Anti‐IL5 therapies for asthma Farne, Hugo A; Wilson, Amanda; Powell, Colin ...
Cochrane database of systematic reviews,
09/2017, Volume:
2017, Issue:
9
Journal Article
Peer reviewed
Open access
Background
This review is the first update of a previously published review in The Cochrane Library (Issue 7, 2015). Interleukin‐5 (IL‐5) is the main cytokine involved in the activation of ...eosinophils, which cause airway inflammation and are a classic feature of asthma. Monoclonal antibodies targeting IL‐5 or its receptor (IL‐5R) have been developed, with recent studies suggesting that they reduce asthma exacerbations, improve health‐related quality of life (HRQoL) and lung function. These are being incorporated into asthma guidelines.
Objectives
To compare the effects of therapies targeting IL‐5 signalling (anti‐IL‐5 or anti‐IL‐5Rα) with placebo on exacerbations, health‐related qualify of life (HRQoL) measures, and lung function in adults and children with chronic asthma, and specifically in those with eosinophilic asthma refractory to existing treatments.
Search methods
We searched the Cochrane Airways Trials Register, clinical trials registries, manufacturers' websites, and reference lists of included studies. The most recent search was March 2017.
Selection criteria
We included randomised controlled trials comparing mepolizumab, reslizumab and benralizumab versus placebo in adults and children with asthma.
Data collection and analysis
Two authors independently extracted data and analysed outcomes using a random‐effects model. We used standard methods expected by Cochrane.
Main results
Thirteen studies on 6000 participants met the inclusion criteria. Four used mepolizumab, four used reslizumab, and five used benralizumab. One study in benralizumab was terminated early due to sponsor decision and contributed no data. The studies were predominantly on people with severe eosinophilic asthma, which was similarly but variably defined. Eight included children over 12 years but these results were not reported separately. We deemed the risk of bias to be low, with all studies contributing data being of robust methodology. We considered the quality of the evidence for all comparisons to be high overall using the GRADE scheme, with the exception of intravenous mepolizumab because this is not currently a licensed delivery route.
All of the anti‐IL‐5 treatments assessed reduced rates of 'clinically significant' asthma exacerbation (defined by treatment with systemic corticosteroids for three days or more) by approximately half in participants with severe eosinophilic asthma on standard of care (at least medium‐dose inhaled corticosteroids (ICS)) with poorly controlled disease (either two or more exacerbations in the preceding year or Asthma Control Questionnaire (ACQ) 1.5 or more). Non‐eosinophilic participants treated with benralizumab also showed a significant reduction in exacerbation rates, but no data were available for non‐eosinophilic participants, and mepolizumab or reslizumab.
We saw modest improvements in validated HRQoL scores with all anti‐IL‐5 agents in severe eosinophilic asthma. However these did not exceed the minimum clinically important difference for ACQ and Asthma Quality of Life Questionnaire (AQLQ), with St. George's Respiratory Questionnaire (SGRQ) only assessed in two studies. The improvement in HRQoL scores in non‐eosinophilic participants treated with benralizumab, the only intervention for which data were available in this subset, was not statistically significant, but the test for subgroup difference was negative.
All anti‐IL‐5 treatments produced a small but statistically significant improvement in mean pre‐bronchodilator forced expiratory flow in one second (FEV1) of between 0.08 L and 0.11 L.
There were no excess serious adverse events with any anti‐IL‐5 treatment, and indeed a reduction in favour of mepolizumab that could be due to a beneficial effect on asthma‐related serious adverse events. There was no difference compared to placebo in adverse events leading to discontinuation with mepolizumab or reslizumab, but significantly more discontinued benralizumab than placebo, although the absolute numbers were small (36/1599 benralizumab versus 9/998 placebo).
Mepolizumab, reslizumab and benralizumab all markedly reduced blood eosinophils, but benralizumab resulted in almost complete depletion, whereas a small number remained with mepolizumab and reslizumab. The implications for efficacy and/or adverse events are unclear.
