Microbiol Spectr. 2022 Mar 22:e0274021. doi: 10.1128/spectrum.02740-21. Online ahead of print.

ABSTRACT

Extensively drug-resistant Pseudomonas aeruginosa (XDRPA) infection is a significant public health threat due to a lack of effective therapeutic options. New β-lactam-β-lactamase inhibitor combinations, including ceftazidime-avibactam (CZA), have shown a high resistance rate to XDRPA. This study was therefore conducted to describe the underlying genomic mechanism of resistance for CZA nonsusceptible XDRPA strains that are non-metallo-β-lactamase (MBL) producers as well as to examine synergism of CZA and other antipseudomonal agents. Furthermore, the synergistic antibacterial activity of the most effective antimicrobial combination against non-MBL-producing XDRPA was evaluated through in vitro experiments. The resistance profiles of 15 CZA-resistant XDRPA strains isolated from clinical specimens in China-Japan Friendship Hospital between January 2017 to December 2020 were obtained by whole-genome sequencing (WGS) analysis. MBL genes blaIMP-1 and blaIMP-45 were found in 2 isolates (2/15, 13.3%); the other underlying CZA-resistance mechanisms involved the decreased OprD porin (13/13), blaAmpC overexpression (8/13) or mutation (13/13), and upregulated efflux pumps (13/13). CZA-imipenem (CZA-IPM) combination was identified to be the most effective against non-MBL-producing XDRPA according to the results of WGS analysis and combined antimicrobial susceptibility tests, with an approximately 16.62-fold reduction in MICs compared to CZA alone. Furthermore, the results of checkerboard analysis and growth curve displayed the synergistic antimicrobial activity of CZA and IPM against non-MBL-producing XDRPA. Electron microscopy also revealed that CZA-IPM combination might lead to more cellular structural alterations than CZA or IPM alone. This study suggested that the CZA-IPM combination has potential for non-MBL-producing XDRPA with blaAmpC overexpression or mutation, decreased OprD porin, and upregulated efflux pumps. IMPORTANCE Handling the infections by extensively drug-resistant Pseudomonas aeruginosa (XDRPA) strains is challenging due to their complicated antibiotic resistance mechanisms in immunosuppressed patients with pulmonary diseases (e.g., cystic fibrosis, chronic obstructive pulmonary disease, and lung transplant), ventilator-associated pneumonia, and bloodstream infections. The current study suggested the potentiality of the ceftazidime-avibactam-imipenem combination against XDRPA with blaAmpC overexpression or mutation, decreased OprD porin, and/or upregulated efflux pumps. Our findings indicate the necessity of combined drug sensitivity tests against XDRPA and also lay a foundation for the development of prevention, control, and treatment strategies in XDRPA infections.

PMID:35315696 | DOI:10.1128/spectrum.02740-21

Acta Biomed. 2022 Mar 14;93(1):e2022021. doi: 10.23750/abm.v93i1.10731.

ABSTRACT

BACKGROUND: Anxiety and depression may affect asthma control. Previously, it has been reported that the hospital anxiety depression scale (HADS) questionnaire was fruitful in the management of adolescents with asthma. This study compared the scores of two different questionnaires, namely the Childhood Anxiety Sensitivity Index (CASI) and Children's Depression Inventory (CDI), with asthma control level and lung function in asthmatic adolescents, evaluated in a real-life setting.

METHODS: A group of adolescents with asthma was consecutively enrolled. Asthma was diagnosed according to the GINA document, and consistently the symptom control grade was assessed. The adolescents completed the CASI, CDI, and Asthma Control Test (ACT) questionnaires. Visual Analogue Scale (VAS) for asthma symptoms perception and doctor's asthma control evaluation were considered. Lung function and clinical characteristics were also assessed.

RESULTS: Totally, 87 asthmatic adolescents (60 males, 27 females, median age 14.2 years) were evaluated. 16.1% of asthmatic adolescents had anxious symptoms detected by CASI, and 11.5% depressive symptoms revealed by CDI. High scores of both CASI and CDI were significantly associated with uncontrolled asthma (p= 0.013 and 0.043, respectively).

CONCLUSIONS: This study showed that anxiety and depression affected asthma control. Thus, in clinical practice, the psychological assessment could be included in asthmatic adolescents' asthma work-up.

PMID:35315428 | DOI:10.23750/abm.v93i1.10731

JCI Insight. 2022 Mar 22;7(6):e152186. doi: 10.1172/jci.insight.152186.

