-
American Journal of Physical Medicine &... May 2021The aim of the present meta-analysis was to explore the association between FokI polymorphism of the vitamin D receptor gene and lumbar spine disc degeneration. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of the present meta-analysis was to explore the association between FokI polymorphism of the vitamin D receptor gene and lumbar spine disc degeneration.
DESIGN
The search was performed in PubMed, Scopus, and Web of Science databases up to January 2020. The authors selected nine studies comprising a total of 1549 cases and 1672 controls. The association analysis included the allelic, dominant, recessive, homozygous, and heterozygous genetic models. Odds ratios with 95% confidence intervals were used to evaluate the association. The Newcastle-Ottawa Scale was used to measure the quality of the studies included in the analyses; a cut-off of 6 stars was applied.
RESULTS
This meta-analysis indicated that FokI polymorphism is significantly associated with lumbar degenerative disc disorder and disc herniation in the homozygous (odds ratio, 1.77; 95% confidence interval, 1.23-2.54; Z test P = 0.002, Q test P = 0.416) and recessive (odds ratio, 1.53; 95% confidence interval, 1.23-1.90; Z test P < 0.000, Q test P = 0.224) models.
CONCLUSIONS
This study indicates that the vitamin D receptor gene FokI polymorphism may be correlated with the risk of developing a lumbar degenerative disc disorder and disc herniation. However, the small sample population studied and the lack of an evaluation of environmental factors must be taken as limitations in the present meta-analysis.
Topics: Deoxyribonucleases, Type II Site-Specific; Genetic Predisposition to Disease; Humans; Intervertebral Disc Degeneration; Lumbar Vertebrae; Polymorphism, Genetic; Receptors, Calcitriol
PubMed: 32932361
DOI: 10.1097/PHM.0000000000001588 -
Journal of Gastroenterology and... Feb 2021Although surveillance colonoscopy is recommended by several guidelines for Crohn's disease (CD), the evidence is insufficient to support the validity of this... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
Although surveillance colonoscopy is recommended by several guidelines for Crohn's disease (CD), the evidence is insufficient to support the validity of this recommendation. Moreover, the efficacy of surveillance colonoscopy for anorectal cancer remains unclear. Therefore, we performed a systematic review of cancer in patients with CD before considering the proper surveillance methods.
METHODS
We conducted a systematic review and meta-analysis examining the incidence of intestinal cancer and a literature review to clarify the characteristic features of cancer in CD. We performed the systematic literature review of studies published up to May 2019.
RESULTS
Overall, 7344 patients were included in eight studies. The standardized incidence ratios (95% confidence intervals) of colorectal cancer (CRC) and small bowel cancer (SBC) were 2.08 (1.43-3.02) and 22.01 (9.10-53.25), respectively. The prevalence of CRC and SBC was 57/7344 (0.77%) and 17/7344 (0.23%), respectively, during a median follow-up of 12.55 years. Additionally, 54 studies reporting 208 anorectal cancer cases were identified. In patients with anorectal cancer, the prognosis for survival was 2.1 ± 2.3 years, and advanced cancer greater than stage T3 occurred in 46/74 patients (62.1%). Many more reports of anorectal cancer were published in Asia than in Western countries.
CONCLUSION
Although we were unable to state a recommendation for surveillance for SBC, we should perform cancer surveillance for CRC in patients with CD. However, the characteristics of cancer may differ according to geography or race. We must establish proper and effective surveillance methods that are independently suitable to detect these differences.
Topics: Anus Neoplasms; Chronic Disease Indicators; Colonoscopy; Colorectal Neoplasms; Crohn Disease; Escherichia coli Proteins; Exodeoxyribonucleases; Follow-Up Studies; Humans; Intestine, Small; Neoplasm Staging; Rectal Neoplasms; Survival Rate; Time Factors
PubMed: 32865278
DOI: 10.1111/jgh.15229 -
Photodermatology, Photoimmunology &... Nov 2020DNA damage is one of the main factors responsible for photoageing and is predominantly attributed to ultraviolet irradiation (UV-R). Photoprotection by conventional...
BACKGROUND
DNA damage is one of the main factors responsible for photoageing and is predominantly attributed to ultraviolet irradiation (UV-R). Photoprotection by conventional sunscreens is exclusively prophylactic, and of no value, once DNA damage has occurred. As a result, the demand for DNA repair mechanisms inhibiting, reversing or delaying the pathologic events in UV-exposed skin has sparked research on anti-photoageing and strategies to improve the effect of conventional sunscreens. This review provides an overview of recent developments in DNA repair enzymes used in sunscreens and their impact on photoageing.
METHODS
A systematic review of the literature, up to March 2019, was conducted using the electronic databases, PubMed and Web of Science. Quality assessment was carried out using the Newcastle-Ottawa scale (NOS) to ensure inclusion of adequate quality studies only (NOS > 5).
