Inn Med (Heidelb). 2024 Jun;65(6):531-532. doi: 10.1007/s00108-024-01724-0. Epub 2024 May 29.

NO ABSTRACT

PMID:38811400 | DOI:10.1007/s00108-024-01724-0

Curr Probl Pediatr Adolesc Health Care. 2024 May 28:101637. doi: 10.1016/j.cppeds.2024.101637. Online ahead of print.

ABSTRACT

During the past quarter century, the diagnosis and treatment of cystic fibrosis (CF) have been transformed by molecular sciences that initiated a new era with discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The knowledge gained from that breakthrough has had dramatic clinical impact. Although once a diagnostic dilemma with long delays, preventable deaths, and irreversible pathology, CF can now be routinely diagnosed shortly after birth through newborn screening programs. This strategy of pre-symptomatic identification has eliminated the common diagnostic "odyssey" that was a failure of the healthcare delivery system causing psychologically traumatic experiences for parents. Therapeutic advances of many kinds have culminated in CFTR modulator treatment that can reduce the effects of or even correct the molecular defect in the chloride channel -the basic cause of CF. This astonishing advance has transformed CF care as described fully herein. Despite this impressive progress, there are challenges and controversies in the delivery of care. Issues include how best to achieve high sensitivity newborn screening with acceptable specificity; what course of action is appropriate for children who are identified through the unavoidable incidental findings of screening tests (CFSPID/CRMS cases and heterozygote carriers); how best to ensure genetic counseling; when to initiate the very expensive but life-saving CFTR modulator drugs; how to identify new CFTR modulator drugs for patients with non-responsive CFTR variants; how to adjust other therapeutic modalities; and how to best partner with primary care clinicians. Progress always brings new challenges, and this has been evident worldwide for CF. Consequently, this article summarizes the major advances of recent years along with controversies and describes their implications with an international perspective.

PMID:38811287 | DOI:10.1016/j.cppeds.2024.101637

Eur Respir J. 2024 May 29:2301966. doi: 10.1183/13993003.01966-2023. Online ahead of print.

ABSTRACT

RATIONALE: The inflammasome is a key regulatory complex of the inflammatory response leading to IL-1β release and activation. IL-1β amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1β in bronchiectasis has not been investigated.

OBJECTIVES: To characterize the role of airway IL-1β in bronchiectasis including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity.

METHODS: Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1β was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1β in the population (High versus Low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air-liquid interface culture were used to study IL-1β effect on cilia function.

MEASUREMENTS AND MAIN RESULTS: Patients with high sputum IL-1β had more severe disease, increased caspase-1 activity and increased Th1, Th2 and neutrophil inflammatory response compared with patients with low IL-1β. The active-dominant form of IL-1β was associated with increased disease severity. High IL-1β was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1β treatment reduced the functionality of cilia and tight junctions of epithelial cells in-vitro.

CONCLUSIONS: A subset of stable bronchiectasis patients show increased airway IL-1β, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction.

PMID:38811046 | DOI:10.1183/13993003.01966-2023

Eur Respir J. 2024 May 29:2400163. doi: 10.1183/13993003.00163-2024. Online ahead of print.

NO ABSTRACT

PMID:38811043 | DOI:10.1183/13993003.00163-2024

Eur Respir J. 2024 May 29:2400826. doi: 10.1183/13993003.00826-2024. Online ahead of print.

NO ABSTRACT

PMID:38811042 | DOI:10.1183/13993003.00826-2024

Cell. 2024 May 23:S0092-8674(24)00472-0. doi: 10.1016/j.cell.2024.04.046. Online ahead of print.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.

PMID:38810646 | DOI:10.1016/j.cell.2024.04.046

Microbiol Spectr. 2024 May 29:e0041024. doi: 10.1128/spectrum.00410-24. Online ahead of print.

