Cancers (Basel). 2022 May 25;14(11):2604. doi: 10.3390/cancers14112604.

ABSTRACT

BACKGROUND: Patients with non-cystic fibrosis bronchiectasis have an increased risk of lung cancer, followed by higher mortality in this population. Because the risk factors of lung cancer have not been well identified, this study aimed to investigate the risk factors of lung cancer in individuals with newly diagnosed bronchiectasis.

METHODS: This cohort study using the Korean National Health Insurance Service database identified 7425 individuals with incident bronchiectasis among those who participated in the health screening exam in 2009. The cohort was followed from baseline to the date of incident: lung cancer, death, or until the end of the study period. We investigated the risk factors of lung cancer in participants with bronchiectasis using the Cox-proportional hazard models.

RESULTS: During median 8.3 years of follow-up duration, 1.9% (138/7425) developed lung cancer. In multivariable analyses, significant factors associated with increased risk of incident lung cancer included: males (adjusted hazard ratio [HR] = 3.54, 95% confidence interval [CI] = 2.17-5.79) than females, the overweight (adjusted HR = 1.55, 95% CI = 1.03-2.35) than the normal weight, current smokers (adjusted HR = 3.10, 95% CI = 2.00-4.79) than never smokers, participants living in the rural area (adjusted HR = 2.54, 95% CI = 1.68-3.85) than those living in the metropolitan area. Among comorbidities, chronic obstructive pulmonary disease was associated with an increased risk of lung cancer (adjusted HR = 1.46, 95% CI = 1.01-2.13) in participants with bronchiectasis. In contrast, mild alcohol consumption was associated with reduced risk of lung cancer (adjusted HR = 0.47, 95% CI = 0.29-0.74) in those with bronchiectasis.

CONCLUSION: This Korean population-based study showed that males, current smoking, overweight, living in rural areas, and comorbid chronic obstructive pulmonary disease are associated with increased risk of lung cancer in individuals with bronchiectasis.

PMID:35681584 | DOI:10.3390/cancers14112604

Cells. 2022 May 28;11(11):1769. doi: 10.3390/cells11111769.

ABSTRACT

Cystic fibrosis (CF) is a rare genetic multisystemic disease, the manifestations of which are due to mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein and can lead to respiratory insufficiency and premature death. CFTR modulators, which were developed in the past decade, partially restore CFTR protein function. Their clinical efficacy has been demonstrated in phase 3 clinical trials, particularly in terms of lung function and pulmonary exacerbations, nutritional status, and quality of life in people with gating mutations (ivacaftor), homozygous for the F508del mutation (lumacaftor/ivacaftor and tezacaftor/ivacaftor), and in those with at least one F508del mutation (elexacaftor/tezacaftor/ivacaftor). However, many questions remain regarding their long-term safety and effectiveness, particularly in patients with advanced lung disease, liver disease, renal insufficiency, or problematic bacterial colonization. The impact of CFTR modulators on other important outcomes such as concurrent treatments, lung transplantation, chest imaging, or pregnancies also warrants further investigation. The French CF Reference Network includes 47 CF centers that contribute patient data to the comprehensive French CF Registry and have conducted nationwide real-world studies on CFTR modulators. This review seeks to summarize the results of these real-world studies and examine their findings against those of randomized control trials.

PMID:35681464 | DOI:10.3390/cells11111769

Mol Pharmacol. 2022 Jun 9:MOLPHARM-AR-2022-000542. doi: 10.1124/molpharm.122.000542. Online ahead of print.

