BJPsych Open. 2022 Jul 28;8(5):e146. doi: 10.1192/bjo.2022.550.

ABSTRACT

The burden of mental illness in young people with chronic liver disease is not known. In this population cohort study in England, we identified 358 individuals (aged ≤25 years) diagnosed with autoimmune hepatitis or liver disease related to cystic fibrosis and 1541 propensity-score-matched controls. By the first year of follow-up, the cumulative burden of psychiatric events in participants with liver disease was high compared with controls: anxiety disorder (6.87 per 100 individuals [95% CI 4.00-9.73] v. 2.22 [95% CI 1.37-3.07]), depression (5.10 [95% CI 2.83-7.37] v. 0.86 [95% CI 0.53-1.19]), substance misuse (10.61 [95% CI 9.50-11.73] v. 1.23 [95% CI 0.71-1.75]) and self-harm (3.09 [95% CI 1.12-5.05] v. 0.20 [95% CI 0.07-0.33]). Participants with liver disease had a 2-fold increase (OR = 1.94, 95% CI 1.45-2.58), a 2.5-fold increase (OR = 2.59, 95% CI 1.91-3.50) and 4.4-fold increase (OR = 4.44; 95% CI 3.46-5.71) in the risk of anxiety, depression and substance misuse, respectively. These findings highlight the need for effective intervention in psychiatric disorders in young people with rare liver disease.

PMID:35900005 | DOI:10.1192/bjo.2022.550

Ned Tijdschr Geneeskd. 2022 May 9;166:D6724.

ABSTRACT

A 23-year-old female complained of excessive wrinkling of her hands after brief exposure to water. The symptoms were characteristic for the diagnosis aquagenic wrinkling of the palms (AWP). This disorder is frequently associated with cystic fibrosis (CF) or CF carrier state. DNA analysis of the cystic fibrosis gene is indicated.

PMID:35899726

Rev Prat. 2022 Jun;72(6):653-655.

NO ABSTRACT

PMID:35899672

Turk J Pediatr. 2022;64(3):549-557. doi: 10.24953/turkjped.2020.1926.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a degenerative disease distinguished by progressive epithelial secretory gland dysfunction associated with recurrent respiratory tract infections. Despite that bacteria have previously been studied as the main cause of CF airway damage, a strong effect of respiratory viral infections is also now recognized. We aimed to detect the relationship between viral infection and exacerbation in children with cystic fibrosis.

METHODS: This is a cross sectional observational study recruiting 60 patients diagnosed as CF following in Cystic Fibrosis Clinic, Children`s Hospital, Cairo University, throughout a period of 7 months. Their age ranged from 6 months to 13 years. Patients had nasal swabs and sputum samples obtained when they developed respiratory exacerbations. Multiplex PCR (polymerase chain reaction) technique was used to detect respiratory viruses from nasal swabs.

RESULTS: We detected viruses in 48 patients during exacerbation (80%), the most common virus was rhinovirus in 43.4% of patients, followed by bocavirus in 20%, adenovirus in 13.3%, enterovirus in 10% and human metapneumovirus in 6.7%. Co-infection with double viruses was detected in 10 patients. Bacterial infection was present in 56.7% of patients; the most common organism was Pseudomonas in 20% of patients, followed by Staphylococcus aureus, methicillin resistant Staphylococcus aureus, Klebsiella and Haemophilus influenzae. CRP was positive in 53.3% of patients. There was a significant relationship between sputum positive bacterial culture and each of influenza A virus, enterovirus and human metapneumovirus.

CONCLUSIONS: This study demonstrated that exacerbation in cystic fibrosis may be exaggerated by viral infections such as influenza A and enterovirus necessitating hospitalization which shows the important protective role of vaccination. Also, a strong relationship was detected between some viruses such as enterovirus, human metapneumovirus and influenza and between bacterial infection.

PMID:35899568 | DOI:10.24953/turkjped.2020.1926

Signal Transduct Target Ther. 2022 Jul 27;7(1):255. doi: 10.1038/s41392-022-01048-1.

ABSTRACT

SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl- is a crucial regulator of host defense, whereas the role of Cl- signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl- concentration ([Cl-]i) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl-]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl-]i. Our findings suggested that Cl- acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl- signaling pathway might be a novel therapeutic strategy for COVID-19.

PMID:35896532 | DOI:10.1038/s41392-022-01048-1

BMJ Case Rep. 2022 Jul 27;15(7):e249727. doi: 10.1136/bcr-2022-249727.

