Choice of intrapleural fibrinolytic agents in the treatment of adult complicated parapneumonic effusion and empyema: Network meta-analysis.

BACKGROUND: The appropriate use of intrapleural fibrinolytic agents in patients with complicated parapneumonic effusion and empyema remains unclear, especially regarding the choice of fibrinolytic agents. We conducted a network meta-analysis comparing outcomes of intrapleural fibrinolytic agents in patients with complicated parapneumonic effusion and empyema. METHODS: MEDLINE and EMBASE were searched through April 2022 to identify randomized controlled trials (RCTs) that investigated outcomes in patients with complicated parapneumonic effusion or empyema who were treated with intrapleural fibrinolytic agents. The outcomes of interest were surgical requirements, bleeding, length of hospital stay, and all-cause mortality. RESULTS: Our analysis included 10 RCTs that enrolled 1085 patients treated with intrapleural tissue plasminogen activator (TPA) (n = 138), TPA + deoxyribonuclease (DNase) (n = 52), streptokinase (n = 311), urokinase (n = 75), DNase (n = 51), or placebo (n = 458). The rates of surgical requirement were significantly lower with TPA and TPA + DNase than with placebo (risk ratio [RR]; 95% confidence interval [CI] = 0.36 [0.14-0.97], p = 0.038, RR [95% CI] = 0.25 [0.08-0.78], p = 0.017, respectively). The risk of bleeding was higher with TPA + DNase than with placebo (RR [95% CI] = 10.91 [1.53-77.99], p = 0.017), as well as TPA and TPA + DNase than with urokinase (RR [95% CI] = 17.90 [1.07-299.44], p = 0.044, RR [95% CI] = 89.3 [2.88-2772.49], p = 0.010, respectively). All-cause mortality was similar among the groups. CONCLUSION: TPA and TPA + DNase reduced the rates of surgical requirement compared with placebo. However, TPA + DNase increased the risk of bleeding compared with placebo. Intrapleural agents for complicated parapneumonic effusion and empyema should be selected with an individual risk assessment.

Modified regimen intrapleural alteplase with pulmozyme in pleural infection management: a tertiary teaching hospital experience.

BACKGROUND: Current management of poorly draining complex effusions favours less invasive image-guided placement of smaller tubes and adjunctive intrapleural fibrinolysis therapy (IPFT). In MIST-2 trial, intrapleural 10 mg alteplase (t-PA) with 5 mg of pulmozyme (DNase) twice daily for 72 h were used. We aimed to assess the effectiveness and safety of a modified regimen 16 mg t-PA with 5 mg of DNase administered over 24 h in the management of complex pleural infection. METHODS: This was a single centre, prospective study involving patients with poorly drained pleural infection. Primary outcome was the change of pleural opacity on chest radiograph at day 7 compared to baseline. Secondary outcomes include volume of fluid drained, inflammatory markers improvement, surgical referral, length of hospitalisation, and adverse events. RESULTS: Thirty patients were recruited. Majority, 27 (90%) patients were successfully treated. Improvement of pleural opacity on chest radiograph was observed from 36.9% [Interquartile range (IQR 21.8-54.9%)] to 18.1% (IQR 8.8-32.7%) of hemithorax (P < 0.05). T-PA/DNase increased fluid drainage from median of 45 mls (IQR 0-100) 24 h prior to intrapleural treatment to 1442 mls (IQR 905-2360) after 72 h; (P < 0.05) and reduction of C-reactive protein (P < 0.05). Pain requiring escalation of analgesia affected 20% patients and 9.9% experienced major adverse events. None required surgical intervention. CONCLUSION: This study suggests that a modified regimen 16 mg t-PA with 5 mg DNase can be safe and effective for patients with poorly drained complex pleural infection. Trial registration The study was registered retrospectively on 07/06/2021 with ClinicalTrials number NCT04915586 ( https://clinicaltrials.gov/ct2/show/NCT04915586 ).

Intrapleural Fibrinolytics and Deoxyribonuclease for Treatment of Indwelling Pleural Catheter-Related Pleural Infection: A Multi-Center Observational Study.

