR modulators during pregnancy, they would likely receive a very different message today.

PMID:36386290 | PMC:PMC9649942 | DOI:10.1016/j.rmcr.2022.101778

Respir Med Case Rep. 2022 Nov 8;40:101776. doi: 10.1016/j.rmcr.2022.101776. eCollection 2022.

ABSTRACT

Before the arrival of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators women with CF and impaired lung function were experiencing a high risk of complications and mortality during and the years after pregnancy. The arrival of the highly efficient CFTR modulator, Elexacaftor-Tezacaftor-Ivacaftor (ETI) resulted in an improvement of lung function, quality of life and fertility. Here we report a case of successful pregnancy and uncomplicated delivery for a CF patient with severely impaired lung function receiving ETI prior to conception.

PMID:36386288 | PMC:PMC9664010 | DOI:10.1016/j.rmcr.2022.101776

Respir Med Case Rep. 2022 Nov 7;40:101774. doi: 10.1016/j.rmcr.2022.101774. eCollection 2022.

ABSTRACT

Cystic fibrosis (CF) is a multi-systemic autosomal recessive disease which mostly involves the respiratory, digestive, and reproductive systems, but it can present with various clinical presentations, especially in adulthood. We describe a 19-year-old boy, a known case of CF who presented with less known clinical presentations of CF, blindness, liver cirrhosis, vitamin A deficiency, and pancytopenia.

PMID:36386283 | PMC:PMC9650065 | DOI:10.1016/j.rmcr.2022.101774

Indian J Dermatol. 2022 May-Jun;67(3):287-289. doi: 10.4103/ijd.IJD_243_17.

ABSTRACT

Dermatitis as an initial manifestation of cystic fibrosis (CF) is unusual. The eruption is usually first noted in the perineum anywhere from several days to few months after birth. It subsequently spreads to the extremities and trunk. We report a 2-month-old male baby who presented with failure to thrive, hypoproteinemia, anemia, and a cutaneous eruption resembling acrodermatitis enteropathica. Oral zinc supplementation resulted in temporary resolution of the dermatitis. A further workup revealed the diagnosis of CF. The rash was responsive to nutritional and pancreatic enzyme supplementation.

PMID:36386118 | PMC:PMC9644797 | DOI:10.4103/ijd.IJD_243_17

Int J Pharm. 2022 Nov 13:122400. doi: 10.1016/j.ijpharm.2022.122400. Online ahead of print.

ABSTRACT

The potential of intra-venous gallium nitrate (GaN) administration against Pseudomonas aeruginosa pneumonia was recently demonstrated in mice and in cystic fibrosis (CF) patients. Likewise, the added value of direct lung delivery of Ga(III) has been shown in rats. Therefore, the design of a drug delivery system specifically engineered for Ga(III) inhalation is imperative to improve its accumulation in lungs. To this purpose, Ga(III) was efficiently encapsulated into hyaluronic acid/chitosan nanoparticles (Ga_HA/CS NPs), whose features were tuned to facilitate access to the target by overcoming mucus and biofilm surrounding bacteria. Then, to improve in vivo lung deposition, Ga_HA/CS NPs were engineered into mannitol-based NEM (Ga_Man NEM). The powders showed optimal in vitro aerosol performance, and sustained release kinetics in lung lining fluids. Moreover, good tolerability and antimicrobial properties were shown in vitro. Intratracheal insufflation of Ga_Man NEM in rats resulted in a significant improvement of Ga(III) persistence in the lungs coupled to a lower Ga(III) concentration in plasma and urine, compared to GaN solution. Noteworthy, the developed formulation significantly modifies the unfavorable Ga(III) kinetic increasing the Ga(III) to the lung and preventing Ga(III) accumulation in the kidney, key responsible for adverse effects, conclusively demonstrating the benefit of Ga_Man NEM to exploit the therapeutic effect of Ga(III) via inhalation route.

PMID:36384182 | DOI:10.1016/j.ijpharm.2022.122400

ERJ Open Res. 2022 Nov 14;8(4):00204-2022. doi: 10.1183/23120541.00204-2022. eCollection 2022 Oct.

ABSTRACT

BACKGROUND: Although short-term efficacy of lumacaftor/ivacaftor and tezacaftor/ivacaftor is clearly established in clinical trials, data on long-term effectiveness is limited. This registry-based cohort study assessed real-world longitudinal outcomes of F508del-homozygous people with cystic fibrosis (pwCF) ≥12 years, up to 3 years after the introduction of dual cystic fibrosis transmembrane conductance regulator (CFTR) modulators.