ABSTRACT

Here we report the first case of an association between cystic fibrosis and Wernicke's encephalopathy. The patient had a history of cystic fibrosis diagnosed in her early 60s associated with pancreatitis and chronic lung disease. She presented with a traumatic hip fracture requiring operative repair. On examination, she was found to have bilateral nystagmus. MRI revealed enhancement of the mammillary bodies. Laboratory results were notable for thiamine deficiency, which in context of the radiographic and physical examination findings, confirmed a diagnosis of Wernicke's encephalopathy. The cause of her low thiamine was thought to be poor dietary intake, weight loss and malabsorption associated with exocrine pancreatic insufficiency in the setting of a history of recurrent pancreatitis. The patient had complete resolution of her symptoms with the initiation of thiamine supplementation and pancreatic enzymes. Although classically associated with fat soluble vitamin deficiencies, there are increasing reports of water-soluble vitamin deficiencies associated with cystic fibrosis.

PMID:35896303 | DOI:10.1136/bcr-2022-249727

Eur Respir Rev. 2022 Jul 27;31(165):220011. doi: 10.1183/16000617.0011-2022. Print 2022 Sep 30.

ABSTRACT

BACKGROUND: Aspergillus fumigatus is a common saprophytic fungus causing allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (CF). The recommended first-line treatment for ABPA is oral steroids, followed by antifungal therapy. However, both treatments are not free from adverse effects; thus, efforts are being made to identify new drugs showing the same effectiveness but with fewer or no side-effects. Therein, biologic drugs have been significantly implemented in clinical practice in treating ABPA in patients with CF.

OBJECTIVE: To systematically review the available literature, providing evidence for the administration of biologic drugs as a new potential treatment of ABPA in both the paediatric and adult populations with CF.

METHODS: A systematic review of the literature published between January 2007 and July 2021 was performed, using a protocol registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42021270932).

RESULTS: A total of 21 studies focusing on the use of biologics in treating ABPA in CF patients was included. We highlighted a paucity of data providing evidence for biologic drug use in ABPA.

CONCLUSION: Scientific evidence is insufficient to support firm conclusions and randomised clinical trials are urgently required to investigate the efficacy and safety of biologics for ABPA in CF patients.

PMID:35896271 | DOI:10.1183/16000617.0011-2022

G3 (Bethesda). 2022 Jul 27:jkac188. doi: 10.1093/g3journal/jkac188. Online ahead of print.

ABSTRACT

Mycobacterium abscessus is an emerging pathogen of concern in cystic fibrosis and immunocompromised patients and is considered one of the most drug-resistant mycobacteria. The majority of clinical M. abscessus isolates carry one or more prophages that are hypothesized to contribute to virulence and bacterial fitness. The prophage McProf was identified in the genome of the Bergey strain of M. chelonae, and is distinct from previously described prophages of M. abscessus. The McProf genome increases intrinsic antibiotic resistance of M. chelonae and drives expression of the intrinsic antibiotic resistance gene, whiB7, when superinfected by a second phage. The prevalence of McProf-like genomes was determined in sequenced mycobacterial genomes. Related prophage genomes were identified in the genomes of 25 clinical isolates of M. abscessus and assigned to the novel cluster, MabR. They share less than 10% gene content with previously described prophages; however, share features typical of prophages, including polymorphic toxin immunity (PT-Imm) systems.

PMID:35894699 | DOI:10.1093/g3journal/jkac188

Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221110354. doi: 10.1177/17534666221110354.

ABSTRACT

BACKGROUND: Anastomotic complications are common after lung transplantation (1.4-33% of cases) and still associated with a high morbi-mortality.

METHODS: The current study is a monocenter retrospective analysis of symptomatic anastomotic complications (SAC) occurring after lung transplantation between 2010 and 2016, using the macroscopic, diameter, and suture (M-D-S) classification from consensus of French experts in bronchoscopy. The objectives were to determine incidence from surgery, risk factors, and impact of survival of SAC. We defined SAC as M-D-S abnormalities (stenosis ⩾ 50% or dehiscence) requiring bronchoscopic or surgical interventions.

RESULTS: A total of 121 patients were included. SAC occurred in 26.5% of patients (n = 32), divided in symptomatic stenosis for 23.7% (n = 29), and symptomatic dehiscence in 2.5% (n = 3). In multivariate analysis, donor bacterial lung infection [HR 2.08 (1.04-4.17), p = 0.04] and age above 50 years [HR 3.26 (1.04-10.26), p = 0.04] were associated with SAC occurrence. Cystic fibrosis etiology was associated with better survival on Kaplan-Meier curve (p < 0.001). SAC [HR 2.15 (1.07-4.32), p = 0.03] was independently associated with worst survival. The 29 symptomatic patients because of stenosis required endoscopic procedure, of whom 16 patients needed bronchial stent placement. Four patients underwent surgery: three patients because of dehiscence and one because of severe bilateral stenosis (re-transplantation).