ABSTRACT

Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the CF transmembrane conductance regulator (CFTR) gene. Converging evidence suggests that CF carriers with only 1 defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control (HC) PBMCs or THP-1 cells incubated with the plasma of these participants. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1β, CXCL8, CREM), implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents. These data suggest that a homozygous as well as a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the finding of lower numbers of circulating monocytes in CF probands and their parents, compared with HCs, and the abundance of mononuclear phagocyte subsets, which correlated with Pseudomonas aeruginosa infection, lung disease severity, and CF progression in the probands. This study provides insight into demonstrated CFTR-related innate immune dysfunction in individuals with CF and carriers of a CFTR mutation that may serve as a target for personalized therapy.

PMID:35315363 | DOI:10.1172/jci.insight.152186

JCI Insight. 2022 Mar 22;7(6):e148841. doi: 10.1172/jci.insight.148841.

ABSTRACT

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o-) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.

PMID:35315358 | DOI:10.1172/jci.insight.148841

Klin Padiatr. 2022 Mar 21. doi: 10.1055/a-1712-4225. Online ahead of print.

ABSTRACT

BACKGROUND: Antibiotic use during asthma exacerbations in paediatric patients is not routinely recommended but common practise in out-patient and in-patient settings. Objective of this study was to analyse frequency of antibiotic use during acute severe asthma exacerbations, antibiotic classes utilized and clinical decision-making.

METHODS: All in-patient admissions over 10 years in a single German Children's University hospital due to acute severe asthma were included in this retrospective analysis. Age, length of stay, oxygen supplementation, treatment, laboratory parameters and chest x-rays of all patients ranging from 1 to 17 years were analysed.

RESULTS: 580 hospital admissions were included in this study. Overall antibiotic use was high but decreased with age (1-5 years 69,6%, 6-11 years 57,6% and 12-17 years 39,7%, p<0.001). Analysis of antibiotic treatment without clear indication showed a consistently lower treatment rate of 28.3%, with macrolides being the most common antibiotic class. Younger age significantly decreased, whereas, increase of CrP value, use of oxygen supplementation and concomitant fever all significantly increased the odds ratio (OR 0.967; 4.366, 2.472 and 2.011 respectively) of receiving antibiotic treatment without clear indication.

CONCLUSION: Antibiotic treatment without clear indication during acute severe asthma is common in this German single-centre cohort. Clinical parameters of more severe disease affect clinician's decision to administer antibiotics despite evidence of bacterial infection or improved outcome.

PMID:35315003 | DOI:10.1055/a-1712-4225

NPJ Genom Med. 2022 Mar 21;7(1):23. doi: 10.1038/s41525-022-00287-z.

ABSTRACT

Traditional carrier screening has been utilized for the detection of carriers of genetic disorders. Since a comprehensive assessment of the carrier frequencies of recessive conditions in the Southern Chinese population is not yet available, we performed a secondary analysis on the spectrum and carrier status for 315 genes causing autosomal recessive disorders in 1543 Southern Chinese individuals with next-generation sequencing data, 1116 with exome sequencing and 427 with genome sequencing data. Our data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.30% of the population) was a carrier for treatable inherited conditions. In alignment with current American College of Obstetricians and Gynecologists (ACOG) pan-ethnic carrier recommendations, 1 in 26 individuals were identified as carriers of cystic fibrosis, thalassemia, and spinal muscular atrophy in the Southern Chinese population. When the >1% expanded carrier screening rate recommendation by ACOG was used, 11 diseases were found to meet the criteria in the Southern Chinese population. Approximately 1 in 3 individuals (35.5% of the population) were carriers of these 11 conditions. If the 1 in 200 carrier frequency threshold is used, and additional seven genes would meet the criteria, and 2 in 5 individuals (38.7% of the population) would be detected as a carrier. This study provides a comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population and can serve as a reference for careful evaluation of the conditions to be included in expanded carrier screening for Southern Chinese people.

PMID:35314707 | DOI:10.1038/s41525-022-00287-z

J Allergy Clin Immunol. 2022 Mar 18:S0091-6749(22)00344-X. doi: 10.1016/j.jaci.2022.03.006. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic rhinosinusitis (CRS) and bronchiectasis commonly co-occur, but most prior studies were not designed to evaluate temporality and causality.

OBJECTIVES: In a sample representing the general population in 37 counties in Pennsylvania, and thus the full spectrum of sinonasal and relevant lung diseases, we evaluated temporality and strength of associations of CRS with non-cystic fibrosis bronchiectasis.