METHODS: Annual data (2010-2019) were retrieved from the Dutch Cystic Fibrosis Registry. Longitudinal trends of per cent predicted forced expiratory volume in 1 s (FEV1 % pred) decline, body mass index (BMI), BMI Z-score and intravenous antibiotic treatment duration before and after CFTR modulator initiation were assessed with linear and negative binomial mixed models.

RESULTS: We included 401 participants (41.9% female, baseline age 24.5 years (IQR 18.0-31.5 years), baseline mean±sd FEV1 70.5±23.4% pred). FEV1 decline improved from -1.36% pred per year to -0.48% pred per year after modulator initiation (change: 0.88% pred, 95% CI: 0.35-1.39%, p=0.001). This change was even 1.40% pred per year (95% CI: -0.0001-2.82%, p=0.050) higher in participants with baseline FEV1 <40% pred. In adults, annual BMI trend was not altered (change: 0.10 kg·m-2·year-1, 95% CI:-0.01-0.21, p=0.079). Annual BMI Z-score in children reversed from -0.08 per year before modulator treatment to 0.06 per year afterwards (change: 0.14 per year, 95% CI: 0.06-0.22, p<0.001). Intravenous antibiotic treatment duration showed a three-fold reduction in the first year after modulator initiation (incidence rate ratios (IRR): 0.28, 95% CI: 0.19-0.40, p<0.001), but the annual trend did not change in the subsequent years (IRR: 1.19, 95% CI: 0.94-1.50, p=0.153).

CONCLUSION: Long-term effectiveness of dual CFTR modulator therapies on FEV1 decline, BMI and intravenous antibiotic treatment duration is less pronounced in a real-world setting than in clinical trials and varies considerably between pwCF and different baseline FEV1 levels.

PMID:36382237 | PMC:PMC9661249 | DOI:10.1183/23120541.00204-2022

ERJ Open Res. 2022 Nov 7;8(4):00340-2022. doi: 10.1183/23120541.00340-2022. eCollection 2022 Oct.

ABSTRACT

Non-cystic fibrosis bronchiectasis (NCFB) is a highly prevalent chronic respiratory disease with substantial burden to both patients and healthcare systems. Persons with NCFB (pwNCFB) are often given complex acute and chronic treatment regimens consisting of medications, airway clearance techniques and exercise. Accordingly, the high burden in NCFB has contributed to lower therapy adherence, with estimates of 53% to medications, 41% to airway clearance and only 16% to all prescribed therapy. Consequent clinical outcomes from lower adherence include reduced quality of life, accelerated lung function decline and recurrent pulmonary exacerbations. In this narrative review, we explore the impact of multifactorial mechanisms underpinning adherence in NCFB and evaluate the available evidence towards interventions to improve uptake of therapy as demonstrated in other chronic respiratory diseases. A holistic approach, starting with a careful review of patient adherence at regular intervals, may increase the success of multidimensional therapeutic interventions in pwNCFB, but robust ongoing studies are an area of need in this population.

PMID:36382236 | PMC:PMC9638830 | DOI:10.1183/23120541.00340-2022

ERJ Open Res. 2022 Nov 7;8(4):00170-2022. doi: 10.1183/23120541.00170-2022. eCollection 2022 Oct.

ABSTRACT

INTRODUCTION: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis and is associated with deleterious clinical outcomes. Insulin is recommended as a treatment by international guidelines. However, there are scarce clinical trial data to support the use of insulin, and little is known about the long-term outcomes of treatment. The aim of this study was to compare the long-term impacts of insulin use versus non-use in CFRD.

METHODS: We used data from the national UK Cystic Fibrosis Registry and adopted a target trial framework. Eligible individuals included those 12 years and older with a new diagnosis of CFRD. Outcomes were change in % predicted forced expiratory volume in 1 s (FEV1 %) and body mass index z-scores (BMI) over a 5-year follow-up period. Treatment strategies were to receive insulin or not for the duration of follow-up. Treatment effect estimates were obtained using two methods to control for confounding: inverse-probability-of-treatment weighted estimation of marginal structural models and the G-formula.

RESULTS: We identified 1613 individuals diagnosed with CFRD between 2008 and 2016 and included 1196 and 1192 in the FEV1 % and BMI outcome analyses respectively. We found no evidence of an effect of insulin on FEV1 % over the 5-year study period. Similarly, we found no overall effect of insulin on BMI; however, there was some evidence for a positive treatment effect in patients with lower baseline BMI.

