Cureus. 2022 Oct 29;14(10):e30833. doi: 10.7759/cureus.30833. eCollection 2022 Oct.

ABSTRACT

Cystic fibrosis (CF) is an inherited disorder most prevalent in the Caucasian population, characterized by a functional abnormality of the transmembrane conductance regulator protein that leads to a wide array of complications, including chronic lung infections. Pseudomonas aeruginosa (PA) is a frequently acquired microbe in CF patients and is associated with deterioration in pulmonary function and increased mortality. Inhaled anti-infective agents are an established curative therapy for CF airway infections, especially with chronic PA lung disease. Amongst them, aztreonam lysine for inhalation (AZLI) is an aerosolized monobactam antibiotic aztreonam, approved for use in CF patients nearly a decade ago. This literature review aims to explore studies based on the efficacy, safety, and tolerability of AZLI use in CF patients with pulmonary infections. We searched for all the relevant articles present in PubMed, Google Scholar, Cochrane Library, EMBASE, ClinicalTrials.gov, and Journal of Cystic Fibrosis for our data collection from 2000 to 2020. The use of AZLI has substantially improved lung function, respiratory symptoms, and remarkably reduced sputum PA density in CF patients, thereby improving the patient's overall quality of life. The adverse effects reported were compatible with CF lung disease. Hence, inhalational therapy with AZLI is highly efficacious and safe in the management of chronic airway infections. More clinical trials need to be conducted in the future to assess its long-term clinical benefits and adverse events as well as to explore the role of AZLI in the setting of acute lung infections.

PMID:36451641 | PMC:PMC9703835 | DOI:10.7759/cureus.30833

J Bras Pneumol. 2022 Nov 28;48(6):e20220265. doi: 10.36416/1806-3756/e20220265. eCollection 2022.

ABSTRACT

OBJECTIVE: There is still limited information on the clinical characteristics and outcomes of cystic fibrosis (CF) patients with COVID-19 in Brazil. The objective of this study was to describe the cumulative incidence of COVID-19 in CF patients, as well as their clinical characteristics and outcomes.

METHODS: This was a prospective cohort study involving unvaccinated adult CF patients and conducted during the first year of the SARS-CoV-2 pandemic in the city of Porto Alegre, in southern Brazil. The clinical course of the disease was rated on the WHO Ordinal Scale for Clinical Improvement. The primary outcome was the number of incident cases of COVID-19.

RESULTS: Between April 30, 2020 and April 29, 2021, 98 CF patients were included in the study. Seventeen patients were diagnosed with COVID-19. For the CF patients, the annual cumulative incidence of COVID-19 was 17.3%, similar to that for the general population, adjusted for age (18.5%). The most common symptoms at diagnosis of COVID-19 were cough (in 59%), dyspnea (in 53%), fatigue (in 53%), and fever (in 47%). Only 6 (35%) of the patients required hospitalization, and 3 (17.6%) required oxygen support. Only 1 patient required mechanical ventilation, having subsequently died.

CONCLUSIONS: During the first year of the SARS-CoV-2 pandemic in southern Brazil, the cumulative incidence rate of COVID-19 was similar between CF patients and the general population. More than 50% of the CF patients with SARS-CoV-2 infection had a mild clinical presentation, without the need for hospital admission, and almost the entire sample recovered completely from the infection, the exception being 1 patient who had advanced lung disease and who died.

PMID:36449821 | DOI:10.36416/1806-3756/e20220265

JAMA Dermatol. 2022 Nov 30. doi: 10.1001/jamadermatol.2022.5208. Online ahead of print.

ABSTRACT

IMPORTANCE: A new treatment for cystic fibrosis combining 3 CFTR modulators-elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)-has recently been approved for cystic fibrosis treatment. The cutaneous adverse effects following treatment with this combination are poorly described in the literature.

OBJECTIVE: To describe the clinicopathological features and treatment response of ELX-TEZ-IVA-associated acneiform eruptions in patients with cystic fibrosis.

DESIGN, SETTING, AND PARTICIPANTS: This case series study was conducted in the Dermatology Department of Cochin Hospital, Paris, France, from July 2021 to June 2022 in collaboration with the Cochin Reference Center for Cystic Fibrosis. Referred patients were examined by senior dermatologists. All patients with cystic fibrosis treated with ELX-TEZ-IVA and referred for an acneiform rash were included.