Authors' conclusions
Overall our study supports the use of anti‐IL‐5 treatments as an adjunct to standard of care in people with severe eosinophilic asthma and poor control. These treatments roughly halve the rate of asthma exacerbations in this population. There is limited evidence for improved HRQoL scores and lung function, which may not meet clinically detectable levels. There were no safety concerns regarding mepolizumab or reslizumab, and no excess serious adverse events with benralizumab, although there remains a question over adverse events significant enough to prompt discontinuation.
Further research is needed on biomarkers for assessing treatment response, optimal duration and long‐term effects of treatment, risk of relapse on withdrawal, non‐eosinophilic patients, children (particularly under 12 years), and comparing anti‐IL‐5 treatments to each other and, in people eligible for both, to anti‐immunoglobulin E. For benralizumab, future studies should closely monitor rates of adverse events prompting discontinuation.
Omalizumab for asthma in adults and children Normansell, Rebecca; Walker, Samantha; Milan, Stephen J ...
Cochrane database of systematic reviews,
01/2014, Volume:
2014, Issue:
1
Journal Article
Peer reviewed
Open access
Background
Asthma is a respiratory (airway) condition that affects an estimated 300 million people worldwide and is associated with significant morbidity and mortality. Omalizumab is a monoclonal ...antibody that binds and inhibits free serum immunoglobulin E (IgE). It is called an 'anti‐IgE' drug. IgE is an immune mediator involved in clinical manifestations of asthma. A recent update of National Institute for Health and Care Excellence (NICE) guidance in 2013 recommends omalizumab for use as add‐on therapy in adults and children over six years of age with inadequately controlled severe persistent allergic IgE‐mediated asthma who require continuous or frequent treatment with oral corticosteroids.
Objectives
To assess the effects of omalizumab versus placebo or conventional therapy for asthma in adults and children.
Search methods
We searched the Cochrane Airways Group Specialised Register of trials for potentially relevant studies. The most recent search was performed in June 2013. We also checked the reference lists of included trials and searched online trial registries and drug company websites.
Selection criteria
Randomised controlled trials examining anti‐IgE administered in any manner for any duration. Trials with co‐interventions were included, as long as they were the same in each arm.
Data collection and analysis
Two review authors independently assessed study quality and extracted and entered data. Three modes of administration were identified from the published literature: inhaled, intravenous and subcutaneous injection. The main focus of the updated review is subcutaneous administration, as this route is currently used in clinical practice. Subgroup analysis was performed by asthma severity. Data were extracted from published and unpublished sources.
Main results
In all, 25 trials were included in the review, including 11 new studies since the last update, for a total of 19 that considered the efficacy of subcutaneous anti‐IgE treatment as an adjunct to treatment with corticosteroids.
For participants with moderate or severe asthma who were receiving background inhaled corticosteroid steroid (ICS) therapy, a significant advantage favoured subcutaneous omalizumab with regard to experiencing an asthma exacerbation (odds ratio (OR) 0.55, 95% confidence interval (CI) 0.42 to 0.60; ten studies, 3261 participants). This represents an absolute reduction from 26% for participants suffering an exacerbation on placebo to 16% on omalizumab, over 16 to 60 weeks. A significant benefit was noted for subcutaneous omalizumab versus placebo with regard to reducing hospitalisations (OR 0.16, 95% CI 0.06 to 0.42; four studies, 1824 participants), representing an absolute reduction in risk from 3% with placebo to 0.5% with omalizumab over 28 to 60 weeks. No separate data on hospitalisations were available for the severe asthma subgroup, and all of these data were reported for participants with the diagnosis of moderate to severe asthma. Participants treated with subcutaneous omalizumab were also significantly more likely to be able to withdraw their ICS completely than those treated with placebo (OR 2.50, 95% CI 2.00 to 3.13), and a small but statistically significant reduction in daily inhaled steroid dose was reported for omalizumab‐treated participants compared with those given placebo (weighted mean difference (WMD) ‐118 mcg beclomethasone dipropionate (BDP) equivalent per day, 95% CI ‐154 to ‐84). However, no significant difference between omalizumab and placebo treatment groups was seen in the number of participants who were able to withdraw from oral corticosteroid (OCS) therapy (OR 1.18, 95% CI 0.53 to 2.63).