BACKGROUND: Indwelling pleural catheters (IPC) are increasingly used for management of recurrent (especially malignant) effusions. Pleural infection associated with IPC use remains a concern. Intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) significantly reduces surgical referrals in non-IPC pleural infection, but data on its use in IPC-related pleural infection are scarce. OBJECTIVE: To assess the safety and efficacy of intrapleural tPA and DNase in IPC-related pleural infection. METHODS: Patients with IPC-related pleural infection who received intrapleural tPA/DNase in five Australian and UK centers were identified from prospective databases. Outcomes on feasibility of intrapleural tPA/DNase delivery, its efficacy and safety were recorded. RESULTS: Thirty-nine IPC-related pleural infections (predominantly Staphylococcus aureus and gram-negative organisms) were treated in 38 patients; 87% had malignant effusions. In total, 195 doses (median 6 [IQR = 3-6]/patient) of tPA (2.5 mg-10 mg) and DNase (5 mg) were instilled. Most (94%) doses were delivered via IPCs using local protocols for non-IPC pleural infections. The mean volume of pleural fluid drained during the first 72 h of treatment was 3,073 (SD = 1,685) mL. Most (82%) patients were successfully treated and survived to hospital discharge without surgery; 7 required additional chest tubes or therapeutic aspiration. Three patients required thoracoscopic surgery. Pleurodesis developed post-infection in 23/32 of successfully treated patients. No major morbidity/mortality was associated with tPA/DNase. Four patients received blood transfusions; none had systemic or significant pleural bleeding. CONCLUSION: Treatment of IPC-related pleural infection with intrapleural tPA/DNase instillations via the IPC appears feasible and safe, usually without additional drainage procedures or surgery. Pleurodesis post-infection is common.

Interventions for bronchiectasis: an overview of Cochrane systematic reviews.

BACKGROUND: Bronchiectasis is a chronic respiratory disease characterised by abnormal dilatation of the bronchi, and presents typically with a chronic productive cough (or chronic wet cough in children) and recurrent infective exacerbations. It significantly impacts daily activities and quality of life, and can lead to recurrent hospitalisations, severe lung function impairment, respiratory failure and even death. OBJECTIVES: To provide an overview of the efficacy and safety of interventions for adults and children with bronchiectasis from Cochrane reviews.To identify gaps in the evidence base that will inform recommendations for new research and reviews, and to summarise information on reported outcomes and make recommendations for the reporting of standard outcomes in future trials and reviews. METHODS: We included Cochrane reviews of non-cystic fibrosis (CF) bronchiectasis. We searched the Cochrane Database of Systematic Reviews. The search is current to 11 February 2015. We also identified trials that were potentially eligible for, but not currently included in, published reviews to make recommendations for new Cochrane reviews. We assessed the quality of included reviews using the AMSTAR criteria. We presented an evidence synthesis of data from reviews alongside an evidence map of clinical trials and guideline data. The primary outcomes were exacerbations, lung function and quality of life. MAIN RESULTS: We included 21 reviews but extracted data from, and rated the quality of, only nine reviews that reported results for people with bronchiectasis alone. Of the reviews with no usable data, two reviews included studies with mixed clinical populations where data were not reported separately for people with bronchiectasis and 10 reviews did not contain any trials. Of the 40 studies included across the nine reviews, three (number of participants nine to 34) included children. The studies ranged from single session to year-long studies. Each review included from one to 11 trials and 28 (70%) trials in the overview included 40 or fewer participants. The total number of participants included in reviews ranged from 40 to 1040. The age range of adult participants was from 36 to 73 years and children ranged from six to 16 years. The proportion of male participants ranged from 21% to 72%. Where reported, mean baseline forced expiratory volume in one second (FEV1) ranged from 1.17 L to 1.66 L and from 47% to 88% predicted. Most of the reviews had search dates older than two years.We have summarised the published evidence as outlined in Cochrane reviews, but it was not possible to draw definitive conclusions. There was inconclusive evidence on the use of long-term antibiotics and nebulised hypertonic saline for reducing exacerbation frequency and evidence that human deoxyribonuclease (RhDNase) increases exacerbation frequency. Improvements in lung function were reported for inhaled corticosteroids (ICS) though this was small and not clinically relevant. Evidence of benefit for hyperosmolar agents and mucolytics was inconclusive. There was limited evidence of improvements in quality of life with airway clearance techniques and physical therapy but evidence of benefit for hyperosmolar agents was inconclusive. Secondary outcomes were not clearly reported in all trials in the included reviews. Improvements in dyspnoea, wheeze and cough-free days were reported for small trials of ICS and LABA (long-acting beta2-agonsts)/ICS and cough reduction was also reported for a small bromhexine trial. Reduction in sputum production was reported for long-term antibiotics and airway clearance techniques but evidence of benefit for hyperosmolar agents was inconclusive.Adverse events were included as outcomes in seven reviews. The review of long-term (four weeks to one year) prophylactic courses of antibiotics reported significantly more cases of wheeze (Peto odd ratio (OR) 8.56, 95% confidence intervals (CI) 1.63 to 44.93), dyspnoea (12 versus three, P value = 0.01) and chest pain (seven versus zero, P value = 0.01) from the same trial (74 participants) but no differences in occurrence of diarrhoea, rash or number of withdrawals. In the review of mucolytics versus placebo, relevant outcomes were not reported for erdosteine comparisons and no significant adverse effects were reported for bromhexine, though adverse events were associated with RhDNase (OR 28.19, 95% CI 3.77 to 210.85, 1 study). Of the remaining five reviews, adverse events were not reported in the single trials included in the ICS review or the physical therapy review and the impact of adverse events in the single trial included in the inhaled LABA/ICS combination versus ICS review were unclear. The reviews of short-term courses of antibiotics and inhaled hyperosmolar agents reported no significant differences in occurrence of adverse events. Fewer admissions to hospital were reported for long-term antibiotics, but this outcome was not reported in all reviews. No reviews reported differences in mortality, but again this outcome was not included in all reviews.We did not explicitly include antibiotic resistance as an outcome in the review, but this was unclear in the Cochrane reviews and evidence from other trials should be considered.We rated all reviews as high quality (AMSTAR), though opportunities for improved reporting (e.g. summary of findings and GRADE evaluation of the evidence) were identified for inclusion in future updates of the reviews. However, the majority of trials were not high quality and confidence in the effects of treatments, therefore, requires additional evidence from larger and more methodologically robust trials. We evaluated the overall coverage of important topics in bronchiectasis by mapping the quality of the current evidence base against published guidelines and identifying high priority areas for new research on; use of short-course and long-term antibiotics, ICS and oral corticosteroids, inhaled hyperosmolars, mucolytics, and use of airway clearance techniques. AUTHORS' CONCLUSIONS: This overview clearly points to significant opportunities for further research aimed at improving outcomes for people with bronchiectasis. We have highlighted important endpoints for studies (particularly exacerbations, quality of life and lung function), and areas of clinical practice that are in most urgent need of evidence-based support (including long-term antibiotics, ICSs and mucolytics).As the evidence is confined to small trials of short duration, it is not currently possible to assess the balance between the benefits and potential harms of treatments for bronchiectasis.

