Rheumatoid arthritis is a multisystemic inflammatory disease that can involve the respiratory system, including the pleural space. Most rheumatoid pleural effusions (PE) are incidentally found and do not require any treatment. Very rarely, however, they can become symptomatic and loculated, leading to lung entrapment or trapped lung. Surgical decortication remains the mainstay of management in such circumstances, although recent studies showed comparable efficacy of intrapleural fibrinolytics (alteplase and dornase alfa) in non-rheumatoid complicated effusions. We present a case of rheumatoid PE leading to lung entrapment successfully treated with intrapleural fibrinolytics without complications and good clinical status at six-month follow-up.

UNASSIGNED: The availability of cystic fibrosis transmembrane conductance regulator (CFTR) modulators opens the possibility of discontinuing some chronic pulmonary therapies to decrease cystic fibrosis (CF) treatment burden. However, CFTR modulators may not adequately address neutrophilic inflammation, which contributes to a self-perpetual cycle of viscous CF sputum, airway obstruction, inflammation, and lung function decline.
UNASSIGNED: This review discusses the emerging role of neutrophil extracellular traps in CF and its role in CF sputum viscosity, airway obstruction, and inflammation, based on a literature search of PubMed (1990-present). We summarize clinical trials and real-world studies that support the efficacy of dornase alfa (Pulmozyme) in improving lung function and reducing pulmonary exacerbation in people with CF (PwCF), and we discuss the potential role of dornase alfa in reducing airway inflammation. We also examine the findings of short-term trials evaluating the discontinuation of mucoactive therapy in PwCF receiving CFTR modulators.
UNASSIGNED: Long-term studies are needed to assess the impact of discontinuing mucoactive therapy in PwCF who are clinically stable while receiving CFTR modulatory therapy. Treatment decisions should take into account the severity of underlying lung disease. People with advanced CF will likely require ongoing mucoactive therapy.

Cumulative evidence from several pre-clinical studies suggests that restoration of plasma DNase activity in a thrombo-inflammatory state may improve clinical outcomes. Following injury, hyperactivated immune cells release large amounts of granular proteins together with DNA, which often accumulate in the surrounding environment in so-called neutrophil extracellular traps (NETs). Degradation of excess NETs by systemic DNase administration offers a promising therapeutic approach to ameliorate inflammation and dissolve intravascular clots. In order to expand the therapeutic utility of human DNase I, a variant of the enzyme was developed that has both a prolonged systemic half-life and a higher catalytic activity compared to Dornase alfa (Pulmozyme®), the recombinant form of DNase I approved for inhaled therapy of cystic fibrosis. The hyperactive enzyme was \"PASylated\" by genetic fusion with a strongly hydrophilic and biodegradable PAS-polypeptide to increase its hydrodynamic volume and retard kidney filtration. A stable TurboCell™ CHO-K1-based cell line was generated which is suitable for the future production of PASylated DNase I according to good manufacturing practice (GMP). Furthermore, a robust bioprocess strategy was devised and an effective downstream process was developed. The final protein product is characterized by excellent purity, favorable physicochemical properties, a 14-fold higher DNA-degrading activity than Dornase alfa and a sustained pharmacokinetic profile, with a 22-fold slower clearance in rats.

UNASSIGNED: Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
UNASSIGNED: Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
UNASSIGNED: We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
UNASSIGNED: Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
UNASSIGNED: LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
UNASSIGNED: NCT04359654.

Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA. These results suggest that pwCF on ETI with mild lung disease do not experience a subclinical deterioration in MCC that could later impact health outcomes after discontinuing HS, and in fact may benefit from improved MCC after stopping DA treatment.

BACKGROUND: One third of children require repeat ventilation tube insertion (VTI) for otitis media. Disease recurrence is associated with persistent middle ear bacterial biofilms. With demonstration that Dornase alfa (a DNase) disrupts middle ear effusion biofilms ex vivo, we identified potential for this as an anti-biofilm therapy to prevent repeat VTI. First, safety and tolerability needed to be measured.
METHODS: This was a phase 1B double-blinded randomized control trial conducted in Western Australia. Children between 6 months and 5 years undergoing VTI for bilateral middle ear effusion were recruited between 2012 and 2014 and followed for two years. Children\'s ears were randomized to receive either Dornase alfa (1 mg/mL) or 0.9 % sodium chloride (placebo) at time of surgery. Children were followed up at 2 weeks post-VTI and at 3-monthly intervals for 2 years. Outcomes assessed were: 1) safety and tolerability, 2) otorrhoea frequency, 3) blocked or extruded ventilation tube (VT) frequency, 4) time to blockage or extrusion, 5) time to infection recurrence and/or need for repeat VTI.
RESULTS: Sixty children (mean age 2.3 years) were enrolled with 87 % reaching study endpoint. Treatment did not change otorrhoea frequency. Hearing improved in all children following VTI, with no indication of ototoxicity. Dornase alfa had some effect on increasing time until VT extrusion (p = 0.099); and blockage and/or extrusion (p = 0.122). Frequency of recurrence and time until recurrence were similar. Fourteen children required repeat VTI within the follow-up period.
CONCLUSIONS: A single application of Dornase alfa into the middle ear at time of VTI was safe, non-ototoxic, and well-tolerated.
BACKGROUND: ACTRN12623000504617.