Participants treated with subcutaneous omalizumab as an adjunct to treatment with corticosteroids required a small but significant reduction in rescue beta2‐agonist medication compared with placebo (mean difference (MD) ‐0.39 puffs per day, 95% CI ‐0.55 to ‐0.24; nine studies, 3524 participants). This benefit was observed in both the moderate to severe (MD ‐0.58, 95% CI ‐0.84 to ‐0.31) and severe (MD ‐0.30, 95% CI ‐0.49 to ‐0.10) asthma subgroups on a background therapy of inhaled corticosteroids; however, no significant difference between subcutaneous omalizumab and placebo was noted for this outcome in participants with severe asthma who were receiving a background therapy of inhaled plus oral corticosteroids. Significantly fewer serious adverse events were reported in participants assigned to subcutaneous omalizumab than in those receiving placebo (OR 0.72, 95% CI 0.57 to 0.91; 15 studies, 5713 participants), but more injection site reactions were observed (from 5.6% with placebo to 9.1% with omalizumab).
To reflect current clinical practice, discussion of the results is limited to subcutaneous use, and trials involving intravenous and inhaled routes have been archived.
Authors' conclusions
Omalizumab was effective in reducing asthma exacerbations and hospitalisations as an adjunctive therapy to inhaled steroids and during steroid tapering phases of clinical trials. Omalizumab was significantly more effective than placebo in increasing the numbers of participants who were able to reduce or withdraw their inhaled steroids. Omalizumab was generally well tolerated, although more injection site reactions were seen with omalizumab. Further assessment in paediatric populations is necessary, as is direct double‐dummy comparison with ICS. Although subgroup analyses suggest that participants receiving prednisolone had better asthma control when they received omalizumab, it remains to be tested prospectively whether the addition of omalizumab has a prednisolone‐sparing effect. It is also not clear whether there is a threshold level of baseline serum IgE for optimum efficacy of omalizumab. Given the high cost of the drug, identification of biomarkers predictive of response is of major importance for future research.
Background
Bacterial vaginosis is an imbalance of the normal vaginal flora with an overgrowth of anaerobic bacteria and a lack of the normal lactobacillary flora. Women may have symptoms of a ...characteristic vaginal discharge but are often asymptomatic. Bacterial vaginosis during pregnancy has been associated with poor perinatal outcomes and, in particular, preterm birth (PTB). Identification and treatment may reduce the risk of PTB and its consequences.
Objectives
To assess the effects of antibiotic treatment of bacterial vaginosis in pregnancy.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2012), searched cited references from retrieved articles and reviewed s, letters to the editor and editorials.
Selection criteria
Randomised trials comparing antibiotic treatment with placebo or no treatment, or comparing two or more antibiotic regimens in pregnant women with bacterial vaginosis or intermediate vaginal flora whether symptomatic or asymptomatic and detected through screening.
Data collection and analysis
Two review authors independently assessed trials for inclusion, trial quality and extracted data. We contacted study authors for additional information.
Main results
We included 21 trials of good quality, involving 7847 women diagnosed with bacterial vaginosis or intermediate vaginal flora.
Antibiotic therapy was shown to be effective at eradicating bacterial vaginosis during pregnancy (average risk ratio (RR) 0.42; 95% confidence interval (CI) 0.31 to 0.56; 10 trials, 4403 women; random‐effects, T² = 0.19, I² = 91%). Antibiotic treatment also reduced the risk of late miscarriage (RR 0.20; 95% CI 0.05 to 0.76; two trials, 1270 women, fixed‐effect, I² = 0%).
Treatment did not reduce the risk of PTB before 37 weeks (average RR 0.88; 95% CI 0.71 to 1.09; 13 trials, 6491 women; random‐effects, T² = 0.06, I² = 48%), or the risk of preterm prelabour rupture of membranes (RR 0.74; 95% CI 0.30 to 1.84; two trials, 493 women). It did increase the risk of side‐effects sufficient to stop or change treatment (RR 1.66; 95% CI 1.02 to 2.68; four trials, 2323 women, fixed‐effect, I² = 0%).