CONCLUSION: Using well-established national registry data, we found no evidence of long-term treatment effects for insulin on FEV1 % or BMI in people with incident CFRD.

PMID:36382232 | PMC:PMC9638829 | DOI:10.1183/23120541.00170-2022

Aust Prescr. 2022 Oct;45(5):171-175. doi: 10.18773/austprescr.2022.063. Epub 2022 Oct 4.

ABSTRACT

Cystic fibrosis is the most common life-limiting autosomal recessive condition in Australia. A defect in the cystic fibrosis transmembrane conductance regulator protein affects chloride transport across epithelial cells. Patients with cystic fibrosis produce thick sticky mucus. This causes problems in multiple organs, particularly the lungs. Cystic fibrosis modulator therapies can partially correct the underlying pathophysiology and improve chloride transport, thereby improving morbidity. Life expectancy is improving, so many patients are now developing chronic diseases associated with ageing. All health professionals should be aware that the cystic fibrosis modulator therapies are metabolised via cytochrome P450 pathways in the liver. There are therefore significant drug-drug interactions with medicines metabolised by the same pathways.

PMID:36382177 | PMC:PMC9584790 | DOI:10.18773/austprescr.2022.063

Chron Respir Dis. 2022 Jan-Dec;19:14799731221131330. doi: 10.1177/14799731221131330.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is characterized by CF transmembrane conductance regulator (CFTR) dysfunction. CFTR protein is expressed in human skeletal muscle; however, its impact on skeletal muscle is unknown. The objectives of this study were to compare quadriceps muscle size and quality between adults with various severities of CFTR protein dysfunction.

METHODS: We conducted a prospective, cross-sectional study comparing 34 adults with severe versus 18 with mild CFTR protein dysfunction, recruited from a specialized CF centre. Ultrasound images of rectus femoris cross-sectional area (RF-CSA) and quadriceps layer thickness for muscle size, and rectus femoris echogenicity (RF-ECHO) (muscle quality) were obtained. Multivariable linear regression models were developed using purposeful selection technique.

RESULTS: People with severe CFTR protein dysfunction had larger RF-CSA by 3.22 cm2, 95% CI (1.03, 5.41) cm2, p=.0049], after adjusting for oral corticosteroid use and Pseudomonas aeruginosa colonization. However, a sensitivity analysis indicated that the result was influenced by the specific confounders being adjusted for in the model. We did not find any significant differences in quadriceps layer thickness or RF-ECHO between the two groups.

CONCLUSION: We found no differential impact of the extent of diminished CFTR protein activity on quadriceps muscle size or quality in our study cohort. Based on these findings, CFTR mutation status cannot be used differentiate leg muscle size or quality in people with CF.

PMID:36380568 | DOI:10.1177/14799731221131330

J Allergy Clin Immunol Pract. 2022 Nov 12:S2213-2198(22)01190-4. doi: 10.1016/j.jaip.2022.10.045. Online ahead of print.

ABSTRACT

BACKGROUND: Hospitalization for severe influenza infection in childhood may result in post-discharge sequelae.

OBJECTIVE(S): To evaluate inpatient management and post-discharge sequelae in children with critical respiratory illness due to influenza with or without pre-existing asthma.

METHODS: Prospective, observational multicenter study of children (8-months to 17-years-old) admitted to a pediatric intensive care or high-acuity unit (11/2019-4/2020) for influenza. Results were stratified by pre-existing asthma. Pre-hospital status, hospital treatments and outcomes were collected. Surveys at approximately 90 days post-discharge evaluated post-discharge health resource use, functional status, and respiratory symptoms.

RESULTS: 165 children with influenza: 56 (33.9%) with and 109 (66.1%) without pre-existing asthma (41.1% and 39.4% fully vaccinated against influenza, respectively). Fifteen (26.7%) patients with and 34 (31.1%) without pre-existing asthma were intubated. More patients with versus without pre-existing asthma received pharmacologic asthma treatments during hospitalization (76.7% vs 28.4%). Of 136 (82.4%) patients with 90-day survey data (46 [33.8%] with and 90 [66.1%] without pre-existing asthma), a similar proportion had an Emergency Department/urgent care visit (4.3%, 6.6%) or hospital readmission (8.6%, 3.3%) for a respiratory condition. Patients with pre-existing asthma more frequently experienced asthma symptoms (78.2% vs 3.3%) and had respiratory specialist visits (52% vs 20%) post-discharge. Ten of 109 (11.1%) patients without pre-existing asthma reported being newly diagnosed with asthma.