ABSTRACT

Loss of prosecretory Cl- channel CFTR activity is considered as the key cause of gastrointestinal disorders in cystic fibrosis including constipation and meconium ileus. Clc-2 is proposed as an alternative Cl- channel in intestinal epithelia that can compensate for CFTR loss-of-function. Lubiprostone is an FDA-approved drug with Clc-2 activation as its presumed mechanism of action. However, relative contribution of Clc-2 in intestinal Cl- secretion and the mechanism of action of lubiprostone remain controversial due to lack of selective Clc-2 inhibitors. Using recently identified selective Clc-2 inhibitor AK-42, we characterized the roles of Clc-2 in Cl- secretion in human intestinal epithelial T84 cells. Clc-2 inhibitor AK-42 had minimal (15%) inhibitory effect on secretory short-circuit current (Isc) induced by cAMP agonists, where subsequently applied CFTR inhibitor (CFTRinh-172) caused 2-3 fold greater inhibition. Similarly, AK-42 inhibited lubiprostone-induced secretory Isc by 20%, whereas CFTRinh-172 caused 2-3 fold greater inhibition. In addition to increasing CFTR and Clc-2-mediated apical Cl- conductance, lubiprostone increased basolateral membrane K+ conductance, which was completely reversed by cAMP-activated K+ channel inhibitor BaCl2 All components of lubiprostone-induced secretion (Clc-2, CFTR and K+ channels) were inhibited by ~65% with the extracellular Ca2+-sensing receptor (CaSR) activator cinacalcet that stimulates cAMP hydrolysis. Lastly, EP4 prostaglandin receptor inhibitor GW627368 pretreatment inhibited lubiprostone-induced secretion by 40% without any effect on forskolin response. Our findings suggest that Clc-2 has minor role in cAMP-induced intestinal Cl- secretion; and lubiprostone is not a selective Clc-2 activator, but general activator of cAMP-gated ion channels in human intestinal epithelial cells. Significance Statement Cl- channel Clc-2 activation is the proposed mechanism of action of the FDA-approved constipation drug lubiprostone. Using first-in-class selective Clc-2 inhibitor AK-42, we showed that Clc-2 has minor contribution in intestinal Cl- secretion induced by lubiprostone and cAMP agonists. We also found that lubiprostone is a general activator of cAMP-gated ion channels in human intestinal epithelial cells (via EP4 receptors). Our findings clarify the roles of Clc-2 in intestinal Cl- secretion and elucidate the mechanism of action of approved-drug lubiprostone.

PMID:35680165 | DOI:10.1124/molpharm.122.000542

J Pediatr (Rio J). 2022 Jun 6:S0021-7557(22)00079-1. doi: 10.1016/j.jped.2022.04.002. Online ahead of print.

ABSTRACT

OBJECTIVE: To analyze the performance of the cystic fibrosis (CF) newborn screening (NBS) program over its first five years in a Brazilian northeastern state.

METHOD: A population-based study using a screening algorithm based on immunoreactive trypsinogen (IRT)/IRT. Data were retrieved from the state referral screening center registry. The program performance was evaluated using descriptive indicators such as the results of an active search, coverage, newborn's age at the time of blood sampling, the time between sample collection and its arrival at the laboratory, and the child's age at diagnosis of disease.

RESULTS: The public CF screening program covered 82.6% of the 1,017,576 births that occurred, with an accumulated five-year incidence of 1:20,767 live births. The median (25th-75th) age at diagnosis was 3.5 (2.3-7.3) months. The sampling before 7 days of life for the first IRT (IRT1) increased between 2013 and 2017 from 42.2 to 48.3%. Around 5% of IRT1 samples and 30% of the second samples were collected after 30 days of life. In the first and second stages of screening, 23.6% and 19.9% of the infants, respectively, were lost to follow-up. In both stages of screening, the samples were retained at the health units for a median (25th-75th) of 9.0 (7.0-13.0) days.

CONCLUSIONS: The coverage by the CF-NBS program was satisfactory as compared to other Brazilian state rates and the percentage of IRT1 samples collected within the first week of life increased progressively. However, time of samples retention at the health units, inappropriate sampling, inherent methodological problems, and loss of follow-up need to improve.

PMID:35679883 | DOI:10.1016/j.jped.2022.04.002

Am J Respir Cell Mol Biol. 2022 Jun 9. doi: 10.1165/rcmb.2022-0089WS. Online ahead of print.

ABSTRACT

Clinical and molecular heterogeneity are common features of human disease. Understanding the basis for heterogeneity has led to major advances in therapy for many cancers and pulmonary diseases such as cystic fibrosis and asthma. Although heterogeneity of risk factors, disease severity and outcomes in survivors are common features of the Acute Respiratory Distress Syndrome (ARDS), many challenges exist in understanding the clinical and molecular basis for disease heterogeneity and using heterogeneity to tailor therapy for individual patients. This report summarizes the proceedings of the 2021 Aspen Lung Conference, which was organized to review key issues related to understanding clinical and molecular heterogeneity in ARDS. The goals were to review new information about ARDS phenotypes, to explore multicellular and multisystem mechanisms responsible for heterogeneity and to review how best to account for clinical and molecular heterogeneity in clinical trial design and assessment of outcomes. The report concludes with recommendations for future research to understand the clinical and basic mechanisms underlying heterogeneity in ARDS in order to advance development of new treatments for this life-threatening critical illness.