In this updated review, treatment before 20 weeks' gestation did not reduce the risk of PTB less than 37 weeks (average RR 0.85; 95% CI 0.62 to 1.17; five trials, 4088 women; random‐effects, T² = 0.06, I² = 49%).
In women with a previous PTB, treatment did not affect the risk of subsequent PTB (average RR 0.78; 95% CI 0.42 to 1.48; three trials, 421 women; random‐effects, T² = 0.19, I² = 72%).
In women with abnormal vaginal flora (intermediate flora or bacterial vaginosis), treatment may reduce the risk of PTB before 37 weeks (RR 0.53; 95% CI 0.34 to 0.84; two trials, 894 women).
One small trial of 156 women compared metronidazole and clindamycin, both oral and vaginal, with no significant differences seen for any of the pre‐specified primary outcomes. Statistically significant differences were seen for the outcomes of prolongation of gestational age (days) (mean difference (MD) 1.00; 95% CI 0.26 to 1.74) and birthweight (grams) (MD 75.18; 95% CI 25.37 to 124.99) however these represent relatively small differences in the clinical setting.
Oral antibiotics versus vaginal antibiotics did not reduce the risk of PTB (RR 1.09; 95% CI 0.78 to 1.52; two trials, 264 women). Oral antibiotics had some advantage over vaginal antibiotics (whether metronidazole or clindamycin) with respect to admission to neonatal unit (RR 0.63; 95% CI 0.42 to 0.92, one trial, 156 women), prolongation of gestational age (days) (MD 9.00; 95% CI 8.20 to 9.80; one trial, 156 women) and birthweight (grams) (MD 342.13; 95% CI 293.04 to 391.22; one trial, 156 women).
Different frequency of dosing of antibiotics was assessed in one small trial and showed no significant difference for any outcome assessed.
Authors' conclusions
Antibiotic treatment can eradicate bacterial vaginosis in pregnancy. The overall risk of PTB was not significantly reduced. This review provides little evidence that screening and treating all pregnant women with bacterial vaginosis will prevent PTB and its consequences. When screening criteria were broadened to include women with abnormal flora there was a 47% reduction in preterm birth, however this is limited to two included studies.
Background
Planned caesarean delivery for women thought be in preterm labour may be protective for baby, but could also be quite traumatic for both mother and baby. The optimal mode of delivery of ...preterm babies for both cephalic and breech presentation remains, therefore, controversial.
Objectives
To assess the effects of a policy of planned immediate caesarean delivery versus planned vaginal birth for women in preterm labour.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (5 August 2013).
Selection criteria
Randomised trials comparing a policy of planned immediate caesarean delivery versus planned vaginal delivery for preterm birth.
Data collection and analysis
Two review authors independently assessed trials for inclusion. Two review authors independently extracted data and assessed risk of bias. Data were checked for accuracy.
Main results
We included six studies (involving 122 women) but only four studies (involving only 116 women) contributed data to the analyses.
Infant
There were very little data of relevance to the three main (primary) outcomes considered in this review: There was no significant difference between planned immediate caesarean section and planned vaginal delivery with respect to birth injury to infant (risk ratio (RR) 0.56, 95%, confidence interval (CI) 0.05 to 5.62; one trial, 38 women) or birth asphyxia (RR 1.63, 95% CI 0.84 to 3.14; one trial, 12 women). The only cases of birth trauma were a laceration of the buttock in a baby who was delivered by caesarean section and mild bruising in another allocated to the group delivered vaginally.
The difference between the two groups with regard to perinatal deaths was not significant (0.29, 95% CI 0.07 to 1.14; three trials, 89 women) and there were no data specifically relating to neonatal admission to special care and/or intensive care unit.