EXPOSURES: Treatment with ELX-TEZ-IVA.

MAIN OUTCOMES AND MEASURES: Onset of acneiform rash, type of lesions, and degree of severity, as well as treatments initiated and response, were evaluated. When performed, skin biopsies were reviewed.

RESULTS: This study included 16 patients (11 women [68.7%]) with a median (range) age of 27 (22-38) years. Six patients (37.5%) developed new-onset acneiform rashes, whereas 10 patients (62.5%) had a relapse (5 patients) or worsening (5 patients) of previous acne. The median (range) onset of acneiform rash was 45 (15-150) days. At inclusion, 11 patients (68.7%) had facial hyperseborrhea, 15 patients (93.7%) had noninflammatory lesions, and 14 (87.5%) had inflammatory lesions of seborrheic regions. Four patients (25.0%) had severe acne with deep inflammatory lesions and pitted scars. A specific pathological pattern of necrotizing infundibular crystalline folliculitis was observed in 4 patients. Topical acne treatments, antibiotics, and isotretinoin were used successfully in these patients, resulting in partial or complete remission in 12 patients (85.7% of patients reevaluated).

CONCLUSIONS AND RELEVANCE: This case series study found that acneiform eruption is an adverse event associated with ELX-TEZ-IVA treatment in patients with cystic fibrosis. Most patients developed mild lesions. However, isotretinoin treatment may be necessary in some patients. The mechanism of ELX-TEZ-IVA-associated acneiform eruption is currently unknown, but the observation of necrotizing infundibular crystalline folliculitis in biopsied patients may guide further exploration.

PMID:36449298 | DOI:10.1001/jamadermatol.2022.5208

Eur J Pediatr. 2022 Nov 30. doi: 10.1007/s00431-022-04734-y. Online ahead of print.

ABSTRACT

Only few studies report long-term evolution of patients with neuroendocrine cell hyperplasia of infancy (NEHI). We report data from a 54-patient cohort followed up in the French network for rare respiratory diseases (RespiRare). Demographic characteristics and respiratory and nutritional evolution were collected at the time of the patient's last scheduled visit. The mean duration of follow-up was 68 months (5 months to 18 years). Fifteen patients (27.8%) were considered clinically cured. During follow-up, hospitalizations for wheezy exacerbations were reported in 35 patients (55%), and asthma diagnosed in 20 (37%). Chest CT scan improvement was noted in 25/44 (56.8%). Spirometry showed a persistent obstructive syndrome in 8/27 (29.6%). A sleep disorder was rare (2/36, 5.5%). Oxygen weaning occurred in 28 of the 45 patients initially treated (62.2%) and was age-dependent (35.7% under 2 years, 70.5% between 2 and 6 years, and 100% after 7 years). Oxygen duration was linked to a biopsy-proven diagnosis (p = 0.02) and to the use of a nutritional support (p = 0.003). Corticosteroids were largely prescribed at diagnosis, with no evident respiratory or nutritional effect during follow-up. Among 23 patients with an initial failure to thrive, 12 (52.2%) had no weight recovery. Initial enteral feeding (17/54, 31.5%) was stopped at a mean age of 43 months (3 to 120), with no effect on cure and oxygen liberation at the last visit. Conclusion: Our results show that NEHI has a globally positive, but unequal, improvement over time. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI. What is Known: • Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose long-term outcome is considered positive from very few studies including heterogeneous populations. What is New: • The 68-month follow-up of our 54-patient cohort showed respiratory/nutritional symptom persistence in 72.2%, oxygen requiring in 34%, and asthma in 37%. When controlled, radiological or functional improvement was noted in 56.8 and 40.7%. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI.

PMID:36449078 | DOI:10.1007/s00431-022-04734-y

Cochrane Database Syst Rev. 2022 Nov 30;11:CD013634. doi: 10.1002/14651858.CD013634.pub2.