CONCLUSIONS: Respiratory health resource use and symptoms are important post-discharge outcomes after influenza critical illness in children with and without pre-existing asthma. Less than half of children were vaccinated for influenza, a tool that could mitigate critical illness and its sequelae.

PMID:36379408 | DOI:10.1016/j.jaip.2022.10.045

ACS Infect Dis. 2022 Nov 15. doi: 10.1021/acsinfecdis.2c00448. Online ahead of print.

ABSTRACT

Patients with cystic fibrosis (CF) have a significantly higher risk of acquiring nontuberculous mycobacteria infections, predominantly due to Mycobacterium abscessus, than the healthy population. Because M. abscessus infections are a major cause of clinical decline and morbidity in CF patients, improving treatment and the detection of this mycobacterium in the context of a polymicrobial culture represents a critical component to better manage patient care. We report here the synthesis of fluorescent Dansyl derivatives of four active cyclipostins and cyclophostin analogues (CyCs) and provide new insights regarding the CyC's lack of activity against Gram-negative and Gram-positive bacteria, and above all into their mode of action against intramacrophagic M. abscessus cells. Our results pointed out that the intracellularly active CyC accumulate in acidic compartments within macrophage cells, that this accumulation appears to be essential for their delivery to mycobacteria-containing phagosomes, and consequently, for their antimicrobial effect against intracellular replicating M. abscessus, and that modification of such intracellular localization via disruption of endolysosomal pH strongly affects the CyC accumulation and efficacy. Moreover, we discovered that these fluorescent compounds could become efficient probes to specifically label mycobacterial species with high sensitivity, including M. abscessus in the presence several other pathogens like Pseudomonas aeruginosa and Staphylococcus aureus. Collectively, all present and previous data emphasized the therapeutic potential of unlabeled CyCs and the attractiveness of the fluorescent CyC as a potential new efficient diagnostic tool to be exploited in future diagnostic developments against mycobacterial-related infections, especially against M. abscessus.

PMID:36379042 | DOI:10.1021/acsinfecdis.2c00448

Cell Mol Life Sci. 2022 Nov 15;79(12):592. doi: 10.1007/s00018-022-04619-1.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that is crucial for fluid homeodynamics throughout the male reproductive tract. Previous evidence shed light on a potential molecular partnership between this channel and aquaporins (AQPs). Herein, we explore the role of CFTR on AQPs-mediated glycerol permeability in mouse Sertoli cells (mSCs). We were able to identify the expression of CFTR, AQP3, AQP7, and AQP9 in mSCs by RT-PCR, Western blot, and immunofluorescence techniques. Cells were then treated with CFTRinh-172, a specific CFTR inhibitor, and its glycerol permeability was evaluated by stopped-flow light scattering. We observed that CFTR inhibition decreased glycerol permeability in mSCs by 30.6% when compared to the control group. A DUOLINK proximity ligation assay was used to evaluate the endogenous protein-protein interactions between CFTR and the various aquaglyceroporins we identified. We positively detected that CFTR is in close proximity with AQP3, AQP7, and AQP9 and that, through a possible physical interaction, CFTR can modulate AQP-mediated glycerol permeability in mSCs. As glycerol is essential for the control of the blood-testis barrier and elevated concentration in testis results in the disruption of spermatogenesis, we suggest that the malfunction of CFTR and the consequent alteration in glycerol permeability is a potential link between male infertility and cystic fibrosis.

PMID:36378343 | DOI:10.1007/s00018-022-04619-1

mBio. 2022 Nov 15:e0254122. doi: 10.1128/mbio.02541-22. Online ahead of print.