There was also no difference between the caesarean or vaginal delivery groups in terms of markers of possible birth asphyxia (RR 1.63, 95% CI 0.84 to 3.14; one trial, 12 women) or Apgar score less than seven at five minutes (RR 0.83, 95% CI 0.43 to 1.60; four trials, 115 women) and no difference in attempts at breastfeeding (RR 1.40, 95% 0.11 to 17.45; one trial, 12 women). There was also no difference in neonatal fitting/seizures (RR 0.22, 95% CI 0.01 to 4.32; three trials, 77 women), hypoxic ischaemic encephalopathy (RR 4.00, 95% CI 0.20 to 82.01;one trial, 12 women) or respiratory distress syndrome (RR 0.55, 95% CI 0.27 to 1.10; three trials, 103 women). There were no data reported in the trials specifically relating to meconium aspiration. There was also no significant difference between the two groups for abnormal follow‐up in childhood (RR 0.65, 95% CI 0.19 to 2.22; one trial, 38 women) or delivery less than seven days after entry (RR 0.95, 95% CI 0.73 to 1.24; two trials, 51 women).
Mother
There were no data reported on maternal admissions to intensive care. However, there were seven cases of major maternal postpartum complications in the group allocated to planned immediate caesarean section and none in the group randomised to vaginal delivery (RR 7.21, 95% CI 1.37 to 38.08; four trials, 116 women).
There were no data reported in the trials specifically relating to maternal satisfaction (postnatal). There was no significant difference between the two groups with regard to postpartum haemorrhage. A number of non‐prespecified secondary outcomes were also considered in the analyses. There was a significant advantage for women in the vaginal delivery group with respect to maternal puerperal pyrexia (RR 2.98, 95% CI 1.18 to 7.53; three trials, 89 women) and other maternal infection (RR 2.63, 95% CI 1.02 to 6.78; three trials, 103 women), but no significant differences in wound infection (RR 1.16, 95% CI 0.18 to 7.70; three trials, 103 women), maternal stay more than 10 days (RR 1.27, 95% CI 0.35 to 4.65; three trials, 78 women) or the need for blood transfusion (results not estimable).
Authors' conclusions
There is not enough evidence to evaluate the use of a policy of planned immediate caesarean delivery for preterm babies. Further studies are needed in this area, but recruitment is proving difficult.
ObjectivesPerforation is the most serious complication associated with endoscopic mucosal resection (EMR). We propose a new classification for the appearance and integrity of the muscularis propria ...(MP) after EMR including various extents of deep mural injury (DMI). Risk factors for these injuries were analysed.DesignEndoscopic images and histological specimens of consecutive patients undergoing EMR of colonic laterally spreading lesions ≥20 mm at a large Australian tertiary referral endoscopy unit were retrospectively analysed using our new DMI classification system. DMI was graded according to MP injury (I/II intact MP without/with fibrosis, III target sign, IV/V obvious transmural perforation without/with contamination). Histological specimens were examined for included MP and patient outcomes were recorded. All type III–V DMI signs were clipped if possible, types I and II DMI were clipped at the endoscopists’ discretion.ResultsEMR was performed in 911 lesions (mean size 37 mm) in 802 patients (male sex 51.4%, mean age 67 years). DMI signs were identified in 83 patients (10.3%). Type III–V DMI was identified in 24 patients (3.0%); clipping was successfully performed in all patients. A clinically significant perforation occurred in two patients (0.2%). Only one of the 59 type I/II cases experienced a delayed perforation. 85.5% of patients with DMI were discharged on the same day, all without sequelae. On multivariable analysis, type III–V DMI was associated with transverse colon location (OR 3.55, p=0.028), en bloc resection (OR 3.84, p=0.005) and high-grade dysplasia or submucosal invasive cancer (OR 2.97, p 0.014).ConclusionsIn this retrospective analysis, use of the new classification and management with clips appeared to be a safe approach. Advanced DMI types (III–V) occurred in 3.0% of patients and were associated with identifiable risk factors. Further prospective clinical studies should use this new classification.Trial registration numberNCT01368289; results.
Background
Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of hospital admissions, disease‐related morbidity and mortality. COPD is a heterogeneous disease with ...distinct inflammatory phenotypes, including eosinophilia, which may drive acute exacerbations in a subgroup of patients. Monoclonal antibodies targeting interleukin 5 (IL‐5) or its receptor (IL‐5R) have a role in the care of people with severe eosinophilic asthma, and may similarly provide therapeutic benefit for people with COPD of eosinophilic phenotype.