METHODS: We completed case-control analyses for each of three primary bronchiectasis case finding methods. We used electronic health records to identify CRS and bronchiectasis with diagnoses, procedure orders, and/or specific text in sinus or chest computerized tomography (CT) scans. Controls never had any indication of bronchiectasis and were frequency-matched to the three bronchiectasis groups on age, sex, and encounter year. There were 5,329 unique persons with bronchiectasis and 33,363 without in the three analyses. Important co-occurring conditions were identified with diagnoses, medication orders, and encounter types. Logistic regression was used to evaluate associations (odds ratios [OR], 95% confidence intervals) of CRS with bronchiectasis while adjusting for confounding variables.

RESULTS: In adjusted analyses, CRS was consistently and strongly associated with all three bronchiectasis definitions. Associations (odds ratio, 95% confidence interval) were strongest for CRS based on sinus CT scan text and were generally stronger for CRS without nasal polyps (e.g., OR = 4.46 [2.09, 9.51] for diagnosis-based bronchiectasis). On average, CRS was identified over six years before bronchiectasis.

CONCLUSION: Precedent CRS was strongly and consistently associated with increased risk of bronchiectasis.

CLINICAL IMPLICATION: Early treatment of sinonasal disease may offer therapeutic strategies for prevention of bronchiectasis.

PMID:35314187 | DOI:10.1016/j.jaci.2022.03.006

Orphanet J Rare Dis. 2022 Mar 21;17(1):129. doi: 10.1186/s13023-022-02279-9.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a common, life-threatening genetic disease in Caucasians but rarely reported in Chinese population. The prevalence and population-specific genetic spectrum of CF in China needs to be systematically estimated and compared with Caucasians.

MATERIALS AND METHODS: We reviewed 30,951 exome-sequencing samples, including 20,909 pediatric patient samples and 10,042 parent samples, from Chinese Children's Rare Disease Genetic Testing Clinical Collaboration System (CCGT). After the in-lab filtration process, 477 candidate variants of CFTR gene were left and 53 variants were manually curated as pathogenic/likely-pathogenic (P/LP). These P/LP variants were adopted to estimate CF prevalence in three methods: the carrier frequency method, the permutation-combinations method and the Bayesian framework method. Allele frequencies of the 477 CFTR variants were compared with non-Finland European (NFE) and East Asian (EAS) from gnomAD database. To investigate the haplotype structure difference of CFTR, another 2067 whole-genome-sequencing samples from CCGT and 195 NFE from 1000 genome project were analyzed by Shapeit4 software.

RESULT: With the 53 manually curated P/LP variants in CFTR gene, we excluded individuals identified or suspected with CF and their parents in our cohorts and estimated the Chinese CF prevalence is approximately 1/128,434. Only 21 (39.6%) of the 53 variants were included in Caucasian specific CF screening panels, resulting in significantly under-estimation of CF prevalence in our children cohort (1/143,171 vs. 1/1,387,395, P = 5e-24) and parent's cohort (1/110,127 vs. 1/872,437, P = 7e-10). The allele frequencies of six pathogenic variants (G970D, D979A, M469V, G622D, L88X, 1898+5G->T) were significantly higher in our cohorts compared with gnomAD-NFE population (all P-value < 0.1). Haplotype analysis showed more haplotype diversity in Chinese compared to Caucasians. In addition, G970D and F508del were founder mutation of Chinese and Caucasians with two SNPs (rs213950-rs1042077) identified as related genotype in exon region.

CONCLUSIONS: Chinese population showed significantly different genetic spectrum pattern in CFTR gene compared with Caucasian population, and thus a Chinese-specific CF screening panel is needed.

PMID:35313924 | DOI:10.1186/s13023-022-02279-9

Expert Rev Respir Med. 2022 Mar 21. doi: 10.1080/17476348.2022.2056021. Online ahead of print.

NO ABSTRACT

PMID:35313109 | DOI:10.1080/17476348.2022.2056021

PLoS One. 2022 Mar 21;17(3):e0265432. doi: 10.1371/journal.pone.0265432. eCollection 2022.