ABSTRACT

The human pathogen Pseudomonas aeruginosa (Pa) is one of the most frequent and severe causes of nosocomial infection. This organism is also a major cause of airway infections in people with cystic fibrosis (CF). Pa is known to have a remarkable metabolic plasticity, allowing it to thrive under diverse environmental conditions and ecological niches; yet, little is known about the central metabolic pathways that sustain its growth during infection or precisely how these pathways operate. In this work, we used a combination of 'omics approaches (transcriptomics, proteomics, metabolomics, and 13C-fluxomics) and reverse genetics to provide systems-level insight into how the infection-relevant organic acids succinate and propionate are metabolized by Pa. Moreover, through structural and kinetic analysis of the 2-methylcitrate synthase (2-MCS; PrpC) and its paralogue citrate (CIT) synthase (GltA), we show how these two crucial enzymatic steps are interconnected in Pa organic acid assimilation. We found that Pa can rapidly adapt to the loss of GltA function by acquiring mutations in a transcriptional repressor, which then derepresses prpC expression. Our findings provide a clear example of how "underground metabolism," facilitated by enzyme substrate promiscuity, "rewires" Pa metabolism, allowing it to overcome the loss of a crucial enzyme. This pathogen-specific knowledge is critical for the advancement of a model-driven framework to target bacterial central metabolism. IMPORTANCE Pseudomonas aeruginosa is an opportunistic human pathogen that, due to its unrivalled resistance to antibiotics, ubiquity in the built environment, and aggressiveness in infection scenarios, has acquired the somewhat dubious accolade of being designated a "critical priority pathogen" by the WHO. In this work, we uncover the pathways and mechanisms used by P. aeruginosa to grow on a substrate that is abundant at many infection sites: propionate. We found that if the organism is prevented from metabolizing propionate, the substrate turns from being a convenient nutrient source into a potent poison, preventing bacterial growth. We further show that one of the enzymes involved in these reactions, 2-methylcitrate synthase (PrpC), is promiscuous and can moonlight for another essential enzyme in the cell (citrate synthase). Indeed, mutations that abolish citrate synthase activity (which would normally prevent the cell from growing) can be readily overcome if the cell acquires additional mutations that increase the expression of PrpC. This is a nice example of the evolutionary utility of so-called "underground metabolism."

PMID:36377867 | DOI:10.1128/mbio.02541-22

Paediatr Respir Rev. 2022 Oct 5:S1526-0542(22)00067-7. doi: 10.1016/j.prrv.2022.10.001. Online ahead of print.

ABSTRACT

Cystic Fibrosis-Related Diabetes (CFRD) is a unique type of diabetes mellitus that shares some features with both type 1 and type 2 diabetes. Yet, its distinguishing feature of acute pulmonary complications associated with hyperglycemia and the catabolic metabolism associated with a relative insulin deficiency poses challenges to the application of traditional definitions and treatments for diabetes mellitus. People with CF (pwCF) undergo rigorous annual screening starting at age 10, a process that is challenging for patients and limited by sensitivity, specificity, and reproducibility. As pwCF continue to live longer, over 50% are expected to develop CFRD over their lifetime, including up to 20% of adolescents. Increasing numbers of people with CFRD will make this disease increasingly relevant to diabetes practitioners. Evidence-guided practice in CFRD care is limited by small and short studies. Our current understanding of CFRD may change significantly with the recent introduction of CF Transmembrane Regulator (CFTR) modulator medications. This review will explore current challenges in the diagnosis and management of CFRD, specifically highlighting knowledge gaps in the pathophysiology of CFRD, optimal screening methods, priorities for research and provide guidance with regards to screening, diagnosis, and treatment.

PMID:36376223 | DOI:10.1016/j.prrv.2022.10.001

J Sport Health Sci. 2022 Oct 29:S2095-2546(22)00103-X. doi: 10.1016/j.jshs.2022.10.003. Online ahead of print.

ABSTRACT

Exercise has long been known for its active role in improving physical fitness and sustaining health. Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases. It is well-documented that exercise maintains and restores homeostasis at the organismal, tissue, cellular, and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions. Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health, including the integrity of barriers, containment of local perturbations, recycling and turnover, integration of circuitries, rhythmic oscillations, homeostatic resilience, hormetic regulation, as well as repair and regeneration. Furthermore, we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise. This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions. We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.

PMID:36374766 | DOI:10.1016/j.jshs.2022.10.003

Microbiol Spectr. 2022 Nov 14:e0304322. doi: 10.1128/spectrum.03043-22. Online ahead of print.