ABSTRACT

BACKGROUND: Chronic arthropathy is a potentially debilitating complication for people with haemophilia - a genetic, X-linked, recessive bleeding disorder, characterised by the absence or deficiency of a clotting factor protein. Staging classifications, such as the Arnold-Hilgartner classification for haemophilic arthropathy of the knee, radiologically reflect the extent of knee joint destruction with underlying chronic synovitis. Management of this highly morbid disease process involves intensive prophylactic measures, and chemical or radioisotope synovectomy in its early stages. However, failure of non-surgical therapy in people with progression of chronic arthropathy often prompts surgical management, including synovectomy, joint debridement, arthrodesis, and arthroplasty, depending on the type of joint and extent of the damage. To date, management of people with mild to moderate chronic arthropathy from haemophilia remains controversial; there is no agreed standard treatment. Thus, the benefits and disadvantages of non-surgical and surgical management of mild to moderate chronic arthropathy in people with haemophilia needs to be systematically reviewed. OBJECTIVES: To assess the efficacy and safety of surgery for mild to moderate chronic arthropathy in people with haemophilia A or B.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, and two trial registers to August 2022. We also handsearched relevant journals and conference abstract books.

SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs comparing surgery and non-surgical interventions, for any joint with chronic arthropathy, in people with haemophilia, who were at least 12 years old.

DATA COLLECTION AND ANALYSIS: The review authors did not identify any trials to include in this review.

MAIN RESULTS: The review authors did not identify any trials to include in this review.

AUTHORS' CONCLUSIONS: The review authors did not identify any trials to include in this review. Due to a lack of research in this particular area, we plan to update the literature search every two years, and will update review if any new evidence is reported. There is a need for a well-designed RCT that assesses the safety and efficacy of surgical versus non-surgical interventions for chronic arthropathy in people with haemophilia.

PMID:36448638 | DOI:10.1002/14651858.CD013634.pub2

Pediatr Pulmonol. 2022 Nov 30. doi: 10.1002/ppul.26257. Online ahead of print.

ABSTRACT

INTRODUCTION: The success of highly effective modulator therapy (HEMT) has led to consideration of simpler regimens for people with CF (PwCF) with opportunities to modify burdensome regimens. Despite the intuitive appeal of discontinuing chronic therapies no longer necessary, this process should be pursued systematically to ensure safety, adherence, and validate patient-centered preferences. We designed a questionnaire to determine the state of use of acid suppressive medications (ASM) and pancreatic enzyme therapy (PERT), current self-withdrawal and provider-directed withdrawal practices, and interest in a standardized withdrawal study.

METHODS: In collaboration with CF Foundation (CFF), a questionnaire was developed and distributed to members of Community Voice (CV, comprised of PwCF and their loved ones), and CF providers regarding the need to study simplifying the gastrointestinal (GI) regimen for PwCF on HEMT.

RESULTS: Approximately 20-40% of CV or CF providers have decreased or stopped ASM for those on HEMT. For PERT, CV and CF providers have decreased dose (34-48% and approximately 25%, respectively) more often than having stopped it altogether (13-24% and 3-12%, respectively). Cumulatively, there is interest in pursuing research in this area (86% CV, 89% CF providers) and willingness to enroll in such a study (80% CV and 89% CF providers).

CONCLUSION: Systematically studying withdrawal of common GI medications, ASM and PERT, is important to CV and CF providers. Decreases in dosing and withdrawal are already taking place without evidence to support this practice. This questionnaire is the first step in designing a GI medication simplification study in PwCF on HEMT. This article is protected by copyright. All rights reserved.

PMID:36448312 | DOI:10.1002/ppul.26257

Transl Med UniSa. 2022 Sep 16;24(2):12-15. doi: 10.37825/2239-9754.1035. eCollection 2022.

ABSTRACT

The Acute Respiratory Distress Syndrome (ARDS) is a common, devastating clinical pattern characterized by life-threatening respiratory failure. In ARDS there is an uncontrolled inflammatory response that results in alveolar damage, with the exudation of protein-rich pulmonary-edema fluid in the alveolar space. Although severe COVID-19 lung failure (CARDS) often meets diagnostic criteria of traditional ARDS, additional features have been reported, such as delayed onset, binary pulmonary compliant states, and hypercoagulable profile. Increased levels of Krebs von den Lungen 6 (KL-6, also known as MUC1) have been reported in both ARDS and CARDS. KL-6 is a transmembrane protein expressed on the apical membrane of most mucosal epithelial cells and it plays a critical role in lining the airway lumen. Abnormalities in mucus production contribute to severe pulmonary complications and death from respiratory failure in patients with diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and acute lung injury due to viral pathogens. Nevertheless, it is not clear what role KL-6 plays in ARDS/CARDS pathophysiology. KL-6 may exert anti-inflammatory effects through the intracellular segment, as proven in animal models of ARDS, while its extracellular segment will enter the blood circulation through the alveolar space when the alveolar epithelial cells are damaged. Therefore, changes in plasma KL-6 levels may be useful in ARDS and CARDS phenotyping, and KL-6 might guide future clinical trials in 'personalized medicine' settings.