ABSTRACT

The Burkholderia cepacia complex (Bcc) is a group of Gram-negative opportunistic bacteria often associated with fatal pulmonary infections in patients with impaired immunity, particularly those with cystic fibrosis (CF) and chronic granulomatous disease (CGD). Some Bcc strains are known to naturally produce pyomelanin, a brown melanin-like pigment known for scavenging free radicals; pigment production has been reported to enable Bcc strains to overcome the host cell oxidative burst. In this work, we investigated the role of pyomelanin in resistance to oxidative stress and virulence in strains J2315 and K56-2, two epidemic CF isolates belonging to the Burkholderia cenocepacia ET-12 lineage. We previously reported that a single amino acid change from glycine to arginine at residue 378 in homogentisate 1,2-dioxygenase (HmgA) affects the pigment production phenotype: pigmented J2315 has an arginine at position 378, while non-pigmented K56-2 has a glycine at this position. Herein, we performed allelic exchange to generate isogenic non-pigmented and pigmented strains of J2315 and K56-2, respectively, and tested these to determine whether pyomelanin contributes to the protection against oxidative stress in vitro as well as in a respiratory infection in CGD mice in vivo. Our results indicate that the altered pigment phenotype does not significantly impact these strains' ability to resist oxidative stress with H2O2 and NO in vitro and did not change the virulence and infection outcome in CGD mice in vivo suggesting that other factors besides pyomelanin are contributing to the pathophysiology of these strains.IMPORTANCEThe Burkholderia cepacia complex (Bcc) is a group of Gram-negative opportunistic bacteria that are often associated with fatal pulmonary infections in patients with impaired immunity, particularly those with cystic fibrosis and chronic granulomatous disease (CGD). Some Bcc strains are known to naturally produce pyomelanin, a brown melanin-like pigment known for scavenging free radicals and overcoming the host cell oxidative burst. We investigated the role of pyomelanin in Burkholderia cenocepacia strains J2315 (pigmented) and K56-2 (non-pigmented) and performed allelic exchange to generate isogenic non-pigmented and pigmented strains, respectively. Our results indicate that the altered pigment phenotype does not significantly impact these strains' ability to resist H2O2 or NO in vitro and did not alter the outcome of a respiratory infection in CGD mice in vivo. These results suggest that pyomelanin may not always constitute a virulence factor and suggest that other features are contributing to the pathophysiology of these strains.

PMID:38809005 | DOI:10.1128/spectrum.00410-24

Rev Paul Pediatr. 2024 May 27;42:e2023162. doi: 10.1590/1984-0462/2024/42/2023162. eCollection 2024.

ABSTRACT

OBJECTIVE: To investigate the effect of bronchodilator on the respiratory mechanics and pulmonary function of children and adolescents with cystic fibrosis.

METHODS: Cross-sectional study on clinically stable children and adolescents with cystic fibrosis aged from six to 15 years. Participants underwent impulse oscillometry and spirometry evaluations before and 15 minutes after bronchodilator inhalation. The Kolmogorov-Smirnov test was applied to verify the sample distribution, and the Student's t-test and Wilcoxon test were used to compare the data before and after bronchodilator inhalation.

RESULTS: The study included 54 individuals with a mean age of 9.7±2.8 years. The analysis showed a statistically significant improvement in impulse oscillometry and spirometry parameters after bronchodilator inhalation. However, according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) recommendations (2020 and 2021), this improvement was not sufficient to classify it as a bronchodilator response.

CONCLUSIONS: The use of bronchodilator medication improved respiratory mechanics and pulmonary function parameters of children and adolescents with cystic fibrosis; however, most patients did not show bronchodilator response according to ATS/ERS recommendations.

PMID:38808869 | DOI:10.1590/1984-0462/2024/42/2023162

J Bras Pneumol. 2024 May 27;50(2):e20240107. doi: 10.36416/1806-3756/e20240107.

NO ABSTRACT

PMID:38808835 | DOI:10.36416/1806-3756/e20240107

J Bras Pneumol. 2024 May 27;50(2):e20230397. doi: 10.36416/1806-3756/e20230397.