DISCUSSION: SAC occurred in 26.5% of patients. Donor lung infection was the only alterable identified factors. The increase rate of SAC in older patients above 50 years of age encourages in regular endoscopic monitoring.

PMID:35894432 | DOI:10.1177/17534666221110354

J Bras Pneumol. 2022 Jul 25;48(4):e20220155. doi: 10.36416/1806-3756/e20220155.

NO ABSTRACT

PMID:35894415 | DOI:10.36416/1806-3756/e20220155

Zhongguo Dang Dai Er Ke Za Zhi. 2022 Jul 15;24(7):771-777. doi: 10.7499/j.issn.1008-8830.2203015.

ABSTRACT

OBJECTIVES: To study the clinical features and gene mutation sites of children with cystic fibrosis (CF), in order to improve the understanding of CF to reduce misdiagnosis and missed diagnosis.

METHODS: A retrospective analysis was performed on the medical records of 8 children with CF who were diagnosed in Hebei Children's Hospital from 2018 to 2021.

RESULTS: Among the 8 children with CF, there were 5 boys and 3 girls, with an age of 3-48 months (median 8 months) at diagnosis, and the age of onset ranged from 0 to 24 months (median 2.5 months). Clinical manifestations included recurrent respiratory infection in 7 children, sinusitis in 3 children, bronchiectasis in 4 children, diarrhea in 8 children, fatty diarrhea in 3 children, suspected pancreatic insufficiency in 6 children, pancreatic cystic fibrosis in 1 child, malnutrition in 5 children, and pseudo-Bartter syndrome in 4 children. The most common respiratory pathogens were Pseudomonas aeruginosa (4 children). A total of 16 mutation sites were identified by high-throughput sequencing, multiplex ligation-dependent probe amplification, and Sanger sequencing, including 5 frameshift mutations, 4 nonsense mutations, 4 missense mutations, 2 exon deletions, and 1 splice mutation. CFTR mutations were found in all 8 children. p.G970D was the most common mutation (3 children), and F508del mutation was observed in one child. Four novel mutations were noted: deletion exon15, c.3796_3797dupGA(p.I1267Kfs*12), c.2328dupA(p.V777Sfs*2), and c.2950G>A(p.D984N).

CONCLUSIONS: p.G970D is the most common mutation type in children with CF. CF should be considered for children who have recurrent respiratory infection or test positive for Pseudomonas aeruginosa, with or without digestive manifestations or pseudo-Bartter syndrome.

PMID:35894192 | DOI:10.7499/j.issn.1008-8830.2203015

J Clin Med. 2022 Jul 22;11(15):4277. doi: 10.3390/jcm11154277.

ABSTRACT

This is a prospective, observational study involving three Cystic Fibrosis (CF) adult patients, evaluating the changes in chest magnetic resonance imaging (MRI) three months after the start of elexacaftor/tezacaftor and ivacaftor therapy. MRI showed a drastic reduction in mucus plugging and bronchial wall thickening, with an improvement in the diffusion-weighted MRI score. Similarly, a marked improvement in spirometric parameters, nutritional status, and sweat chloride was observed. Our preliminary data confirm that chest MRI could be a useful tool to assess disease progression in CF patients on modulatory drug therapy.

PMID:35893365 | DOI:10.3390/jcm11154277

J Fungi (Basel). 2022 Jul 22;8(8):758. doi: 10.3390/jof8080758.

ABSTRACT

Germination of conidia is an essential process within the Aspergillus life cycle and plays a major role during the infection of hosts. Conidia are able to avoid detection by the majority of leukocytes when dormant. Germination can cause severe health problems, specifically in immunocompromised people. Aspergillosis is most often caused by Aspergillus fumigatus (A. fumigatus) and affects neutropenic patients, as well as people with cystic fibrosis (CF). These patients are often unable to effectively detect and clear the conidia or hyphae and can develop chronic non-invasive and/or invasive infections or allergic inflammatory responses. Current treatments with (tri)azoles can be very effective to combat a variety of fungal infections. However, resistance against current azoles has emerged and has been increasing since 1998. As a consequence, patients infected with resistant A. fumigatus have a reported mortality rate of 88% to 100%. Especially with the growing number of patients that harbor azole-resistant Aspergilli, novel antifungals could provide an alternative. Aspergilloses differ in defining characteristics, but germination of conidia is one of the few common denominators. By specifically targeting conidial germination with novel antifungals, early intervention might be possible. In this review, we propose several morphotypes to disrupt conidial germination, as well as potential targets. Hopefully, new antifungals against such targets could contribute to disturbing the ability of Aspergilli to germinate and grow, resulting in a decreased fungal burden on patients.