PMID:36447946 | PMC:PMC9673987 | DOI:10.37825/2239-9754.1035

Cureus. 2022 Oct 28;14(10):e30786. doi: 10.7759/cureus.30786. eCollection 2022 Oct.

ABSTRACT

Introduction Diverticula of the appendix is a rare entity, may be complicated by inflammation/infection, and clinically mimics acute appendicitis. The reported associated risk factors include male gender, Hirschprung's disease, cystic fibrosis and adult age, where some reports claim that they are also associated with an increased risk of appendiceal malignancy. Imaging has a place in pre-operative diagnosis, however, most of the cases were diagnosed during a pathological examination after surgery. They are associated with a higher rate of perforation (more than four times compared with classical acute appendicitis). In this review, we present a case series of five patients diagnosed with diverticulitis and one with diverticulosis of the appendix that were managed at a single centre. Our aim is to explore the common clinical, radiological, and intra-operative findings associated with this disease as well as the outcome of management. Materials and methods A total number of six cases of diverticular disease of the appendix diagnosed and managed at Basildon University hospital in the period between 2016 and 2020 were studied. The demographic details and clinical data including presenting symptoms, laboratory results, radiological characteristics, intraoperative findings and histopathological features were analysed. Results The study group included four males and two females, with an age range of 20-84 years. The most common presenting clinical symptoms were right iliac fossa abdominal pain, nausea, anorexia, and diarrhoea. Half of the cases showed a thickened appendix in the pre-operative CT scan. An inflamed or perforated appendix was seen in five cases as well as inflammation of the diverticula. Conclusion Appendiceal diverticulitis is an uncommon pathology that imitates acute appendicitis, and appendicectomy is the standard treatment. Prophylactic appendicectomy is recommended for non-inflamed diverticula - this is due to the potential risk of inflammation, perforation, and the risk of developing an appendiceal neoplasm.

PMID:36447679 | PMC:PMC9701316 | DOI:10.7759/cureus.30786

Cell Stress. 2022 Aug 8;6(8):72-75. doi: 10.15698/cst2022.08.270. eCollection 2022 Aug.

ABSTRACT

Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend healthspan in humans. We recently demonstrated that reduced PI3K activity in cardiomyocytes delays cardiac growth, causing subnormal contractility and cardiopulmonary functional capacity, as well as increased risk of mortality at young age. In stark contrast, in aged mice, experi-mental attenuation of PI3K signaling reduced the age-dependent decline in cardiac function and extended maximal lifespan, suggesting a biphasic effect of PI3K on cardiac health and survival. The cardiac anti-aging effects of reduced PI3K activity coincided with enhanced oxida-tive phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed in-creased PI3K signaling, as indicated by increased phos-phorylation of the serine/threonine-protein kinase AKT. Hence, late-life cardiac-specific targeting of PI3K might have a therapeutic potential in cardiac aging and related diseases.

PMID:36447531 | PMC:PMC9662025 | DOI:10.15698/cst2022.08.270

Prenat Diagn. 2022 Nov 29. doi: 10.1002/pd.6276. Online ahead of print.

ABSTRACT

OBJECTIVES: Cystic fibrosis (CF) is one of the most common severe autosomal recessive disorders. Prenatal or preconception CF screening is offered in some countries. A maternal blood sample in early pregnancy can provide circulating trophoblasts and offers a DNA source for genetic analysis of both the mother and the fetus. This study aimed to develop a cell-based noninvasive prenatal test (NIPT) to screen for the 50 most common CF variants.

METHODS: Blood samples were collected from 30 pregnancies undergoing invasive diagnostics and circulating trophoblasts were harvested in 27. CF testing was conducted using two different methods: By fragment length analysis and by our newly developed NGS-based CF analysis RESULTS: In all 27 cases, cell-based NIPT provided a result using both methods in agreement with the invasive test result.