Objectives
To assess the efficacy and safety of monoclonal antibody therapies targeting IL‐5 signalling (anti‐IL‐5 or anti‐IL‐5Rα) compared with placebo in the treatment of adults with COPD.
Search methods
We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, clinical trials registries, manufacturers' websites, and reference lists of included studies. Our most recent search was 23 September 2020.
Selection criteria
We included randomised controlled trials comparing anti‐IL‐5 therapy with placebo in adults with COPD.
Data collection and analysis
Two review authors independently extracted data and analysed outcomes using a random‐effects model.The primary outcomes were exacerbations requiring antibiotics or oral steroids, hospitalisations due to exacerbation of COPD, serious adverse events, and quality of life. We used standard methods expected by Cochrane. We used the GRADE approach to assess the certainty of the evidence.
Main results
Six studies involving a total of 5542 participants met our inclusion criteria. Three studies used mepolizumab (1530 participants), and three used benralizumab (4012 participants). The studies were on people with COPD, which was similarly defined with a documented history of COPD for at least one year. We deemed the risk of bias to be generally low, with all studies contributing data of robust methodology.
Mepolizumab 100 mg reduces the rate of moderate or severe exacerbations by 19% in those with an eosinophil count of at least 150/μL (rate ratio (RR) 0.81, 95% confidence interval (CI) 0.71 to 0.93; participants = 911; studies = 2, high‐certainty evidence). When participants with lower eosinophils are included, mepolizumab 100 mg probably reduces the exacerbation rate by 8% (RR 0.92, 95% CI 0.82 to 1.03; participants = 1285; studies = 2, moderate‐certainty evidence). Mepolizumab 300 mg probably reduces the rate of exacerbations by 14% in participants all of whom had raised eosinophils (RR 0.86, 95% CI 0.70 to 1.06; participants = 451; studies = 1, moderate‐certainty evidence); the evidence was uncertain for a single small study of mepolizumab 750 mg. In participants with high eosinophils, mepolizumab probably reduces the rate of hospitalisation by 10% (100 mg, RR 0.90, 95% CI 0.65 to 1.24; participants = 911; studies = 2, moderate‐certainty evidence) and 17% (300 mg, RR 0.83, 95% CI 0.51 to 1.35; participants = 451; studies = 1, moderate‐certainty evidence). Mepolizumab 100 mg increases the time to first moderate or severe exacerbation compared to the placebo group, in people with the eosinophilic phenotype (hazard ratio (HR) 0.78, 95% CI 0.66 to 0.92; participants = 981; studies 2, high‐certainty evidence). When participants with lower eosinophils were included this difference was smaller and less certain (HR 0.87, 95% CI 0.75 to 1.0; participants = 1285; studies 2, moderate‐certainty evidence). Mepolizumab 300 mg probably increases the time to first moderate or severe exacerbation in participants who all had eosinophilic phenotype (HR 0.77, 95% CI 0.60 to 0.99; participants = 451; studies = 1, moderate‐certainty evidence).
Benralizumab 100 mg reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/μL (RR 0.63, 95% CI 0.49 to 0.81; participants = 1512; studies = 2, high‐certainty evidence). Benralizumab 10 mg probably reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/μL (RR 0.68, 95% CI 0.49 to 0.94; participants = 765; studies = 1, moderate‐certainty evidence).
There was probably little or no difference between the intervention and placebo for quality of life measures. Where there were differences the mean difference fell below the pre‐specified minimum clinically significant difference.
Treatment with mepolizumab and benralizumab appeared to be safe. All pooled analyses showed that there was probably little or no difference in serious adverse events, adverse events, or side effects between the use of a monoclonal antibody therapy compared to placebo.
Authors' conclusions
We found that mepolizumab and benralizumab probably reduce the rate of moderate and severe exacerbations in the highly selected group of people who have both COPD and higher levels of blood eosinophils. This highlights the importance of disease phenotyping in COPD, and may play a role in the personalised treatment strategy in disease management.
Further research is needed to elucidate the role of monoclonal antibodies in the management of COPD in clinical practice. In particular, it is not clear whether there is a threshold blood eosinophil level above which these drugs may be effective. Studies including cost effectiveness analysis may be beneficial given the high cost of these therapies, to support use if appropriate.