PMID:35893126 | DOI:10.3390/jof8080758

Adv Respir Med. 2022 Jul 20;90(4):237-245. doi: 10.3390/arm90040033.

ABSTRACT

Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker of eosinophilic airway inflammation and therapeutic response to corticosteroid treatment of respiratory diseases. Atopic dermatitis (AD), one of the most common allergic conditions of the skin, is a factor influencing the increase of FeNO. The main aim of this study was to determine differences between levels of FeNO in patients with AD and healthy controls as measured by an electrochemical analyzer. In total, 54 teenagers and adults with AD were recruited and compared with 34 healthy volunteers. The measurements of FeNO were taken using the Hyp'Air FeNO in participants. FeNO was statistically significantly higher in patients with AD than in healthy controls (60.5 ± 35.1 vs. 14.8 ± 5.1 ppb, p &lt; 0.001). We found a strong positive significant correlation between FeNO and the number of positive skin prick tests among AD patients (R = 0.754, p &lt; 0.001). There was no correlation between FeNO and duration of disease as well as SCORAD index among patients. Moreover, we also found no FeNO difference between the mild and moderate forms of AD. The presence of AD and the increasing number of positive skin prick tests increase FeNO, so the results of this measurement should be interpreted with caution in patients with respiratory diseases suffering from AD.

PMID:35892744 | DOI:10.3390/arm90040033

Cells. 2022 Jul 25;11(15):2295. doi: 10.3390/cells11152295.

ABSTRACT

The plasma membrane (PM) stability of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein which when mutated causes Cystic Fibrosis (CF), relies on multiple interaction partners that connect CFTR to signaling pathways, including cAMP signaling. It was previously shown that activation of exchange protein directly activated by cAMP 1 (EPAC1) by cAMP promotes an increase in CFTR PM levels in airway epithelial cells. However, the relevance of this pathway in other tissues, particularly the intestinal tissue, remains uncharacterized. Here, we used Western blot and forskolin-induced swelling assay to demonstrate that the EPAC1 protein is not expressed in the intestinal organoid model, and consequently the EPAC1 stabilization pathway is not in place. On the other hand, using cell surface biotinylation, EPAC1-mediated stabilization of PM CFTR is observed in intestinal cell lines. These results indicate that the EPAC1 stabilization pathway also occurs in intestinal cells and is a potential target for the development of novel combinatorial therapies for treatment of CF.

PMID:35892592 | DOI:10.3390/cells11152295

Int J Neonatal Screen. 2022 Jun 23;8(3):38. doi: 10.3390/ijns8030038.

ABSTRACT

Cystic fibrosis (CF) newborn screening (NBS) was universally adopted in 2009 in the United States. Variations in NBS practices between states may impact the timing of diagnosis and intervention. Quantitative metrics can provide insight into NBS programs (NBSP), but the nuances cannot be elucidated without additional feedback from programs. This study was designed to determine facilitators and barriers to timely diagnosis and intervention following NBS for CF. The median age at the first CF event for infants with CF within each state was used to define early and late states (n = 15 per group); multiple CF centers were invited in states with more than two CF centers. Thirty states were eligible, and 61 NBSP and CF centers were invited to participate in structured interviews to determine facilitators and barriers. Once saturation of themes was reached, no other interviews were conducted. Forty-five interviews were conducted (n = 16 early CF center, n = 12 late CF center, n = 11 early NBSP, and n = 6 late NBSP). Most interviewees reported good communication between CF centers and NBSP. Communication between primary care providers (PCPs) and families was identified as a challenge, leading to delays in referral and subsequent diagnosis. The misperception of low clinical risk in infants from racial and ethnic minority groups was a barrier to early diagnostic evaluation for all groups. NBSP and CF centers have strong relationships. Early diagnosis may be facilitated through more engagement with PCPs. Quality improvement initiatives should focus on continuing strong partnerships between CF centers and NBS programs, improving education, communication strategies, and partnerships with PCPs, and improving CF NBS timeliness and accuracy.

PMID:35892468 | DOI:10.3390/ijns8030038

Vaccines (Basel). 2022 Jul 8;10(7):1100. doi: 10.3390/vaccines10071100.