CONCLUSION: This study shows that cell-based NIPT for CF screening provides a reliable result without the need for partner- and proband samples. This article is protected by copyright. All rights reserved.

PMID:36447355 | DOI:10.1002/pd.6276

Pediatr Pulmonol. 2022 Nov 29. doi: 10.1002/ppul.26261. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF).

METHODS: Lung function (FEV1 ), body mass index (BMI) and microbiologic data were collected at initiation and 3-month intervals for 1 year. Blood was analyzed at baseline and 6 months for cytokines and immune cell populations via flow cytometry and compared to non-CF controls.

RESULTS: Sample size was 48 pwCF, 28 (58.3%) males with a mean age of 28.8±10.7 years. Significant increases in %predicted FEV1 and BMI were observed through 6 months of ETI therapy with no change thereafter. Changes in FEV1 and BMI at 3 months were significantly correlated (r=57.2, p<0.01). There were significant reductions in Pseudomonas and Staphylococcus positivity (percent of total samples) in pwCF through 12 months of ETI treatment. Healthy controls (n=20) had significantly lower levels of circulating neutrophils, IL-6, IL-8, and IL-17A and higher levels of IL-13 compared to pwCF at baseline (n=48). After 6 months of ETI, pwCF had significant decreases in IL-8, IL-6, and IL-17A levels and normalization of peripheral blood immune cell composition.

CONCLUSIONS: In pwCF, ETI significantly improved clinical outcomes, reduced systemic pro-inflammatory cytokines, and restored circulating immune cell composition after 6 months of therapy. This article is protected by copyright. All rights reserved.

PMID:36444736 | DOI:10.1002/ppul.26261

Pediatr Pulmonol. 2022 Nov 29. doi: 10.1002/ppul.26263. Online ahead of print.

ABSTRACT

PURPOSE: Cystic Fibrosis (CF) was added to the German newborn bloodspot screening (NBS) panel in 2016. This study assesses parental perceptions of CF-NBS and confirmatory testing.

METHODS: Prospective questionnaire-based survey administered to parents of children with positive CF-NBS over 40 months after initiation of CF-NBS in Southwest Germany. Parental perceptions were compared to results from Bavaria and Switzerland.

RESULTS: Questionnaires with 29 standardized questions were sent to 343 families with children born between October 2016 and January 2020. 178 (51.9%) replied. Although required by law, only a minority were informed about CF-NBS by a physician. The information provided about NBS was sufficient for 78% of parents. Regarding the information about positive CF-NBS, 52.9% were satisfied but the majority expressed negative emotions (89.5%). While most of these were resolved after confirmatory diagnostics, 17% of parents of children with false-positive CF-NBS and 66.7% of children confirmed with CF remained anxious. Waiting time for sweat testing was > 3 days in 56.1%, considerably longer than in more centralized screening systems. Parents who waited for a maximum of 3 days were significantly more satisfied. 70.7% of parents were satisfied with the information given during confirmatory diagnostics and 91.4% were satisfied with participating in CF-NBS.

CONCLUSIONS: CF-NBS stands in high regard with parents. Smooth organization, timely initiation of confirmatory testing, and professional communication are most important to limit parental anxiety. A more centralized system of confirmatory diagnostics appears advantageous in several regards as it reduces time from positive NBS to final diagnosis and increases parental satisfaction. This article is protected by copyright. All rights reserved.

PMID:36444714 | DOI:10.1002/ppul.26263

Cell Mol Bioeng. 2022 Jul 5;15(5):355-366. doi: 10.1007/s12195-022-00727-x. eCollection 2022 Oct.

ABSTRACT

INTRODUCTION: The surface modification of nanoparticles (NP) with a dense layer of polyethylene glycol (PEG) has been widely used to improve NP circulation time, bioavailability, and diffusion through biological barriers [e.g. extracellular matrix (ECM), mucus]. While linear PEG coatings are commonly used, branched PEG coatings have not been widely explored as a design parameter for NP drug delivery systems.