Inhaled hyperosmolar agents for bronchiectasis Hart, Anna; Sugumar, Karnam; Milan, Stephen J ...
Cochrane database of systematic reviews,
05/2014, Volume:
2014, Issue:
5
Journal Article
Peer reviewed
Open access
Background
Mucus retention in the lungs is a prominent feature of bronchiectasis. The stagnant mucus becomes chronically colonised with bacteria, which elicit a host neutrophilic response. This fails ...to eliminate the bacteria, and the large concentration of host‐derived protease may contribute to the airway damage. The sensation of retained mucus is itself a cause of suffering, and the failure to maintain airway sterility probably contributes to the frequent respiratory infections experienced by many patients.
Hypertonic saline inhalation is known to accelerate tracheobronchial clearance in many conditions, probably by inducing a liquid flux into the airway surface, which alters mucus rheology in a way favourable to mucociliary clearance. Inhaled dry powder mannitol has a similar effect. Such agents are an attractive approach to the problem of mucostasis, and deserve further clinical evaluation.
Objectives
To determine whether inhaled hyperosmolar substances are effective in the treatment of bronchiectasis.
Search methods
We searched the Cochrane Airways Group Specialised Register, trials registries, and the reference lists of included studies and review articles. Searches are current up to April 2014.
Selection criteria
Any randomised controlled trial (RCT) using hyperosmolar inhalation in patients with bronchiectasis not caused by cystic fibrosis.
Data collection and analysis
Two review authors assessed studies for suitability. We used standard methods recommended by The Cochrane Collaboration.
Main results
Eleven studies met the inclusion criteria of the review (1021 participants).
Five studies on 833 participants compared inhaled mannitol with placebo but poor outcome reporting meant we could pool very little data and most outcomes were reported by only one study. One 12‐month trial on 461 participants provided results for exacerbations and demonstrated an advantage for mannitol in terms of time to first exacerbation (median time to exacerbation 165 versus 124 days for mannitol and placebo respectively (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63 to 0.96, P = 0.022) and number of days on antibiotics for bronchiectasis exacerbations was significantly better with mannitol (risk ratio (RR) 0.76, 95%CI 0.58 to 1.00, P = 0.0496). However, exacerbation rate per year was not significantly different between mannitol and placebo (RR 0.92 95% CI 0.78 to 1.08). The quality of this evidence was rated as moderate. There was also an indication, from only three trials, again based on moderate quality evidence, that mannitol improves health‐related quality of life (mean difference (MD) ‐2.05; 95% CI ‐3.69 to ‐0.40). An analysis of adverse events data, also based on moderate quality evidence, revealed no difference between mannitol and placebo (OR 0.96; 95% CI 0.61 to 1.51). Two additional small trials on 25 participants compared mannitol versus no treatment and the data from these studies were inconclusive.
Four studies (combined N = 113) compared hypertonic saline versus isotonic saline. On most outcomes there were conflicting results and the opportunities for the statistical aggregation of data from studies was very limited. It is not possible to draw robust conclusions for this comparison and judgments should be reserved until further data are available.
Authors' conclusions
There is an indication from a single, large, unpublished study that inhaled mannitol increases time to first exacerbation in patients with bronchiectasis. In patients with near normal lung function, spirometry does not change dramatically with mannitol and adverse events are not more frequent than placebo. Further investigation is required in a patient population with impaired lung function.