PMID:35679511 | DOI:10.1165/rcmb.2022-0089WS

Eur J Pediatr. 2022 Jun 9. doi: 10.1007/s00431-022-04510-y. Online ahead of print.

ABSTRACT

Early diagnosis of neuroendocrine cell hyperplasia of infancy (NEHI) is crucial as, conversely to the other causes of intersititial lung disease, corticosteroids are not recommended. Diagnosis is historically based on lung biopsy (NEHI), but in current practice, a clinical and radiological approach is more and more preferred (NEHI syndrome). This national study aimed to address diagnosis and initial management of patients followed up for a NEHI pattern in pediatric centers for rare lung diseases (RespiRare, France). Data on neonatal and familial events, symptoms at diagnosis, explorations performed and results, and therapeutic management were collected by questionnaire. Fifty-four children were included (boys 63%). The mean onset of symptoms was 3.8 ± 2.6 months. The most frequent symptoms at diagnosis were tachypnea (100%), retraction (79.6%), crackles (66.7%), and hypoxemia (59.3%). The mean NEHI clinical score, evocative when ≥ 7/10, was 7.9 ± 1.4 (76% with a score ≥ 7). All chest CT-scans showed ground glass opacities evolving at least the middle lobe and the lingula. Lung biopsy was performed in 38.9% of the cases and was typical of NEHI in only 52.4%, even when the clinical presentation was typical. Initial treatments were oxygen (83.6%) and more curiously intravenous pulses of steroids (83.3%) and azithromycin (70.2%).

CONCLUSION: This national cohort of patients underlines diagnosis difficulties of NEHI. A composite clinical and radiological score should help clinicians for limiting the use of anti-inflammatory drugs.

WHAT IS KNOWN: •Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose diagnosis is essential to limit corticosteroids therapy.

WHAT IS NEW: •In this national cohort of 54 patients with a NEHI pattern, diagnosis is mainly based on clinical symptoms and chest CT-scan results. The newly proposed clinical score and, when performed, the lung biopsies are faulted in 25 and 50% of the cases, respectively. •Corticosteroids are widely used. Such results plead for a new composite score to formally diagnose NEHI.

PMID:35678871 | DOI:10.1007/s00431-022-04510-y

J Antimicrob Chemother. 2022 Jun 9:dkac187. doi: 10.1093/jac/dkac187. Online ahead of print.

ABSTRACT

OBJECTIVES: Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin.

METHODS: This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI.

RESULTS: Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI.

CONCLUSIONS: Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.

PMID:35678460 | DOI:10.1093/jac/dkac187

Health Sci Rep. 2022 Jun 6;5(4):e604. doi: 10.1002/hsr2.604. eCollection 2022 Jul.

ABSTRACT

BACKGROUND: The goal of mucoactive therapies in cystic fibrosis (CF) is to enhance sputum clearance and to reduce a progressive decline in lung function over the patient's lifetime. We aimed to investigate the level of consensus among specialists from Italian CF Centers on appropriateness of therapeutic use of dornase alfa (rhDNase) for CF patients.

METHOD: A consensus on appropriate prescribing in CF mucoactive agents was appraised by an online Delphi method, based on a panel of 27 pulmonologists, coordinated by a Scientific Committee of six experts in medical care of patients with CF.

RESULTS: Full or very high consensus was reached on several issues related to therapeutic use of dornase alfa for CF patients in clinical practice.

CONCLUSIONS: The consensus reached on a number of topics regarding use of mucoactive agents in patients with CF can help guide clinicians in daily practice based on expert experience and define the most appropriate therapeutic strategy for the individual patient.

PMID:35677472 | PMC:PMC9169509 | DOI:10.1002/hsr2.604

J Patient Exp. 2022 Jun 1;9:23743735221103025. doi: 10.1177/23743735221103025. eCollection 2022.