NO ABSTRACT

PMID:38808828 | DOI:10.36416/1806-3756/e20230397

BMC Pulm Med. 2024 May 28;24(1):260. doi: 10.1186/s12890-024-03069-8.

ABSTRACT

BACKGROUND: Physical activity is a crucial demand on cystic fibrosis treatment management. The highest value of oxygen uptake (VO2peak) is an appropriate tool to evaluate the physical activity in these patients. However, there are several other valuable CPET parameters describing exercise tolerance (Wpeak, VO2VT1, VO2VT2, VO2/HRpeak, etc.), and helping to better understand the effect of specific treatment (VE, VT, VD/VT etc.). Limited data showed ambiguous results of this improvement after CFTR modulator treatment. Elexacaftor/tezacaftor/ivacaftor medication improves pulmonary function and quality of life, whereas its effect on CPET has yet to be sufficiently demonstrated.

METHODS: We performed a single group prospective observational study of 10 adolescent patients with cystic fibrosis who completed two CPET measurements between January 2019 and February 2023. During this period, elexacaftor/tezacaftor/ivacaftor treatment was initiated in all of them. The first CPET at the baseline was followed by controlled CPET at least one year after medication commencement. We focused on interpreting the data on their influence by the novel therapy. We hypothesized improvements in cardiorespiratory fitness following treatment. We applied the Wilcoxon signed-rank test. The data were adjusted for age at the time of CPET to eliminate bias of aging in adolescent patients.

RESULTS: We observed significant improvement in peak workload, VO2 peak, VO2VT1, VO2VT2, VE/VCO2 slope, VE, VT, RQ, VO2/HR peak and RR peak. The mean change in VO2 peak was 5.7 mL/kg/min, or 15.9% of the reference value (SD ± 16.6; p= 0.014). VO2VT1 improved by 15% of the reference value (SD ± 0.1; p= 0.014), VO2VT2 improved by 0.5 (SD ± 0.4; p= 0.01). There were no differences in other parameters.

CONCLUSION: Exercise tolerance improved after elexacaftor/tezacaftor/ivacaftor treatment initiation. We suggest that the CFTR modulator alone is not enough for recovering physical decondition, but should be supplemented with physical activity and respiratory physiotherapy. Further studies are needed to examine the effect of CFTR modulators and physical therapy on cardiopulmonary exercise tolerance.

PMID:38807122 | DOI:10.1186/s12890-024-03069-8

Transplant Proc. 2024 May 27:S0041-1345(24)00285-9. doi: 10.1016/j.transproceed.2024.05.016. Online ahead of print.

ABSTRACT

Pneumonia is a common nosocomial complication in transplant patients. Stenotrophomonas maltophilia is recognized as a common cause and is typically seen in immunocompromised and critically ill patients. S. maltophilia, a nonfermenting gram-negative rod, ranks as the third most common nosocomial pathogen, following Pseudomonas aeruginosa and Acinetobacter. The bacteria are frequently found in environmental sources and are prevalent in healthcare facilities, including in tap water faucets, shower outlets, air-cooling systems, intravenous fluids, catheters, dialysis machines, and oxygen humidifiers. This bacterium possesses the ability to rapidly form biofilms, enabling it to colonize new surfaces in less than 24 hours. While S. maltophilia generally exhibits low virulence, there remains uncertainty among many clinicians regarding whether it is merely a colonizer or the primary cause of infection. Although S. maltophilia infections are rare in immunocompetent individuals, the species is increasingly recognized as an opportunistic pathogen in vulnerable populations such as those with cystic fibrosis, cancer, and other conditions leading to immunosuppression. S. maltophilia now recognized as a causative agent in various clinical syndromes, primarily affecting the lungs and bloodstream. We present a case of S. maltophilia-associated lung infection in a kidney transplant recipient, emphasizing the significance of underlying diseases and associated signs and symptoms.