METHODS: NPs were densely coated with either linear 2, 5, 10 kDa linear PEG or with 10 kDa star-shaped, 4-arm branched PEG. NP cellular uptake was evaluated in HEK-293T and A549 cells. NP stability was evaluated in fetal bovine serum over 24 h using dynamic light scattering. Diffusion of NPs within a Matrigel ECM model and sputum (mucus) collected from individuals with cystic fibrosis (CF) lung disease were analyzed through multiple particle tracking.

RESULTS: PEG-coated NPs appeared more stable in serum compared to uncoated NPs, but the reduction in total protein adsorbed was most significant for branched PEG coated NP. All PEGylated NPs had similar cellular uptake in HEK-293T and A549 cells. Interestingly, branched-PEG coated NPs had the largest diffusion coefficient and moved most rapidly through Matrigel. However in CF mucus, linear 2 and 5 kDa PEG coated NPs had the largest fraction of rapidly diffusing particles while branched PEG coated NPs had less hindered mobility compared to linear 10 kDa PEG coated NPs.

CONCLUSION: Branched PEGylation may have the potential to increase NP efficiency in reaching target cells based on an apparent increase in diffusion through an ECM model while maintaining NP stability and uptake in target cells comparable to their linear PEG counterparts.

PMID:36444352 | PMC:PMC9700551 | DOI:10.1007/s12195-022-00727-x

BMC Gastroenterol. 2022 Nov 28;22(1):494. doi: 10.1186/s12876-022-02553-x.

ABSTRACT

BACKGROUND: CF patients experience several episodes of pulmonary exacerbations and reduction in their lung function progressively. Lung function is not the only diagnostic index by physicians to decide if CF patients require antibiotic therapy following pulmonary exacerbations. Non-invasive fecal indicators are increasingly being used to assess intestinal inflammation. Calprotectin is the most extensively utilized fecal biomarker in recent CF researches.

METHODS: In this longitudinal study, 30 CF patients (1-18 years) without current infectious gastroenteritis were recruited from Mofid Children's Hospital and Masih Daneshvari Hospital, Tehran, Iran. Then, fecal calprotectin levels were evaluated before treatment, two weeks after systemic antibiotic administration, as well as recurrence of pulmonary exacerbation after first post-hospital discharge.

RESULTS: The initial fecal calprotectin level in CF patients receiving antibiotics was 651.13 ± 671.04, significantly decreasing two weeks after antibiotic therapy and following recurrence (171.81 ± 224.40, 607.93 ± 549.89, respectively; P < 0.01). Following systemic antibiotic treatment, the patient's respiratory and GI symptoms improved (P < 0.01).

CONCLUSION: Our findings revealed that fecal calprotectin modifications are associated with CF pulmonary exacerbations and antibiotic treatment could reduce calprotectin levels. Therefore, the fecal calprotectin level could be considered as a diagnostic tool and an index to follow the response to treatment in CF pulmonary exacerbations.

PMID:36443671 | DOI:10.1186/s12876-022-02553-x

J Control Release. 2022 Nov 25:S0168-3659(22)00788-X. doi: 10.1016/j.jconrel.2022.11.043. Online ahead of print.

ABSTRACT

Inflammation is a key pathological driver in cystic fibrosis (CF). Current therapies are ineffective in treating and preventing the escalation of inflammatory events often exacerbated by superimposed infection. In this work, we propose a novel treatment based on the pulmonary administration of anakinra, a non-glycosylated recombinant form of IL-1Ra. An inhalable dry powder of anakinra was successfully developed to meet the specific needs of lung drug delivery. The new formulation was investigated in vitro for aerodynamic performances and activity and in vivo for its pharmacological profile, including the pharmacokinetics, treatment schedule, antimicrobial and anti-inflammatory activity and systemic toxicity. The protein was structurally preserved inside the formulation and retained its pharmacological activity in vitro immediately after preparation and over time when stored at ambient conditions. Anakinra when delivered to the lungs showed an improved and extended therapeutic efficacy in CF models in vivo as well as higher potency compared to systemic delivery. Peripheral side effects were significantly reduced and correlated with lower serum levels compared to systemic treatment. These findings provide proof-of-concept demonstration for anakinra repurposing in CF through the pulmonary route.

PMID:36442616 | DOI:10.1016/j.jconrel.2022.11.043

Pediatr Surg Int. 2022 Nov 28;39(1):12. doi: 10.1007/s00383-022-05296-8.