ABSTRACT

The Partnership Enhancement Program (PEP) is a 6-hour relationship-centered communication training for intact cystic fibrosis (CF) teams. The aim of this study was to analyze qualitative responses from survey participants regarding their takeaways from the training. A total of 210 professionals participated in 20 pilot workshops at 19 care centers in the United States from November 2018 to December 2019. After the workshop, qualitative feedback was captured by PEP facilitators during a feedback gathering session or submitted immediately in writing by participants. The manuscript team used grounded theory and qualitative methods of coding to identify recurring themes across participant responses. Thematic analysis revealed 5 primary themes and a web of interconnected subthemes. Primary themes include the acquisition of skills to improve communication, strengthened patient/provider connection, improved quality of communication, improved team building, and the ability to change and enhance practice. Participants who completed PEP training endorse acquiring communication skills that increase coproduction of care with patients and caregivers as well as improve relationships across the healthcare system.

PMID:35677227 | PMC:PMC9168940 | DOI:10.1177/23743735221103025

Front Pediatr. 2022 May 23;10:858410. doi: 10.3389/fped.2022.858410. eCollection 2022.

ABSTRACT

Airway clearance therapy (ACT) is one of the cornerstone treatment modalities to improve mucociliary clearance for patients with bronchiectasis. The progression of lung disease in patients with bronchiectasis can be evaluated by spirometry and multiple breath washout (MBW) and it is advised to monitor these on a regular basis. However, the short term effect of ACT on spirometry and MBW parameters is insufficiently clear and this variability may impact standardization. For cystic fibrosis (CF), available literature refutes a short time effect on spirometry and MBW parameters in children, however, for primary ciliary dyskinesia (PCD) no data are available. We performed a single-center, prospective cross-over study to evaluate the short term effect of a single ACT session using positive expiratory pressure mask on forced expiratory volume in 1 s (FEV1) and lung clearance index (LCI), derived from MBW, compared to no ACT (control) in pediatric patients with CF and PCD. A total of 31 children were included: 14 with PCD and 17 with CF. For the whole group, there was no difference in median change of FEV1 pp between the treatment and the control group (p 0.969), nor in median change of LCI (p 0.294). For the CF subgroup, the mean change in FEV1 pp with ACT was -1.4% (range -9 to + 5) versus -0.2% (range -6 to + 5) for no ACT (p 0.271), the mean change in LCI with ACT was + 0.10 (range -0.7 to + 1.2) versus + 0.17 (range -0.5 to + 2.8) for no ACT (p 0.814). In the PCD subgroup, the mean change in FEV1 pp with ACT was + 1.0 (range -7 to + 8) versus -0.3 (range -6 to + 5) for no ACT (p 0.293) and the mean change in LCI with ACT was -0.46 (range -3.7 to + 0.9) versus -0.11 (range -1.4 to + 1.3) for no ACT (p 0.178). There was no difference between PCD and CF for change in FEV1 pp after ACT (p = 0.208), nor for LCI (p = 0.095). In this small group of pediatric patients, no significant short-term effect of chest physiotherapy on FEV1 pp nor LCI in PCD and CF values nor variability was documented.

PMID:35676908 | PMC:PMC9167999 | DOI:10.3389/fped.2022.858410

Clin Infect Dis. 2022 Jun 9:ciac453. doi: 10.1093/cid/ciac453. Online ahead of print.

ABSTRACT

BACKGROUND: Non-tuberculous Mycobacterium (NTM) infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification.

METHODS: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid.

RESULTS: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in eight patients, potentially contributing to lack of treatment response in four cases but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these.

CONCLUSIONS: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

PMID:35676823 | DOI:10.1093/cid/ciac453

Pediatr Pulmonol. 2022 Jun 8. doi: 10.1002/ppul.26037. Online ahead of print.

ABSTRACT

BACKGROUND & OBJECTIVES: Cystic fibrosis-related diabetes (CFRD) affects 50% of CF adults. Gut microbial imbalance (dysbiosis) aggravates their inflammatory response and contributes to insulin resistance (IR). We hypothesized that probiotics may improve glucose tolerance by correcting dysbiosis.