RESULTS
Out of the 352 publications, 52 were considered relevant to the key question and included in the present review. Two major enzymes were found to play a major role in DNA damage repair in sunscreens: photolyase and T4 endonuclease V. These enzymes are capable of identifying and removing UV-R-induced dimeric photoproducts. Clinical studies revealed that sunscreens with liposome-encapsulated types of photolyase and/or T4 endonuclease V can enhance these repair mechanisms.
CONCLUSION
There is a lack of randomized controlled trials demonstrating the efficacy of DNA repair enzymes on photoageing, or a superiority of sunscreens with DNA repair enzymes compared to conventional sunscreens. Further studies are mandatory to further reveal pathogenic factors of photoageing and possible therapeutic strategies against it.
Topics: Animals; DNA Damage; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Deoxyribonuclease (Pyrimidine Dimer); Humans; Skin Aging; Sunscreening Agents; Ultraviolet Rays; Viral Proteins
PubMed: 32772409
DOI: 10.1111/phpp.12597 -
The Cochrane Database of Systematic... May 2020Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review.
OBJECTIVES
To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences. Date of last search: 12 December 2019.
SELECTION CRITERIA
All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment.
DATA COLLECTION AND ANALYSIS
Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE.
MAIN RESULTS
Six studies (reported in 36 unique publications) were included with a total of 784 participants. Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population. Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole. While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies. Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality. For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF. For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations. In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa).
AUTHORS' CONCLUSIONS
There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa. The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.
Topics: Administration, Inhalation; Adult; Child; Cystic Fibrosis; Deoxyribonuclease I; Forced Expiratory Volume; Humans; Mannitol; Mucociliary Clearance; Powders; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Function Tests; Vital Capacity
PubMed: 32358807
DOI: 10.1002/14651858.CD008649.pub4 -
Journal of Microbiology, Immunology,... Dec 2020Polymorphisms of vitamin D receptors (VDRs), ApaI, BsmI, FokI, and TaqI might affect susceptibility to tuberculosis (TB). In this systematic review and meta-analysis,... (Meta-Analysis)
Meta-Analysis
Vitamin D receptor ApaI (rs7975232), BsmI (rs1544410), Fok1 (rs2228570), and TaqI (rs731236) gene polymorphisms and susceptibility to pulmonary tuberculosis in an Iranian population: A systematic review and meta-analysis.
Polymorphisms of vitamin D receptors (VDRs), ApaI, BsmI, FokI, and TaqI might affect susceptibility to tuberculosis (TB). In this systematic review and meta-analysis, all published articles which investigated the effects of these polymorphisms on the risk of TB in the Iranian population were retrieved. PubMed and Scopus were searched with no date or language restrictions. In this meta-analysis, the Comprehensive Meta-Analysis (CMA) version 2.0 and random effects model were applied. The association of polymorphisms with TB risk was assessed by measuring the odds ratio (ORs) at 95% CI. Heterogeneity was investigated based on Cochran Q-test and I2-index statistics. The significance level was set at 0.05. Also, Egger's regression intercept was determined to measure publication bias. A total of six articles on Iranian populations were included. TaqI (5/6 included studies) showed a significant association with the increased risk of TB based on ORs (allele comparison: 1.57 (1.0, 2.3), p-value: 0.02; additive model of tt/TT: 1.57 (0.9, 2.5), p-value: 0.05; recessive model (tt/Tt + TT): 1.99 (1.2, 3.2), p-value: 0.00; dominant model (tt + Tt/TT): 1.98 (1.1, 3.5), p-value: 0.01). BsmI showed a significant positive effect on TB risk only in its dominant genotype (bb + bB/BB) (1.44 (1.0, 1.9); p-value: 0.02). FokI and ApaI did not show any significant effects on TB development in Iranian populations. Findings showed the significant effect of TaqI polymorphism in all genetic models and the dominant model of BsmI on the increased risk of TB. However, the effects of TaqI and BsmI should be further investigated in a larger sample size.
Topics: Aged; Aged, 80 and over; Deoxyribonucleases, Type II Site-Specific; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Iran; Male; Middle Aged; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Receptors, Calcitriol; Tuberculosis, Pulmonary; Vitamin D Deficiency
PubMed: 31740220
DOI: 10.1016/j.jmii.2019.08.011 -
The Cochrane Database of Systematic... Nov 2018Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review.
OBJECTIVES
To determine whether the timing of dornase alfa inhalation (in relation to airway clearance techniques or morning versus evening inhalation) has an impact on objective and subjective measures of clinical efficacy in people with cystic fibrosis.