PMID:38806313 | DOI:10.1016/j.transproceed.2024.05.016

Food Funct. 2024 May 28. doi: 10.1039/d4fo00325j. Online ahead of print.

ABSTRACT

Children with Cystic Fibrosis (CF) are more likely to have intestinal dysbiosis due to recurrent antibiotic therapy and the conventional hypercaloric diet administered to them. This study aimed at evaluating the effect of isolated prebiotic components and probiotic strains, and their combinations as potential synbiotics, on the intestinal microbiota of CF children. A static in vitro colonic fermentation model was used by colonizing vials with faecal inoculum, a culture medium, and the substrates to be tested. Post treatment, aliquots were taken to determine ammonium, lactate, and short-chain fatty acids production and to profile the microbiota composition by 16s rRNA sequencing. At genus level, Escherichia-Shigella decreased (15.8%) with the treatment pectin + L. rhamnosus, followed by the beta-glucan + L. salivarius (15.5%). Inversely, the most increase in Bacteroides (44%) was obtained by the treatment with Pectin + L. reuteri. Lactate and acetic acid production was significantly increased with prebiotics and their combinations with L. rhamnosus and L. salivarius. In conclusion, the use of beta-glucan and pectin in combination with probiotic strains from the Lactobacillaceae family suggest potential to modulate dysbiosis and metabolic activity on CF colonic microbiota, encouraging further studies in animal studies or clinical settings to confirm the findings in vivo.

PMID:38804915 | DOI:10.1039/d4fo00325j

Am Fam Physician. 2024 May;109(5):388-390.

NO ABSTRACT

PMID:38804748

Front Pharmacol. 2024 May 13;15:1423979. doi: 10.3389/fphar.2024.1423979. eCollection 2024.

NO ABSTRACT

PMID:38803436 | PMC:PMC11128889 | DOI:10.3389/fphar.2024.1423979

JAC Antimicrob Resist. 2024 May 27;6(3):dlae078. doi: 10.1093/jacamr/dlae078. eCollection 2024 Jun.

ABSTRACT

BACKGROUND: This multicentre, observational, retrospective chart review study assessed ceftaroline fosamil treatment patterns and outcomes in adults hospitalized with community-acquired pneumonia (CAP) in usual care settings.

METHODS: Anonymized patient data were extracted from hospital records of adults with CAP who received ≥4 consecutive IV ceftaroline fosamil doses at sites in Brazil, Colombia, France, Greece, Italy, Russia and Spain.

RESULTS: The dataset included 185 patients (58.9% male; mean age 62.2 years), of whom 128 (69.2%) had severe CAP defined by CURB-65, PSI/PORT score or physician judgement. Streptococcus pneumoniae (n = 44; 23.8%) and Staphylococcus aureus [MSSA (n = 15) and MRSA (n = 14)] were the most frequently identified pathogens. Clinical response occurred in 151 (81.6%) patients overall, and in 104 (81.3%) severe CAP patients. Response within ≤4 and >4 days occurred in 79 (42.7%) and 62 (33.5%) patients (unknown, n = 10), respectively. Twenty (10.8%) patients required readmission within 30 days. Thirty-day all-cause mortality rates were 9.7% (n = 18) overall and 10.2% (n = 13) in severe CAP. In sensitivity analysis using ICU admission as a more objective marker of severe CAP (n = 75), clinical response and 30 day mortality occurred in 57 (76.0%) and 10 (13.3%) patients, respectively. Overall, clinical response to ceftaroline fosamil was associated with >60% shorter length of ICU stay (3.6 versus 9.2 days), and >30% lower hospital costs ($8449 versus $12 559) versus non-responders.

CONCLUSIONS: Ceftaroline fosamil was effective in treating adults with CAP, including severe CAP, in Europe and Latin America. Clinical response to ceftaroline fosamil was associated with reductions in healthcare resource use compared with non-responders.