METHODS: A single center prospective pilot study assessing the effect of Vivomixx® probiotic (450 billion/sachet) on clinical status, spirometry, lung clearance index (LCI) and Quality of life (QOL) questionnaires; inflammatory parameters (urine and stool metabolomics, blood cytokines); and glucose metabolism (oral glucose tolerance test (OGTT), continuous glucose monitoring (CGM), and homeostasis model assessment of IR (HOMA-IR) in CF patients.

RESULTS: Twenty-three CF patients (six CFRD), mean age 17.7±8.2 years. After four months of probiotic administration, urinary Cysteine (p=0.018), Lactulose (p=0.028), Arabinose (p=0.036), Mannitol (p=0.041), and Indole 3-lactate (p=0.046) significantly increased, while 3-methylhistidine (p=0.046) and N-acetyl glutamine (p=0.047) decreased. Stool 2-Hydroxyisobutyrate (p=0.022) and 3-Methyl-2-oxovalerate (p=0.034) decreased. Principal Component analysis, based on urine metabolites, found significant partitions between subjects at the end of treatment compared to baseline (p=0.004). After two months of probiotics, the digestive symptoms domain of CFQ-R improved (p=0.007). In the non-diabetic patients, a slight decrease in HOMA-IR, from 2.28 to 1.86, was observed. There was no significant change in spirometry results, LCI, blood cytokines and CGM.

CONCLUSIONS: Changes in urine and stool metabolic profiles, following the administration of probiotics, may suggest a positive effect on glucose metabolism in CF. Larger long-term studies are needed to confirm our findings. Understanding the interplay between dysbiosis, inflammation, and glucose metabolism may help preventing CFRD. This article is protected by copyright. All rights reserved.

PMID:35676769 | DOI:10.1002/ppul.26037

Environ Sci Pollut Res Int. 2022 Jun 8. doi: 10.1007/s11356-022-21134-9. Online ahead of print.

ABSTRACT

Di-(2-ethylhexyl) phthalate (DEHP) is a kind of environmental endocrine disruptors (EEDs), which has been confirmed to cause serious consequences, such as cryptorchidism. Patients with unilateral cryptorchidism still had oligospermia or infertility even if they received orchidopexy before puberty. Testicular dysgenesis syndrome (TDS) attributes this kind of problems to the abnormal testicular development during the embryonic period, and considers that the environmental exposure factors during pregnancy play a major role. Therefore, for unilateral cryptorchidism, even if one testicle has dropped to scrotum, it may be exposed to these substances and cause damage. Cystic fibrosis transmembrane conduction regulator (CFTR) is very important for the maturation of male reproductive system. Previously, cryptorchidism was thought to cause abnormal expression of heat sensitive protein CFTR in testis, but the expression of CFTR in healthy side (descended side) testis was not clear. In this study, we established SD rats with unilateral cryptorchidism by exposure to DEHP (500 mg/kg/day) during pregnancy, and detected the expression of CFTR and downstream signal NF-κB/COX-2/PGE2 in bilateral testis. Finally, we found that the expression of CFTR and downstream signal NF-κB/COX-2/PGE2 in the undescended testis was significantly abnormal, but the expression of them in the descended testis was also abnormal to some extent. Therefore, we speculate that in addition to high temperature will affect the expression of CFTR, there may be other factors that cause abnormal expression of CFTR induced by DEHP, and lead to abnormal male reproductive function eventually, but the specific mechanism needs to be further studied.

PMID:35676569 | DOI:10.1007/s11356-022-21134-9

Obstet Gynecol. 2022 Jun 1;139(6):1149-1151. doi: 10.1097/AOG.0000000000004792. Epub 2022 May 2.

ABSTRACT

Early pregnancy loss can be treated medically with mifepristone followed by misoprostol, with ultrasonographic confirmation of pregnancy expulsion. Alternative strategies that ascertain treatment success remotely are needed. We compared percent decline in human chorionic gonadotropin (hCG) level with treatment success or failure between patients who received mifepristone pretreatment followed by misoprostol or misoprostol alone for early pregnancy loss between 5 and 12 weeks of gestation to determine a threshold decline that might predict success. Early pregnancy loss treatment success was associated with a greater percent hCG level decline compared with treatment failure, but no threshold was able to predict success. Additional research is needed to understand hCG trends after medical management of early pregnancy loss to develop reliable protocols for remote follow-up.