SEARCH METHODS
Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), clinical trial registries and international cystic fibrosis conference proceedings.Date of the most recent search: 06 June 2018.
SELECTION CRITERIA
Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the trial with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation.
DATA COLLECTION AND ANALYSIS
Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed.
MAIN RESULTS
We identified 115 trial reports representing 55 trials, of which five trials (providing data on 122 participants) met our inclusion criteria. All five trials used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials (98 participants) compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second (very-low quality evidence). Similarly, forced vital capacity (low-quality evidence) and quality of life (very-low quality evidence) were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small trials in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial (25 participants), morning versus evening inhalation had no impact on lung function or symptoms (low-quality evidence).
AUTHORS' CONCLUSIONS
The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and trials with variable follow-up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alfa inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.
Topics: Administration, Inhalation; Adolescent; Child; Combined Modality Therapy; Cystic Fibrosis; Deoxyribonuclease I; Drug Administration Schedule; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Therapy; Time Factors; Young Adult
PubMed: 30480755
DOI: 10.1002/14651858.CD007923.pub5 -
Heart & Lung : the Journal of Critical... 2019Inhaled mucoactive agents are used to enhance airway clearance, however efficacy and safety are unclear in adults with acute respiratory conditions.
BACKGROUND AND OBJECTIVES
Inhaled mucoactive agents are used to enhance airway clearance, however efficacy and safety are unclear in adults with acute respiratory conditions.
METHODS
We systematically reviewed randomized controlled trials assessing respiratory function; safety; length of stay (LOS); mucus; radiology; and oxygenation.
RESULTS
No adverse events were reported for dornase alfa (n = 63), N-acetylcysteine (NAC, n = 50), ambroxol (n = 140), hypertonic saline (n = 33), heparin (n = 384), mannitol (n = 20) or isotonic saline. During invasive ventilation, NAC, dornase alfa and saline had no effect on mucus. Postoperatively, mucus characteristics improved with NAC (n = 10). Ambroxol lowered LOS (mean difference 4 days) and halved complications following lung carcinoma resection (n = 140). Heparin improved ventilator-free days (n = 130, mean difference 3.9-4.6) and intensive care LOS (n = 223, 3.2 days), but not ventilator-acquired pneumonia.
CONCLUSION
Dornase alfa, hypertonic saline and NAC were ineffective for atelectasis/mucus plugging while intubated. More data are required to support using NAC, ambroxol and heparin during acute illness.
Topics: Acute Disease; Administration, Inhalation; Adult; Ambroxol; Deoxyribonuclease I; Expectorants; Humans; Lung Diseases; Mannitol; Mucociliary Clearance; Recombinant Proteins
PubMed: 30409442
DOI: 10.1016/j.hrtlng.2018.09.010 -
The Cochrane Database of Systematic... Sep 2018Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.
OBJECTIVES
To investigate efficacy and tolerability of treatment with nebulised hypertonic saline on people with CF compared to placebo and or other treatments that enhance mucociliary clearance.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases.Date of most recent searches: 08 August 2018.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed all identified trials and data, and assessed trial quality. The quality of the evidence was assessed using GRADE.
MAIN RESULTS
A total of 17 trials (966 participants, aged 4 months to 63 years) were included; 19 trials were excluded, three trials are ongoing and 16 are awaiting classification. We judged 14 of the 17 included trials to have a high risk of bias due to participants ability to discern the taste of the solutions.Hypertonic saline 3% to 7% versus placeboAt four weeks, we found very low-quality evidence from three placebo-controlled trials (n = 225) that hypertonic saline (3% to 7%, 10 mL twice-daily) increased the mean change from baseline of the forced expiratory volume at one second (FEV) (% predicted) by 3.44% (95% confidence interval (CI) 0.67 to 6.21), but there was no difference between groups in lung clearance index in one small trial (n = 10). By 48 weeks the effect was slightly smaller in one trial (n = 134), 2.31% (95% CI -2.72 to 7.34) (low-quality evidence). No deaths occurred in the trials. Two trials reporting data on exacerbations were not combined as the age difference between the participants in the trials was too great. One trial (162 adults) found 0.5 fewer exacerbations requiring antibiotics per person in the hypertonic saline group; the second trial (243 children, average age of two years) found no difference between groups (low-quality evidence). There was insufficient evidence reported across the trials to determine the rate of different adverse events such as cough, chest tightness, tonsillitis and vomiting (very low-quality evidence). Four trials (n = 80) found very low-quality evidence that sputum clearance was better with hypertonic saline.A further trial was performed in adults with an acute exacerbation of lung disease (n = 132). The effects of hypertonic saline on short-term lung function, 5.10% higher (14.67% lower to 24.87% higher) and the time to the subsequent exacerbation post-discharge, hazard ratio 0.86 (95% CI 0.57 to 1.30) are uncertain (low-quality evidence). No deaths were reported. Cough and wheeze were reported but no serious adverse events (very low-quality evidence).Hypertonic saline versus mucus mobilising treatments Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two (61 participants) provided data for inclusion in the review. There was insufficient evidence from one three-week trial (14 