PMID:38803385 | PMC:PMC11128847 | DOI:10.1093/jacamr/dlae078

Zhongguo Dang Dai Er Ke Za Zhi. 2024 May 15;26(5):506-511. doi: 10.7499/j.issn.1008-8830.2310080.

ABSTRACT

OBJECTIVES: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder.

METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children's Hospital from January 2018 to August 2023, and a literature review was performed.

RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66).

CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.

PMID:38802912 | DOI:10.7499/j.issn.1008-8830.2310080

Clin Immunol. 2024 May 25:110265. doi: 10.1016/j.clim.2024.110265. Online ahead of print.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population. Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.

PMID:38801928 | DOI:10.1016/j.clim.2024.110265

Cureus. 2024 Apr 25;16(4):e59018. doi: 10.7759/cureus.59018. eCollection 2024 Apr.

ABSTRACT

Introduction Previous studies have demonstrated an increased incidence of gastrointestinal (GI) pathologies, specifically celiac disease (CD) and eosinophilic esophagitis (EoE), in patients with cystic fibrosis (CF). However, there is minimal data available regarding endoscopic findings in pediatric patients with CF and GI mucosal disease. Methods A retrospective chart review was performed on patients with CF under 18 years of age who underwent esophagogastroduodenoscopy (EGD) or colonoscopy with biopsy over a 15-year period at our institution. Patient characteristics including assigned sex at birth, CF genetic mutations (if identified), and cystic fibrosis transmembrane conductance regulator (CFTR) modulator use were recorded. Data obtained at the time of biopsy included body mass index (BMI), indication for the procedure, exocrine pancreatic status, visual endoscopic findings, and histologic findings. Results A total of 72 patients with CF were included in the study. 24% (n=17) were found to have abnormal endoscopic biopsy results. EoE (13% of all patients, n=9) and CD (6% of all patients, n=4) were the most common GI diagnoses present on endoscopic biopsy. All 3 patients taking CFTR modulator medications at the time of endoscopy had normal biopsy results. Of the 17 patients found to have abnormal pathology results, 14 (82%) were taking proton-pump inhibitor (PPI) medication at the time of endoscopy. Conclusion This study highlights the probable increased frequency of GI disease in the pediatric CF population. These findings underscore the importance of maintaining a broad differential diagnosis while considering utilization of endoscopy with biopsy in pediatric patients with CF who have GI symptoms.

PMID:38800303 | PMC:PMC11127755 | DOI:10.7759/cureus.59018

Sleep Med X. 2024 Apr 18;7:100111. doi: 10.1016/j.sleepx.2024.100111. eCollection 2024 Dec.

ABSTRACT

There are significant variations in practice regarding the use of sleep studies in children with symptoms of sleep disordered breathing (SDB) prior to adenotonsillectomy. Current UK guidance recommends the selective use of sleep studies to confirm a diagnosis of obstructive sleep apnoea (OSA) when there is diagnostic uncertainty, in children with comorbidities, or to assess perioperative risk when severe OSA is suspected. We have developed a novel paediatric sleep service over the past decade based on the routine use of multi-channel sleep studies (MCSS) before adenotonsillectomy. We present the results of a prospective evaluation assessing the impact of our service on treatment outcomes. We conducted a prospective service evaluation of 49 children with SDB seen between July 2021 and August 2022. We used medical records and a sleep study database to determine treatment outcomes. Otolaryngologists completed a questionnaire before each multi-channel sleep study to help evaluate the impact of sleep study findings on surgical decision making. Questionnaire responses before MCSS showed that clinicians thought 66 % of children were 'likely', 'very likely' or 'definitely' would require surgery but only 54 % of children underwent surgery following their sleep study. We estimate that the use of MCSS was associated with a 21 % reduction in children undergoing surgery in this small sample. We conclude that our use of MCSS facilitates conservative management, allowing a significant reduction in the number of children with SDB undergoing surgery, but further validation of MCSS against polysomnography is required.

PMID:38800098 | PMC:PMC11127274 | DOI:10.1016/j.sleepx.2024.100111