Neutrophils, key players of the immune system, also promote tumor development through the formation of neutrophil extracellular traps (NETs) in a process called NETosis. NETs are extracellular networks of DNA, histones and cytoplasmic and granular proteins (calprotectin, myeloperoxidase, elastase, etc.) released by neutrophils upon activation. NETs regulate tumor growth while promoting angiogenesis and invasiveness, and tumor cells also stimulate NETosis. Although NETosis seems to be increased in cancer patients, an increase of NETs in plasma may also be mediated by an impaired degradation by plasma DNaseI, as evidenced in several immunological disorders like lupus nephritis. However, this has never been evidenced in bladder cancer (BC) patients. Herein, we aimed to evaluate the occurrence of increased NETosis in plasma and tumor tissue of BC patients, to ascertain whether it is mediated by a reduced DNaseI activity and degradation, and to in vitro explore novel therapeutic interventions.
We recruited 71 BC patients from whom we obtained a plasma sample before surgery and a formalin-fixed paraffin embedded tumor tissue sample, and 64 age- and sex-matched healthy controls from whom we obtained a plasma sample. We measured NETs markers (cell-free fDNA, calprotectin, nucleosomes and neutrophil elastase) and the DNaseI activity in plasma with specific assays. We also measured NETs markers in BC tissue by immunofluorescence. Finally, we evaluated the ability of BC and control plasma to degrade in vitro-generated NETs, and evaluated the performance of the approved recombinant human DNaseI (rhDNaseI, Dornase alfa, Pulmozyme®, Roche) to restore the NET-degradation ability of plasma. In vitro experiments were performed in triplicate. Statistical analysis was conducted with Graphpad (v.8.0.1).
NETosis occurs in BC tissue, more profusely in the muscle-invasive subtype (P<0.01), that with the worst prognosis. Compared to controls, BC patients had increased NETosis and a reduced DNaseI activity in plasma (P<0.0001), which leads to an impairment to degrade NETs (P<0.0001). Remarkably, this can be therapeutically restored with rhDNaseI to the level of healthy controls.
To the best of our knowledge, this is the first report demonstrating that BC patients have an increased NETosis systemically and in the tumor microenvironment, in part caused by an impaired DNaseI-mediated NET degradation. Remarkably, this defect can be therapeutically restored in vitro with the approved Dornase alfa, thus Pulmozyme® could become a potential therapeutic tool to locally reduce BC progression.