participants) to determine the effects of hypertonic saline on FEV % predicted, mean difference (MD) 1.60% (95% CI -7.96 to 11.16) (very low-quality evidence). In the second trial, rhDNase led to a greater increase in FEV % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease, MD 8.00% (95% CI 2.00 to 14.00) (low-quality evidence). One cross-over trial (47 participants) reported 15 exacerbations during treatment with hypertonic saline and 18 exacerbations in the rhDNase group (low-quality evidence). Increased cough was reported in 13 participants using hypertonic saline and 17 on daily rhDNase in one cross-over trial of 47 people (low-quality evidence). There was insufficient evidence to assess rates of other adverse events reported. No deaths were reported.One trial (12 participants) compared hypertonic saline to amiloride and one (29 participants) to sodium-2-mercaptoethane sulphonate. Neither trial found a difference between treatments in any measures of sputum clearance; additionally the comparison of hypertonic saline and sodium-2-mercaptoethane sulphonate reported no differences in courses of antibiotics or adverse events (very low-quality evidence).One trial (12 participants) compared hypertonic saline to mannitol but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-quality evidence).
AUTHORS' CONCLUSIONS
Regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (very low-quality evidence from three trials), but this was not sustained at 48 weeks (low-quality evidence from one trial). The review did show that nebulised hypertonic saline reduced the frequency of pulmonary exacerbations (although we found insufficient evidence for this outcome in children under six years of age) and may have a small effect on improvement in quality of life in adults.Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function at three months; qualifying this we highlight that while the study did demonstrate that the improvement in FEV was greater with daily rHDNase, there were no differences seen in any of the secondary outcomes.Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the quality of the evidence ranged from very low to at best moderate, according to the GRADE criteria.
Topics: Administration, Inhalation; Controlled Clinical Trials as Topic; Cystic Fibrosis; Forced Expiratory Volume; Humans; Mucociliary Clearance; Nebulizers and Vaporizers; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic
PubMed: 30260472
DOI: 10.1002/14651858.CD001506.pub4 -
The Cochrane Database of Systematic... Sep 2018Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review.
OBJECTIVES
To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 23 April 2018.Clinicaltrials.gov and the International Clinical Trials Registry Platform were also searched to identify unpublished or ongoing trials. Date of most recent search: 07 June 2018.
SELECTION CRITERIA
All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance.
DATA COLLECTION AND ANALYSIS
Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. GRADE was used to assess the level of evidence.
MAIN RESULTS
The searches identified 69 trials, of which 19 (2565 participants) met our inclusion criteria. Fifteen trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years.Dornase alfa compared to placebo or no treatmentDornase alfa improved forced expiratory volume at one second at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed no difference between groups for changes in quality of life. There was a decrease in pulmonary exacerbations with dornase alfa in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs.Dornase alfa: daily versus alternate dayOne cross-over trial (43 children) found no differences between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence).Dornase alfa compared to other medications that improve airway clearanceResults for these comparisons were mixed. One trial (43 children) showed a greater improvement in forced expiratory volume at one second for dornase alfa compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported no difference in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found a difference in quality of life favouring dornase alfa when compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence).When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash.
AUTHORS' CONCLUSIONS
There is evidence to show that, compared with placebo, therapy with dornase alfa improves lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.
Topics: Adolescent; Child; Child, Preschool; Cystic Fibrosis; Deoxyribonuclease I; Expectorants; Forced Expiratory Volume; Humans; Infant; Mannitol; Randomized Controlled Trials as Topic; Recombinant Proteins; Saline Solution, Hypertonic; Vital Capacity
PubMed: 30187450
DOI: 10.1002/14651858.CD001127.pub4 -
The Cochrane Database of Systematic... Feb 2018Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review.
OBJECTIVES
To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences.Date of last search: 28 September 2017.
SELECTION CRITERIA
All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment.
DATA COLLECTION AND ANALYSIS
Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE.
MAIN RESULTS
Six studies (reported in 50 publications) were included with a total of 784 participants.Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population.Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole.While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies.Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality.For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF.For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations.In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa).
AUTHORS' CONCLUSIONS
There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa.The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.
Topics: Administration, Inhalation; Adult; Child; Cystic Fibrosis; Deoxyribonuclease I; Humans; Mannitol; Mucociliary Clearance; Powders; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Function Tests
PubMed: 29424930
DOI: 10.1002/14651858.CD008649.pub3