ABSTRACT

The genetic disease cystic fibrosis (CF) results when mutations in the gene for the anion channel CFTR reduce CFTR's activity below a critical level. CFTR activity = N·PO·γ (number of channels x open probability x channel conductance). Small molecules are now available that partially restore CFTR function with dramatic improvements in health of CF subjects. Continued evaluation of these and other compounds in development will be aided by accurate assessments of CFTR function. However, measuring CFTR activity in vivo is challenging and estimates vary widely. The most accurate known measure of CFTR activity in vivo is the 'β/M' ratio of sweat rates, which is produced by stimulation with a β-adrenergic agonist cocktail referenced to the same individual's methacholine-stimulated sweat rate. The most meaningful metric of CFTR activity is to express it as a percent of normal function, so it is critical to establish β/M carefully in a population of healthy control subjects. Here, we analyze β/M from a sample of 50 healthy adults in which sweat rates to cholinergic and β-adrenergic agonists were measured repeatedly (3 times) in multiple, (~50) identified sweat glands from each individual (giving ~20,000 measurements). The results show an approximately 7-fold range, 26-187% of the WT average set to 100%. These provide a benchmark against which other measures of CFTR activity can be compared. Factors contributing to β/M variation in healthy controls are discussed.

PMID:35312728 | DOI:10.1371/journal.pone.0265432

Arch Bronconeumol. 2021 Aug 24:S0300-2896(21)00219-2. doi: 10.1016/j.arbres.2021.08.005. Online ahead of print.

NO ABSTRACT

PMID:35312590 | DOI:10.1016/j.arbres.2021.08.005

Arch Bronconeumol. 2021 Oct 1:S0300-2896(21)00329-X. doi: 10.1016/j.arbres.2021.09.011. Online ahead of print.

NO ABSTRACT

PMID:35312571 | DOI:10.1016/j.arbres.2021.09.011

Arch Bronconeumol. 2021 Nov 17:S0300-2896(21)00377-X. doi: 10.1016/j.arbres.2021.11.002. Online ahead of print.

NO ABSTRACT

PMID:35312538 | DOI:10.1016/j.arbres.2021.11.002

Arch Bronconeumol. 2022 Feb 24:S0300-2896(22)00081-3. doi: 10.1016/j.arbres.2022.01.010. Online ahead of print.

ABSTRACT

In recent years, personalized or precision medicine has made effective inroads into the management of diseases, including respiratory diseases. The route to implementing this approach must invariably start with the identification and validation of biological biomarkers that are closely related to the diagnosis, treatment, and prognosis of respiratory patients. In this respect, biological biomarkers of greater or lesser reliability have been identified for most respiratory diseases and disease classes, and a large number of studies are being conducted in the search for new indicators. The aim of this review is to update the reader and to analyze the existing scientific literature on the existence and diagnostic, therapeutic, and prognostic validity of the most important biological biomarkers in the main respiratory diseases, and to identify future challenges in this area.

PMID:35312523 | DOI:10.1016/j.arbres.2022.01.010

Arch Bronconeumol. 2022 Jan 17:S0300-2896(22)00015-1. doi: 10.1016/j.arbres.2022.01.003. Online ahead of print.

ABSTRACT

In recent years, personalized or precision medicine has made effective inroads into the management of diseases, including respiratory diseases. The route to implementing this approach must invariably start with the identification and validation of biological biomarkers that are closely related to the diagnosis, treatment, and prognosis of respiratory patients. In this respect, biological biomarkers of greater or lesser reliability have been identified for most respiratory diseases and disease classes, and a large number of studies are being conducted in the search for new indicators. The aim of this review is to update the reader and to analyze the existing scientific literature on the existence and diagnostic, therapeutic, and prognostic validity of the most important biological biomarkers in the main respiratory diseases, and to identify future challenges in this area.

PMID:35312522 | DOI:10.1016/j.arbres.2022.01.003

Arch Bronconeumol. 2021 Dec 17:S0300-2896(21)00397-5. doi: 10.1016/j.arbres.2021.12.003. Online ahead of print.

NO ABSTRACT

PMID:35312519 | DOI:10.1016/j.arbres.2021.12.003

Front Microbiol. 2022 Mar 3;13:842017. doi: 10.3389/fmicb.2022.842017. eCollection 2022.