UNASSIGNED: Dornase alfa (Pulmozyme, Tigerase) is a purified solution of recombinant human DNase, clinically developed for the treatment of pulmonary diseases in patients with cystic fibrosis (CF). The action of the drug is aimed at destroying the viscous secretion, rich in DNA strands of neutrophils, through their fragmentation, the density of the secretion decreases, and the aeration of the lower respiratory tract improves. The similarity of pathological processes with the formation of viscous exudate on the surface of the mucous membrane in diseases of the upper respiratory tract and ear initiated studies on the use of Dornase alpha in otorhinolaryngology.
METHODS: The analysis of materials of domestic and foreign authors on the effectiveness of the use of the drug Dornase alfa in otorhinolaryngology was carried out.
RESULTS: The review included 132 patients (10 studies) in whom Dornase alfa was used to treat CF-associated nasal and paranasal sinus diseases. Analysis of the literature revealed only 3 studies, one of which consisted of two parts, examining the effect of Dornase alpha on middle ear exudate: two studies were demonstrated in an animal model; one - in vitro on samples of middle ear effusion which were aspirated through a myringotomy incision from patients with recurrent acute otitis media; and one in clinical 40 patients (40 ears) for hydrolysis of exudate in the tympanostomy tubes.
CONCLUSIONS: Analysis of studies on the use of Dornase alfa demonstrates an improvement in clinical symptoms in all patients with CF and chronic rhinosinusitis. In experimental studies on an animal model, as well as in vitro research on exudate from the middle ear, Dornase alfa has demonstrated high efficacy and safety. Dornase alfa is a drug with high potential, further research is needed for wider use in ENT practice, especially in otiatrics.
UNASSIGNED: Препарат дорназа альфа («Пульмозим», «Тигераза») — это очищенный раствор рекомбинантной человеческой ДНазы, разработан клинически для лечения легочных заболеваний у пациентов с муковисцидозом (МВ). Действие препарата направлено на разрушение вязкого секрета, богатого нитями ДНК нейтрофилов, путем их фрагментации, густота секрета снижается — и аэрация нижних дыхательных путей улучшается. Схожесть патологических процессов с образованием вязкого экссудата на поверхности слизистой оболочки при заболеваниях верхних дыхательных путей и уха инициировала исследования по применению дорназы альфа в оториноларингологии.
UNASSIGNED: Проведен анализ материалов отечественных и зарубежных авторов по эффективности применения препарата дорназа альфа в оториноларингологии.
UNASSIGNED: В обзор включены 132 пациента (10 исследований), у которых препарат дорназа альфа применялся для лечения заболеваний полости носа и околоносовых пазух, ассоциированных с МВ. Анализ литературы выявил только три исследования, одно из которых состояло из двух частей, по изучению влияния дорназы альфа на экссудат среднего уха: два исследования продемонстрированы на животной модели, одно исследование — in vitro, на образцах выпота из среднего уха пациентов с рецидивирующим острым средним отитом, полученных при шунтировании, и одно исследование — клиническое, 40 пациентов (40 ушей), для гидролиза экссудата в тимпаностомических трубках.
UNASSIGNED: Анализ исследований по применению дорназы альфа демонстрирует улучшение клинической симптоматики у всех пациентов с МВ и хроническим риносинуситом. В экспериментальных исследованиях на животной модели, а также в работе in vitro (на экксудате из среднего уха) дорназа альфа продемонстрировала высокую эффективность и безопасность. Дорназа альфа — препарат с высоким потенциалом, необходимы дальнейшие исследования для более широкого применения этого препарата в лор-практике, особенно в отиатрии.

UNASSIGNED: Literature regarding clinical benefits of dornase alfa (DNase) in pediatric patients without cystic fibrosis is lacking. In December 2020, the study institution implemented restrictions to limit DNase use in this patient population. The primary objective was adherence to DNase ordering restrictions. Secondary objectives included length of stay, respiratory function, and use of inhaled mucolytic agents.
UNASSIGNED: This single-center retrospective chart review included patients less than 18 years of age who received DNase one year prior to through one year after order restriction implementation. Data collected included patient demographics and respiratory clinical parameters. Dosing regimens for DNase, n-acetylcysteine, and hypertonic saline were collected, as well as changes in length of stay (LOS) and adherence to ordering restrictions.
UNASSIGNED: Of 101 total DNase orders, 45 were placed after implementation of ordering restrictions and 16 (36%) met all ordering criteria. Hospital and intensive care unit (ICU) LOS after implementation of restrictions were not significantly different (p = 0.767 and p = 0.219, respectively). There was no significant change in patients\' mean oxygenation index (p = 0.252) or FiO2% (p = 0.113) 24 hours after DA administration.
UNASSIGNED: Respiratory function did not significantly change after DNase administration. Implementing restrictions on DNase did not impact intensive care unit or hospital LOS. Adherence to DNase ordering restrictions could be improved.

BACKGROUND: Dornase alfa (DNase) is the only mucus-degrading agent that has proven efficacy in cystic fibrosis (CF). Few studies have evaluated the effects of DNase on the lung clearance index (LCI). We report the experience of two CF centers in which LCI monitoring was used to evaluate the efficacy of DNase therapy.
METHODS: This is a prospective and observational study, evaluating the effects of DNase therapy on LCI values in three CF children followed at CF centers in Florence and Catania, Italy. In both centers, LCI was performed routinely, every 3-6 months, based on the clinical picture and severity of the lung disease. In this study, we evaluated the LCI before and after long-term DNase therapy.
RESULTS: DNase improved LCI values in the absence of respiratory exacerbations: in case n. 1 LCI decreased by 39% in 16 months (from 11.1 to 6.8); in case n. 2 by 20% in 12 months (from 9.3 to 7.4); in case n. 3 by 24% in 16 months (from 9.3 to 7.0).
CONCLUSIONS: This case series confirms the efficacy of DNase therapy in CF children, as demonstrated by the LCI reduction in treated patients. Furthermore, our results suggest that LCI is a sensitive marker of disease and can be used for the evaluation of response to treatment.