ABSTRACT

INTRODUCTION: Exomphalos is an anterior abdominal wall defect resulting in herniation of contents into the umbilical cord. Severe associated chromosomal anomalies and congenital heart disease (CHD) are known to influence mortality, but it is not clear which cardiac anomalies have the greatest impact on survival.

METHODS: We performed a retrospective review of the treatment and outcome of patients with exomphalos over a 30-year period (1990-2020), with a focus on those with the combination of exomphalos major and major CHD (EMCHD).

RESULTS: There were 123 patients with exomphalos identified, 59 (48%) had exomphalos major (ExoMaj) (defect > 5 cm or containing liver), and 64 (52%) exomphalos minor (ExoMin). In the ExoMaj group; 17% had major CHD (10/59), M:F 28:31, 29% premature (< 37 weeks, 17/59) and 14% had low birth-weight (< 2.5 kg, 8/59). In the ExoMin group; 9% had major CHD (6/64), M:F 42:22, 18% premature and 10% had low birth-weight. The 5-year survival was 20% in the EMCHD group versus 90% in the ExoMaj with minor or no CHD [p < 0.0001]. Deaths in the EMCHD had mainly right heart anomalies and all of them required mechanical ventilation (MV) for pulmonary hypoplasia prior to cardiac intervention. In contrast, survivors did not require mechanical ventilation prior to cardiac intervention.

CONCLUSION: EMCHD is associated with high mortality. The most significant finding was high mortality in those with right heart anomalies in combination with pulmonary hypoplasia, especially if pre-intervention mechanical ventilation is required.

PMID:36441283 | DOI:10.1007/s00383-022-05296-8

Pharmacol Res Perspect. 2022 Dec;10(6):e01015. doi: 10.1002/prp2.1015.

ABSTRACT

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in CF patients (≥6 years) with ≥1 Phe508del mutation and a minimal function mutation. In October 2019, ETI became available on compassionate use basis for Dutch CF patients with severe lung disease. Our objective was to investigate safety and efficacy of ETI in this patient group in a real-life setting. A multicenter longitudinal observational study was conducted to examine changes in FEV1 , BMI, and adverse events at initiation and 1, 3, 6, and 12 months after starting ETI. The number of exacerbations was recorded in the 12 months before and the 12 months after ETI treatment. Patients eligible for compassionate use had a FEV1 <40% predicted. Wilcoxon signed-rank test analyzed changes over time. Twenty subjects were included and followed up for up to 12 months after starting ETI. Treatment was well tolerated with mild side effects reported, namely, rash (15%) and stomach ache (20%) with 80% resolving within 1 month. Mean absolute increase of FEV1 was 11.8/13.7% (p ≤ .001) and BMI was 0.49/1.87 kg/m2 (p < .001-0.02) after 1/12 months, respectively. In comparison to the number of exacerbations pretrial, there was a marked reduction in exacerbations after initiation. Our findings show long-term effects of treatment with ETI in patients with severe CF lung disease in a real-life setting. Treatment with ETI is associated with increased lung function and BMI, less exacerbations, and only mild side effects.

PMID:36440690 | DOI:10.1002/prp2.1015

Cureus. 2022 Oct 25;14(10):e30660. doi: 10.7759/cureus.30660. eCollection 2022 Oct.

ABSTRACT

Non-cystic fibrosis bronchiectasis has recently been under the spotlight due to a better detection rate with advanced imaging techniques. Recurrent infections in such patients are the main cause of their deterioration. This invariably leads to a catastrophic wheel of decline in lung function, reinfection, and repeated hospital consultations. The main goal of their management is based on the principles of prevention and vigorous treatment of recurrent infections. This review aimed to gather recent therapeutic options for inhaled antibacterial use in such patients and compare them for their properties of safety and efficacy. Studies done in the last 10 years on adult patients were gathered using the Medical Subject Headings (MeSH) strategy and later sorted using the inclusion/exclusion criteria. Research engines used include Google Scholar, PubMed, and the Saudi Digital Library. Out of the 31,739 articles identified initially, 1362 were screened. The final eight selected papers were assessed for quality by using the quality assessment checklist, the Cochrane bias assessment tool, the Scale for the Assessment of Narrative Review Articles (SANRA) tools and cross-examined by co-authors. We concluded that the use of inhaled antibiotics as an adjuvant and follow-up treatment option is associated with better short and long-term prognoses in patients. They lead to lesser systemic side effects than the oral and intravenous varieties available on the market. However, the establishment of a hierarchy among the subgroups remains a grey area that needs further research.