ABSTRACT

Pseudomonas aeruginosa is an important opportunistic human pathogen. Using its arsenal of virulence factors and its intrinsic ability to adapt to new environments, P. aeruginosa causes a range of complicated acute and chronic infections in immunocompromised individuals. Of particular importance are burn wound infections, ventilator-associated pneumonia, and chronic infections in people with cystic fibrosis. Antibiotic resistance has rendered many of these infections challenging to treat and novel therapeutic strategies are limited. Multiple clinical studies using well-characterised virulence factors as vaccine antigens over the last 50 years have fallen short, resulting in no effective vaccination being available for clinical use. Nonetheless, progress has been made in preclinical research, namely, in the realms of antigen discovery, adjuvant use, and novel delivery systems. Herein, we briefly review the scope of P. aeruginosa clinical infections and its major important virulence factors.

PMID:35891262 | DOI:10.3390/vaccines10071100

Pharmaceutics. 2022 Jul 7;14(7):1425. doi: 10.3390/pharmaceutics14071425.

ABSTRACT

Bacteriophages, viruses that infect and replicate within bacteria, impact bacterial responses to antibiotics in complex ways. Recent studies using lytic bacteriophages to treat bacterial infections (phage therapy) demonstrate that phages can promote susceptibility to chemical antibiotics and that phage/antibiotic synergy is possible. However, both lytic and lysogenic bacteriophages can contribute to antimicrobial resistance. In particular, some phages mediate the horizontal transfer of antibiotic resistance genes between bacteria via transduction and other mechanisms. In addition, chronic infection filamentous phages can promote antimicrobial tolerance, the ability of bacteria to persist in the face of antibiotics. In particular, filamentous phages serve as structural elements in bacterial biofilms and prevent the penetration of antibiotics. Over time, these contributions to antibiotic tolerance favor the selection of resistance clones. Here, we review recent insights into bacteriophage contributions to antibiotic susceptibility, resistance, and tolerance. We discuss the mechanisms involved in these effects and address their impact on bacterial fitness.

PMID:35890320 | DOI:10.3390/pharmaceutics14071425

Microorganisms. 2022 Jul 19;10(7):1454. doi: 10.3390/microorganisms10071454.

ABSTRACT

Mycobacterium abscessus (M. abscessus) is an opportunistic pathogen usually colonizing abnormal lung airways and is often seen in patients with cystic fibrosis. Currently, there is no vaccine available for M. abscessus in clinical development. The treatment of M. abscessus-related pulmonary diseases is peculiar due to intrinsic resistance to several commonly used antibiotics. The development of either prophylactic or therapeutic interventions for M. abscessus pulmonary infections is hindered by the absence of an adequate experimental animal model. In this review, we outline the critical elements related to M. abscessus virulence mechanisms, host-pathogen interactions, and treatment challenges associated with M. abscessus pulmonary infections. The challenges of effectively combating this pathogen include developing appropriate preclinical animal models of infection, developing proper diagnostics, and designing novel strategies for treating drug-resistant M. abscessus.

PMID:35889173 | DOI:10.3390/microorganisms10071454

Microorganisms. 2022 Jul 14;10(7):1421. doi: 10.3390/microorganisms10071421.

ABSTRACT

Infections caused by Mycobacterium abscessus (Mab), an environmental non-tuberculous mycobacterium, are difficult to eradicate from patients with pulmonary diseases such as cystic fibrosis and bronchiectasis even after years of antibiotic treatments. In these people, the low oxygen pressure in mucus and biofilm may restrict Mab growth from actively replicating aerobic (A) to non-replicating hypoxic (H) stages, which are known to be extremely drug-tolerant. After the exposure of Mab A and H cells to drugs, killing was monitored by measuring colony-forming units (CFU) and regrowth in liquid medium (MGIT 960) of 1-day-old A cells (A1) and 5-day-old H cells (H5). Mab killing was defined as a lack of regrowth of drug-exposed cells in MGIT tubes after &gt;50 days of incubation. Out of 18 drugs tested, 14-day treatments with bedaquiline-amikacin (BDQ-AMK)-containing three-drug combinations were very active against A1 + H5 cells. However, drug-tolerant cells (persisters) were not killed, as shown by CFU curves with typical bimodal trends. Instead, 56-day treatments with the nitrocompounds containing combinations BDQ-AMK-rifabutin-clarithromycin-nimorazole and BDQ-AMK-rifabutin-clarithromycin-metronidazole-colistin killed all A1 + H5 Mab cells in 42 and 56 days, respectively, as shown by lack of regrowth in agar and MGIT medium. Overall, these data indicated that Mab persisters may be killed by appropriate drug combinations.

PMID:35889140 | DOI:10.3390/microorganisms10071421