Intrapleural use of tissue plasminogen activator and DNase in pleural infection.

BACKGROUND: More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial. METHODS: We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. RESULTS: The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P=0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P=0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P=0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P=0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. CONCLUSIONS: Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.).

Recombinant human deoxyribonuclease improves atelectasis in mechanically ventilated children with cardiac disease.

OBJECTIVE: To investigate whether a mucolytic agent, recombinant human deoxyribonuclease (rhDNase), improves atelectasis in children with cardiac illness requiring mechanical ventilation. DESIGN: A retrospective cohort study on consecutive patients receiving short-term (< or =14 days) rhDNase therapy for atelectasis in the cardiac intensive care unit from January 2005 through February 2007 was carried out. Data relating to patient characteristics, gas exchange, ventilatory parameters, and chest radiographs were collected and analyzed. The effectiveness of rhDNase therapy in the presence of neutrophils and/or bacteria in the pre-rhDNase therapy tracheal aspirates was also investigated. RESULTS: rhDNase was effective in significantly improving established atelectasis without any major changes in gas exchange and ventilatory parameters. Therapeutic effect of rhDNase is most effective in ameliorating atelectasis in the lungs within 10 doses. rhDNase was more effective in improving chest radiographic atelectasis score in patients who had > moderate amounts of polymophonuclear neutrophils (P value = 0.0008), or bacteria (P value = 0.007) or both (P value = 0.004) present in their pre-rhDNase therapy trachea aspirate. No adverse effects were seen with rhDNase administration in the study cohort. CONCLUSIONS: rhDNase can be safely and effectively used to improve atelectasis in mechanically ventilated children with cardiac disease especially in the presence of bacteria and/or moderate amounts of polymophonuclear neutrophils in the pre-rhDNase therapy tracheal aspirate.

[Drug-induced interstitial pneumonia associated with inhalation of fibrinolysin-deoxyribonuclease (ElaseR)].