ABSTRACT

Heterogeneous environments such as the chronically infected cystic fibrosis lung drive the diversification of Pseudomonas aeruginosa populations into, e.g., mucoid, alginate-overproducing isolates or small-colony variants (SCVs). In this study, we performed extensive genome and transcriptome profiling on a clinical SCV isolate that exhibited high cyclic diguanylate (c-di-GMP) levels and a mucoid phenotype. We observed a delayed, stepwise decrease of the high levels of c-di-GMP as well as alginate gene expression upon passaging the SCV under noninducing, rich medium growth conditions over 7 days. Upon prolonged passaging, this lagging reduction of the high c-di-GMP levels under noninducing planktonic conditions (reminiscent of a hysteretic response) was followed by a phenotypic switch to a large-colony morphology, which could be linked to mutations in the Gac/Rsm signaling pathway. Complementation of the Gac/Rsm signaling-negative large-colony variants with a functional GacSA system restored the SCV colony morphotype but was not able to restore the high c-di-GMP levels of the SCV. Our data thus suggest that expression of the SCV colony morphotype and modulation of c-di-GMP levels are genetically separable and follow different evolutionary paths. The delayed switching of c-di-GMP levels in response to fluctuating environmental conditions might provide a unique opportunity to include a time dimension to close the gap between short-term phenotypic and long-term genetic adaptation to biofilm-associated growth conditions. IMPORTANCE Extreme environments, such as those encountered during an infection process in the human host, make effective bacterial adaptation inevitable. While bacteria adapt individually by activating stress responses, long-term adaptation of bacterial communities to challenging conditions can be achieved via genetic fixation of favorable traits. In this study, we describe a two-pronged bacterial stress resistance strategy in the opportunistic pathogen Pseudomonas aeruginosa. We show that the production of adjusted elevated c-di-GMP levels, which drive protected biofilm-associated phenotypes in vivo, resembles a stable hysteretic response which prevents unwanted frequent switching. Cellular hysteresis might provide a link between individual adaptability and evolutionary adaptation to ensure the evolutionary persistence of host-adapted stress response strategies.

PMID:36374016 | DOI:10.1128/spectrum.03043-22

Cochrane Database Syst Rev. 2022 Nov 14;11:CD001021. doi: 10.1002/14651858.CD001021.pub4.

ABSTRACT

BACKGROUND: Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review.

OBJECTIVES: To evaluate the effects of long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug-sensitivity reactions and survival).

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries. Date of last search: 28 June 2022.

SELECTION CRITERIA: We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic).

DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system.

MAIN RESULTS: The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials. Inhaled antibiotics compared to placebo We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates. Different antibiotics or regimens compared Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEV1) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high.

AUTHORS' CONCLUSIONS: Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

PMID:36373968 | DOI:10.1002/14651858.CD001021.pub4

Pediatr Pulmonol. 2022 Nov 13. doi: 10.1002/ppul.26243. Online ahead of print.

ABSTRACT

BACKGROUND: While the positive effect of Trikafta on cystic fibrosis (CF) pulmonary disease is well established, there is limited data about its effect on bone mineral density (BMD), body composition and exercise capacity.

METHODS: A pilot single center study. BMD and body composition were measured three months after the initiation of Trikafta (study group) and compared to values obtained two years earlier. CF patients not treated with Trikafta, for whom BMD was measured two years apart, served as controls. Spirometry, lung clearance index (LCI), sweat test, six-minute walk test (6MWT) and cardio-pulmonary exercise test (CPET) were performed before and three months after the initiation of Trikafta.

RESULTS: Nine study patients, aged 18.6±4.7 years, and nine controls. For the study group, BMI and hip and spine BMD increased significantly (19.4±2.6 to 20.3±2.19 BMI, p=0.05; 0.73±0.098 to 0.81±0.12gr/cm2 hip, p=0.017; 0.76±0.14 to 0.82±0.14gr/cm2 spine, p=0.025). For the control group, there was no difference in hip or spine BMD. Lean body mass, %fat z-score and fat mass/height2 z-score increased significantly (34770.23±10521.21 to 37430.16±10330.09gr, p=0.017; -0.8±0.75 to 0.46±0.58, p=0.012; and -0.98±0.66 to -0.04±0.51, p=0.025, respectively). 6MWT improved from 541.1±48.9 to 592.9±54.5m (p=0.046). As expected, FEV1%pred increased (p=0.008) and sweat chloride decreased significantly (p=0.017). In CPET, VE/VCO2 improved, indicating better ventilatory efficiency.

CONCLUSIONS: To the best of our knowledge, this is the first study evaluating the metabolic effects of Trikafta. The results are encouraging and offer hope beyond the well-established effect on pulmonary disease. Larger long-term studies are warranted to unpin the underlying physiological mechanisms. This article is protected by copyright. All rights reserved.

PMID:36372909 | DOI:10.1002/ppul.26243