PMID:36439573 | PMC:PMC9685586 | DOI:10.7759/cureus.30660

Front Genet. 2022 Nov 9;13:1035468. doi: 10.3389/fgene.2022.1035468. eCollection 2022.

ABSTRACT

Congenital absence of the vas deferens (CAVD) is a major cause of obstructive azoospermia. Mutations of CFTR and ADGRG2 cause the majority of CAVD. Despite this, 10%-20% of CAVD patients remain without a clear genetic diagnosis. Herein, the CFTR and ADGRG2 genes were first sequenced using Sanger sequencing in 50 CAVD patients. Whole-exome sequencing (WES) was used to further identify potential novel genetic causes in CAVD with hypospadias. In total, 29 of 50 CAVD patients carried at least one CFTR mutation, but no ADGRG2 mutation was found. 5T was found to be the most frequent variant in our CAVD populations. Seven CAVD patients with hypospadias were further analyzed using WES. No homozygous or compound heterozygous mutations related to disorders of sex development (DSDs) or male infertility were identified by WES. CAVD with hypospadias presented lower testicular volume (9.71 ± 2.14 ml vs. 14.45 ± 2.93 ml, p < 0.001) and higher FSH level (FSH: 7.28 ± 3.91 IU/L vs. 4.24 ± 1.96 IU/L, p = 0.027) than CAVD without hypospadias. It is worth noting that neither CFTR or ADGRG2 mutation nor homozygous or compound heterozygous gene mutations were identified in seven CAVD cases with hypospadias. However, nine heterozygous or hemizygous mutations were selected as potential pathogenic genes in CAVD with hypospadias. In conclusion, CFTR variants, especially 5T, play a major role in the Chinese CAVD population. CAVD with hypospadias shows relatively lower testicular spermatogenesis, suggesting a different genetic basis or pathogenic factor from cystic fibrosis/CAVD or unilateral renal agenesis/CAVD.

PMID:36437957 | PMC:PMC9682239 | DOI:10.3389/fgene.2022.1035468

BMC Pulm Med. 2022 Nov 28;22(1):446. doi: 10.1186/s12890-022-02243-0.

ABSTRACT

BACKGROUND: Obstructive sleep apnea (OSA), nocturnal hypoxemia and excessive daytime sleepiness (EDS) are common comorbidities in people with cystic fibrosis (pwCF). Most of the data showing this originates from children and adolescents. The aim of this study was to collect data on sleep parameters, EDS and pulmonary function from a large cohort of adult pwCF.

METHODS: Full overnight polysomnography (PSG) was performed. EDS was determined using the Epworth Sleepiness Scale (ESS). Demographic and clinical data (body mass index [BMI], pulmonary function, capillary blood gases) were collected.

RESULTS: A total of 52 adult pwCF were included (mean age 30.7 ± 8.0 years, mean percent predicted forced expiratory volume in 1 s [ppFEV1] of 52.1 ± 14.8). Overall AHI was in the normal range (4.5 ± 4.0/h); 21/52 pwCF (40%) had an apnea-hypopnea index > 5/h. Nocturnal hypoxemia was found in 25% of participants and this was associated with ppFEV1 (p = 0.014), awake oxygen saturation (SpO2; p = 0.021) and awake partial pressure of oxygen (pO2; p = 0.003); there were no significant differences in age, lung function and BMI were found for pwCF with versus without OSA (all p > 0.05). Eight pwCF (15%) had an ESS score > 10 (indicating EDS). OSA was best predicted by awake pO2 (area under the curve [AUC] 0.66, p = 0.048), while nocturnal hypoxemia was best predicted by ppFEV1 (AUC 0.74, p = 0.009), awake pO2 (AUC 0.76, p = 0.006) and awake SpO2 (AUC 0.71; p = 0.025).

CONCLUSION: OSA, nocturnal hypoxemia and EDS were common in adult pwCF, but no strong predictors were identified. Therefore, we suggest regular PSG and ESS scoring in adult pwCF, regardless of disease severity.

PMID:36437445 | DOI:10.1186/s12890-022-02243-0