A 73-year-old man was referred to our department because of sputum production and fever. He had under-gone a total laryngectomy for laryngeal cancer. His chest radiograph showed patchy ground-glass shadows in both lung fields. He was treated with antibiotics for pneumonia, but his symptoms continued, and the size of the patchy shadows in the chest radiograph increased. Inhalation therapy with ElaseR had been started from one day before fever arose. Withdrawal of ElaseR treatment resolved his symptoms. We therefore suspected drug-induced interstitial pneumonia. Transbronchial lung biopsy specimens showed infiltration of lymphocytes in the alveolar septa and thickening of those septa. A bronchoalveolar lavage revealed an increased number of lymphocytes, and the CD4/CD8 ratio was 0.3. A drug lymphocyte stimulation test (DLST) with peripheral blood lymphocytes was strongly positive (S.I. 2127%) for ElaseR. The anti-nuclear antigen (ANA) was detected (x640), and the anti-single strand DNA antibody titer was also high (123.4 IU/ml). About 10 weeks after the withdrawal of ElaseR, the infiltrative shadows and the abnormal laboratory findings improved spontaneously. On the basis of these findings, we arrived at a diagnosis of drug-induced interstitial pneumonia associated with inhalation of ElaseR.

Foreign body sarcoma: effects of foreign DNA, beta-carotene and paprika applied to the implant surface.

Sarcoma arises extremely rarely on foreign bodies in man, but is aggressive and often lethal. A coating for implants which would further reduce the risk in man is desirable. The incidence in mice is much greater, and responds to chemical treatment of the implant surface. Coating with histones increases tumour yield. Accordingly, related substances, foreign DNA, DNase and a mixture of the two, were tested for anticancer activity by application to 25 mm nitrocellulose filters in groups of 30-45 BALB/c mice, in comparison with untreated filters. Other substances reported to influence neoplasia, paprika, beta-carotene, rhodamine and tuftsin; and substances expected to be neutral, oxyprenolol, liquid paraffin, iodine, and adenosine diphosphate were similarly tested against concurrent untreated controls for comparison. Bovine DNA (p = 0.01) and DNA/DNase mixture (p = 0.04) and DNase fomented tumour growth by 55, 45 and 59% respectively. Paprika and beta-carotene did so by 70% (p = 0.05). The other substances were inert. None were candidates for an anti-sarcoma coating.

The safety and efficacy of a proteolytic ointment in the treatment of chronic ulcers of the lower extremity.

BACKGROUND: Elase is a widely used ointment consisting of a combination of 2 proteolytic enzymes, fibrinolysin and desoxyribonuclease (DNAse). It is said to promote debridement of necrotic and purulent debris from skin ulcers. OBJECTIVE: Our purpose was to assess the efficacy and safety of this ointment and its components in the treatment of chronic ulcers of the lower extremity. METHODS: This was a double-blind, randomized, prospective study of 84 patients with leg ulcers exhibiting necrotic and purulent debris, who were treated for 21 days with twice-daily applications of the ointment, fibrinolysin, DNAse, or who received the ointment vehicle (placebo). We assessed 6 efficacy features: ulcer size, purulent exudate, necrotic tissue, erythema, pain, and overall condition of the lesion at days 8, 15, and 21 after initiation of treatment. We also assessed the frequency of adverse effects. RESULTS: All treatments produced some improvement in the efficacy parameters and overall condition of the ulcers by week 3, but no statistically significant difference was found when compared with placebo. No serious adverse effects were noted. A later retrospective reanalysis of the data found a statistically significant reduction of purulent exudate only at days 3 and 7 of treatment in the group treated with the complete ointment, but not in the other features. CONCLUSION: The proteolytic ointment provides no long-term clinical benefit in reducing purulent exudate, pain, erythema, necrotic tissue, or overall condition of chronic leg ulcers when compared with either of its two components or placebo.

Aerosol delivery and safety of recombinant human deoxyribonuclease in young children with cystic fibrosis: a bronchoscopic study. Pulmozyme Pediatric Broncoscopy Study Group.

The purpose of this study was to assess the delivery to the lungs and the short-term safety of recombinant human deoxyribonuclease (rhDNase, Pulmozyme) in children with cystic fibrosis younger than 5 years of age compared with older children. Patients between the ages of 3 months and 10 years had bronchoscopic examination with bronchoalveolar lavage (BAL) after administration of an aerosol dose of 2.5 mg of rhDNase. After recovery from the procedure, patients were discharged home for an additional 13 days of rhDNase therapy. During this time adverse events were recorded to assess short-term safety. A total of 98 patients were enrolled, 65 (66%) aged 3 months to 5 years and 33 (34%) aged 5 years to 10 years. Deoxyribonuclease concentrations in BAL fluid were variable (interquartile range, 752 to 3943 micrograms/mL epithelial lining fluid [ELF]) and did not depend on patient age, weight, or height or differ when delivered through a mouthpiece or mask. The median value for the BAL DNA concentration in the younger group was 432 micrograms/mL ELF compared with 703 micrograms/mL ELF in the older patients. This study demonstrates the value of bronchoscopy and BAL for assessing nebulized medication delivery in young children and shows that aerosolized medications can be delivered to and are present in comparable amounts in the lower airways of younger and older children. Exposure to rhDNase appears to be safe over 2 weeks in infants and young children with cystic fibrosis.