PMID:35675613 | DOI:10.1097/AOG.0000000000004792

Rev Inst Med Trop Sao Paulo. 2022 Jun 6;64:e36. doi: 10.1590/S1678-9946202264036. eCollection 2022.

ABSTRACT

Burkholderia cepacia complex (BCC) is group of widespread gram-negative bacillus organized in over 20 phylogenetically distinct bacterial species. According to previous studies, BCC species pathogens are widely reported in patients with cystic fibrosis (CF), but not in individuals with diabetes mellitus (DM). In this case report, a 42-year-old male patient with DM and a foot infection caused by BCC is presented. The patient was hospitalized after antibiotic treatment failure and improved after two surgical debridement procedures and a high-dose extended infusion (EI) of meropenem. The team of vascular surgeons and the infectious disease specialists worked fervently to solve the case. Finally, a scoping review was conducted to map BCC infections in patients with DM.

PMID:35674634 | DOI:10.1590/S1678-9946202264036

J Bras Pneumol. 2022 Jun 6;48(3):e20210237. doi: 10.36416/1806-3756/e20210237. eCollection 2022.

ABSTRACT

OBJECTIVE: Pulmonary disease in cystic fibrosis (CF) is characterised by recurrent episodes of pulmonary exacerbations (PExs), with acute and long-term declines in lung function (FEV1). The study sought to determine whether routine spirometry increases the frequency of PEx diagnosis, resulting in benefits to long-term pulmonary function.

METHODS: CF patients in the 5- to 18-year age bracket were followed for 1 year, during which they underwent spirometry before every medical visit. The main variables were the frequency of PEx diagnosis and use of antibiotics; the use of spirometry as a criterion for PEx diagnosis (a decline ≥ 10% in baseline FEV1); and median percent predicted FEV1 over time. The data were compared with those for the previous 24-month period, when spirometry was performed electively every 6 months.

RESULTS: The study included 80 CF patients. PExs were diagnosed in 27.5% of the visits, with a mean frequency of 1.44 PExs per patient/year in 2014 vs. 0.88 PExs per patient/year in 2012 (p = 0.0001) and 1.15 PExs per patient/year in 2013 (p = 0.05). FEV1 was used as a diagnostic feature in 83.5% of PExs. In 21.9% of PExs, the decision to initiate antibiotics was solely based on an acute decline in FEV1. The median percent predicted FEV1 during the follow-up year was 85.7%, being 78.5% in 2013 and 76.8% in 2012 (p > 0.05). The median percent predicted FEV1 remained above 80% during the two years after the study.

CONCLUSIONS: Routine spirometry is associated with higher rates of diagnosis and treatment of PExs, possibly impacting long-term pulmonary function.

PMID:35674545 | DOI:10.36416/1806-3756/e20210237

Sultan Qaboos Univ Med J. 2022 May;22(2):295-299. doi: 10.18295/squmj.6.2021.089. Epub 2022 May 26.

ABSTRACT

Mycobacterium abscessus complex (MABSC) is a rapidly growing mycobacterium and may rarely cause disseminated infections in immunocompromised patients. In patients with cystic fibrosis (CF), it peaks between the ages of 11 and 15 years. We present a five-month-old infant with coexisting CF and progressive familial intrahepatic cholestasis (PFIC) who had pulmonary and cutaneous dissemination of MABSC infection. The management of this disseminated infection in an infant with two coexisting chronic diseases was challenging and resulted in the rapid deterioration of lung function and progression of PFIC to liver cirrhosis with a fatal outcome.

PMID:35673280 | PMC:PMC9155037 | DOI:10.18295/squmj.6.2021.089

BMC Infect Dis. 2022 Jun 7;22(1):529. doi: 10.1186/s12879-022-07514-z.