ABSTRACT

Mycobacterium abscessus is a member of the non-tuberculous mycobacteria (NTM) group, responsible for chronic infections in individuals with cystic fibrosis (CF) or those otherwise immunocompromised. While viewed traditionally as an opportunistic pathogen, increasing research into M. abscessus in recent years has highlighted its continued evolution into a true pathogen. This is demonstrated through an extensive collection of virulence factors (VFs) possessed by this organism which facilitate survival within the host, particularly in the harsh environment of the CF lung. These include VFs resembling those of other Mycobacteria, and non-mycobacterial VFs, both of which make a notable contribution in shaping M. abscessus interaction with the host. Mycobacterium abscessus continued acquisition of VFs is cause for concern and highlights the need for novel vaccination strategies to combat this pathogen. An effective M. abscessus vaccine must be suitably designed for target populations (i.e., individuals with CF) and incorporate current knowledge on immune correlates of protection against M. abscessus infection. Vaccination strategies must also build upon lessons learned from ongoing efforts to develop novel vaccines for other pathogens, particularly Mycobacterium tuberculosis (M. tb); decades of research into M. tb has provided insight into unconventional and innovative vaccine approaches that may be applied to M. abscessus. Continued research into M. abscessus pathogenesis will be critical for the future development of safe and effective vaccines and therapeutics to reduce global incidence of this emerging pathogen.

PMID:35308378 | PMC:PMC8928063 | DOI:10.3389/fmicb.2022.842017

Pediatr Pulmonol. 2022 Mar 20. doi: 10.1002/ppul.25899. Online ahead of print.

ABSTRACT

The recent development of disease-modifying treatments in Spinal Muscular Atrophy (SMA) type 1 shifted these patients' management from palliative to proactive. The aim of this study was to assess patients' nocturnal gas exchanges prior to NIV initiation and their clinical evolution in order to determine if capnia is a good criterion to decide when to introduce respiratory support. This multicentric retrospective study reports the respiratory management and evolution of 17 SMA type 1 children (10 females) for whom treatment with Nusinersen was initiated between 2016 and 2018. Median [IQR] age at diagnosis and at first Nusinersen injection was of 4 [3;8] and 4 [3;9] months, respectively. Patients were followed during 38 [24;44] months. Thirteen (76%) patients were started on Non-Invasive Ventilation (NIV) at a median [IQR] age of 12 [9;18] months. Repeated hospitalizations and ICU admissions were needed for 11 of them. Blood gas and nocturnal gas exchange recordings performed prior to NIV initiation were always normal. 9/13 X-ray performed prior to NIV showed atelectasis and/or acute lower respiratory tract infections. There was a significant decrease in the total number of hospital admissions between the first and second year of treatment (p=0.04). This study shows that patients do not present with nocturnal hypoventilation before respiratory decompensations and NIV initiation, and suggests that a delay in NIV initiation might result in respiratory complications. There is a need for disease-centered guidelines for the respiratory management of these patients, including NIV indications. This article is protected by copyright. All rights reserved.

PMID:35307979 | DOI:10.1002/ppul.25899

Intern Med J. 2022 Mar;52(3):508-509. doi: 10.1111/imj.15715.

NO ABSTRACT

PMID:35307926 | DOI:10.1111/imj.15715

Respir Med. 2022 Mar 1;196:106798. doi: 10.1016/j.rmed.2022.106798. Online ahead of print.

ABSTRACT

BACKGROUND: Evidence on resistance-training programs for cystic fibrosis (CF) is limited and the possible benefits of the addition of neuromuscular electrical stimulation (NMES) are unknown. This study aimed to evaluate the effects of a supervised resistance-training program, associated or not with NMES, on muscle strength, aerobic fitness, lung function and quality of life in children with CF presenting mild-to-moderate pulmonary impairment.

METHODS: This is a randomized controlled trial including CF patients aged between 6 and 17years. Subjects were randomly allocated to control (CON); exercise (EX); or exercise and NMES (EX + NMES) groups, and evaluated at baseline and at the end of an 8-week individualized exercise-program (3 days/week, 60min/session). NMES was applied in the quadriceps and the interscapular region, simultaneously to the exercises. CON group followed the CF team recommendations. The main outcome measures were lung function, cardiorespiratory fitness, functional capacity, quality of life and muscle strength.

RESULTS: Twenty-seven patients, aged 12.6 ± 3.0 years, were analyzed. No significant interactions were found for cardiorespiratory fitness. Functional capacity presented significant differences, indicating a better performance in both EX and EX + NMES. No significant changes between groups were seen for quality of life and lung function. As for muscle strength, EX and EX + NMES presented large effect sizes and significant differences, compared to CON, for quadriceps (p = 0.004, η2p = 0.401), pectoral (p = 0.001, η2p = 0.487), dorsal (p = 0.009, η2p = 0.333) and handgrip (p = 0.028, η2p = 0.278).

CONCLUSION: A resistance exercise-training program led to improvements in muscle strength and functional capacity in CF patients with mild-to-moderate pulmonary impairment. The addition of NMES to the training program resulted in no extra favorable effects.

PMID:35306386 | DOI:10.1016/j.rmed.2022.106798