[Pneumonitis in a patient who inhaled a fibrinolysin-deoxyribonuclease mixture].

A 56-year-old man was transferred to our department from the department of oral surgery, with a high fever and a cough. He had inhaled a fibrinolysin-deoxyribonuclease mixture (Elase) to treat inflammation in the oral cavity after resection of an oral tumor. A chest X-ray film showed diffuse patchy shadows in both lung fields. Bronchoalveolar lavage fluid had an abnormally high number of lymphocytes and transbronchial lung biopsy revealed interstitial infiltration by lymphocytes and histiocytes, with granulomatous lesions. The patient was treated with steroids, and his clinical condition improved markedly. He accidentally inhaled the drug again, and the coughing and fever began again. The drug lymphocyte stimulation test was positive only for the fibrinolysin-deoxyribonuclease mixture. Based on these findings, we diagnosed pneumonitis induced by this fibrinolysin-deoxyribonuclease mixture. To our knowledge, this is the first reported case of pneumonitis caused by this fibrinolysin-doxyribonuclease mixture.

DNase trials in cystic fibrosis.

Cystic fibrosis (CF) is a disease with a high morbidity and mortality from pulmonary disease. Sputum from CF patients contains high levels of deoxyribonucleic acid (DNA), which contribute to its viscoelasticity. Recombinant deoxyribonuclease (rhDNase) has been developed and in vitro studies have showed reduction in the viscoelasticity of CF sputum. This article reviews the in vivo clinical trials conducted to determine the safety and efficacy of this treatment. Phase 1 studies showed preliminary safety data and some evidence of clinical benefit. The two Phase 2 short-term studies showed improvement in pulmonary function and important safety data. The Phase 3 study, which included 968 patients, showed improvement in forced expiratory volume in one second (FEV1) of 5.8% and 5.6% in patients treated once and twice daily, respectively. The risk of developing an exacerbation of infection was reduced by 28% with once daily and 37% with twice daily treatment, compared to placebo. The drug was safe and there was some improvement in quality of life data. Longer-term open labelled studies, the results of intermittent administration, administration to severely ill patients, and the use of different delivery systems are reviewed. In conclusion, recombinant deoxyribonuclease is a new treatment which has been shown to benefit patients with cystic fibrosis when used in conjunction with conventional treatment.

Interaction of membrane-bound Fc gamma receptors with the cytoskeletal matrix.

Binding of ligands to cell surface receptors may induce an interaction of the receptors with the cell cytoskeleton. This interaction may decrease the solubility of the receptors in nonionic detergents. We studied effect of binding of various 125I-labeled immunoglobulin ligands to Fc gamma receptors on guinea pig peritoneal macrophages and human placental syncytiotrophoblast plasma membranes on an interaction of these receptors with the cytoskeletal matrix. The receptor-cytoskeleton association was evaluated by measurement radioactivity of bound ligands in pellets and supernatants obtained after lysis of cells or membranes in a nonionic detergent NP-40. Binding of soluble immune complexes or crosslinking of IgG bound induces much stronger insolubilization of the receptors than binding of monomeric or aggregated IgG. It shows that the interaction of the receptors with the cytoskeletal matrix strongly depends on the degree of cross-linking of the Fc gamma receptors by ligands bound. The observed effects were IgG Fc region-specific. Isolated, purified putative Fc gamma receptors from guinea pig peritoneal macrophages and from human placental syncytiotrophoblast plasma membranes do not interact with free G or F actin. We also studied association of the guinea pig peritoneal macrophage Fc gamma receptor with the cytoskeleton, before and after shedding of macrophage membrane proteins. The results obtained showed that the macrophages have only one class of Fc gamma receptors interacting with the cytoskeletal matrix. Effect of a cytoskeleton-destabilizing buffer and DNAse I on release of the receptors from the cytoskeleton suggests that insolubilization of ligand-Fc gamma R complexes was caused, at least partially, by an interaction of the receptors with actin filaments in the cytoskeleton. The results presented in this paper suggest that the cytoskeleton might play a role in transmission of signals from Fc gamma receptors to the cells. They underline the role of immune complexes as physiological ligands for Fc receptors and correlate well with activation of cells via their Fc receptors (e.g. superoxide burst) observed by other authors after treatment of the cells with immune complexes, but not with monomeric or aggregated IgG.