ABSTRACT

BACKGROUND: Pandoraea species are multidrug-resistant glucose-nonfermenting gram-negative bacilli that are usually isolated from patients with cystic fibrosis (CF) and from water and soil. Reports of diseases, including bloodstream infections, caused by Pandoraea spp. in non-CF patients are rare, and the clinical and microbiological characteristics are unclear. The identification of Pandorea spp. is limited by conventional microbiological methods and may be misidentified as other species owing to overlapping biochemical profiles. Here, we report the first case of obstructive cholangitis with bacteremia caused by Pandoraea apista in a patient with advanced colorectal cancer. A 61-year-old man with advanced colorectal cancer who underwent right nephrectomy for renal cell carcinoma 4 years earlier with well-controlled diabetes mellitus was admitted to our hospital with fever for 2 days. The last chemotherapy (regorafenib) was administered approximately 3 weeks ago, and an endoscopic ultrasound-guided hepaticogastrostomy was performed 2 weeks ago under hospitalization for obstructive jaundice. Two days prior, he presented with fever with chills. He was treated with piperacillin-tazobactam for obstructive cholangitis and showed improvement but subsequently presented with exacerbation. Bacterial isolates from the blood and bile samples were identified as P. apista using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and 16S ribosomal RNA sequencing. Based on the susceptibility results of the isolates, he was successfully treated with oral trimethoprim-sulfamethoxazole 160 mg/800 mg/day for 14 days for P. apista infection.

CONCLUSIONS: Pandoraea species are often misidentified. Therefore, multiple approaches should be used to identify them, and decisions regarding antimicrobial treatment should be based on actual in vitro susceptibility. Only seven cases of Pandoraea spp. bloodstream infections have been reported, and we report the first case of cholangitis with bacteremia.

PMID:35672730 | DOI:10.1186/s12879-022-07514-z

Br J Clin Pharmacol. 2022 Jun 7. doi: 10.1111/bcp.15434. Online ahead of print.

ABSTRACT

BACKGROUND: Drug hypersensitivity reactions (DHR) to antibiotics are common and a substantial issue in managing patients with cystic fibrosis (CF).

AIMS: To assess the prevalence and clinical features of the DHR to antibiotics as well as risk factors in patients with CF.

METHOD: A 20-year retrospective study was conducted among 226 CF patients (100 children and 126 adults) attending our center. Swedish Registry for Cystic Fibrosis and electronic medical records enabled us to ascertain the number and routes of antibiotic courses. All suspected DHR were evaluated.

RESULTS: The patients had a total of 16910 antibiotic courses, of which 6832 (40%) were intravenously administered. Of 226 enrolled CF patients, 70 (31%) developed overall 131 DHR to antibiotics. The prevalence of DHR increased with advancing age (p< 0.001). Beta-lactams elicited 71% of all DHR and piperacillin was the most common single culprit (30% of intravenous and 24% of all DHR). Reactions were mild to moderate and mostly limited to skin; no severe cutaneous adverse reactions were observed. Additionally, anaphylaxis was rare constituting 2.3% (3/131) of all DHR. Patients with DHR were exposed to significantly more courses of antibiotics than those without DHR ((median 124 vs. 46, retrospectively, p< 0.001).

CONCLUSIONS: DHR to antibiotics, particularly to beta-lactams, are increased in CF patients, and associated with a higher number of cumulative exposures because of recurrent infections. However, severe cutaneous or systemic DHR, such as anaphylaxis, appear to be rare.

PMID:35671007 | DOI:10.1111/bcp.15434

J Chem Inf Model. 2022 Jun 7. doi: 10.1021/acs.jcim.2c00059. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a highly pathogenic Gram-negative microorganism associated with high mortality levels in burned or immunosuppressed patients or individuals affected by cystic fibrosis. Studies support a colonization mechanism whereby P. aeruginosa can breakdown the host cell membrane phospholipids through the sequential action of two enzymes: (I) hemolytic phospholipase C acting upon phosphatidylcholine or sphingomyelin to produce phosphorylcholine (Pcho) and (II) phosphorylcholine phosphatase (PchP) that hydrolyzes Pcho to generate choline and inorganic phosphate. This coordinated action provides the bacteria with carbon, nitrogen, and inorganic phosphate to support growth. Furthermore, PchP exhibits a distinctive inhibition mechanism by high substrate concentration. Here, we combine kinetic assays and computational approaches such as molecular docking, molecular dynamics, and free-energy calculations to describe the inhibitory site of PchP, which shares specific residues with the enzyme's active site. Our study provides insights into a coupled inhibition mechanism by the substrate, allowing us to postulate that the integrity of the inhibition site is needed to the correct functioning of the active site. Our results allow us to gain a better understanding of PchP function and provide the basis for a rational drug design that might contribute to the treatment of infections caused by this important opportunistic pathogen.

PMID:35670773 | DOI:10.1021/acs.jcim.2c00059