It is not possible to draw firm conclusions regarding the effect of nebulised hypertonic saline due to significant differences in the methodology, patient groups, and findings amongst the limited data available. The data suggest that it is unlikely to have benefit over isotonic saline in patients with milder disease, and hence future studies should test its use in those with more severe disease
Background Endoscopic resection (ER) for large colonic lesions is a safe and effective outpatient treatment. Postprocedural pain creates concern for perforation and often results in postprocedure ...admission (PPA). Carbon dioxide (CO2 ) insufflation has been shown to reduce pain scores after routine colonoscopy, but an influence on more critical outcomes such as PPA has not been shown. Objective To assess the outcomes of patients undergoing ER for large colonic lesions, comparing those having air versus those having CO2 insufflation. Design Prospective, observational, cohort study. Setting Academic, high-volume, tertiary-care referral center. Patients Consecutive patients referred for ER of sessile colorectal polyps ≥20 mm. Intervention ER with air or CO2. Main Outcome Measurements Rates of PPA, technical outcomes, complication rates. Results ER was performed on 575 lesions ≥20 mm, 228 with CO2 insufflation. Mean lesion size was 36.5 mm. Lesion and patient characteristics were similar in both groups. The use of CO2 was associated with a 62% decrease in the PPA rate from 8.9% to 3.4% ( P = .01). This was mainly because of an 82% decrease in PPA for pain from 5.7% to 1.0% ( P = .006). There were no significant difference in the rates of complications. Multiple logistical regression was performed. The adjusted odds ratio (OR) of PPA (OR 0.39; 95% confidence interval CI, 0.16-0.95; P = .04) and PPA for pain (OR 0.18; 95% CI, 0.04-0.78; P = .02) in the CO2 group remained significant. Limitations Single center, nonrandomized study. Conclusion CO2 insufflation significantly reduces PPA after ER of large colonic lesions, primarily because of reduced PPA for pain. CO2 insufflation should be routinely used during ER of large colonic lesions.
Mepolizumab versus placebo for asthma Powell, Colin; Milan, Stephen J; Dwan, Kerry ...
Cochrane Database of Systematic Reviews,
07/2015
7
Journal Article
Peer reviewed
Open access
Mepolizumab is a human monoclonal antibody against interleukin-5 (IL-5), the main cytokine involved in the activation of eosinophils, which in turn causes airway inflammation. Recent studies have ...suggested these agents may have a role in reducing exacerbations and improving health-related quality of life (HRQoL). There are no recommendations for the use of mepolizumab in adults or children in the recent update of the BTS/SIGN guidelines (BTS/SIGN 2014).
To compare the effects of mepolizumab with placebo on exacerbations and HRQoL in adults and children with chronic asthma.
We searched the Cochrane Airways Group Register (CAGR) of trials, clinical trial registries, manufacturers' websites and the reference lists of included studies. Searches were conducted in November 2013 and updated in November 2014.
We included randomised controlled trials comparing mepolizumab versus placebo in adults and children with asthma.
Two authors independently extracted data and analysed outcomes using a random-effects model. We used standard methods expected by The Cochrane Collaboration.
Eight studies on 1707 participants met the inclusion criteria. Only two studies included children (over 12 years of age), but they did not report separate findings for the adolescents. Seven studies involved intravenous mepolizumab alone; one included a subcutaneous arm. There was heterogeneity in the severity and clinical pattern of asthma among the participants in the eight studies, varying from mild to moderate atopic asthma, to persistent asthma and eosinophilic asthma with recurrent exacerbations. Selection bias was a concern in several of the studies included in this review.Four trials compared intravenous mepolizumab to placebo in relation to HRQoL. Two studies measured scores from the Asthma Quality of Life Questionnaire (AQLQ), which showed a non-significant difference between mepolizumab and placebo (mean difference (MD) 0.21, 95% confidence interval (CI) - 0.01 to 0.44; participants = 682), in the direction favouring mepolizumab. The third study used the St. George's Respiratory Questionnaire (SGRQ) and found a significant difference between mepolizumab and placebo (MD 6.40, 95% CI 3.15 to 9.65; participants = 576), which indicated a clinically important benefit favouring mepolizumab. A fourth study noted that there was no significant difference but did not provide any data. The two studies in people with eosinophilic asthma showed a reduction in clinically significant exacerbation rates (Risk Ratio 0.52, 95% CI 0.43 to 0.64; participants = 690). However, an analysis of four studies that were not confined to people with eosinophilic asthma indicated considerable heterogeneity and no significant difference in people with one or more exacerbations between mepolizumab and placebo using a random-effects model (Risk Ratio 0.67, 95% CI 0.34 to 1.31; participants = 468; I(2) = 59%).The analysis of serious adverse events indicated a significant difference favouring mepolizumab (Risk ratio 0.49, 95% CI 0.30 to 0.80; participants = 1441; studies = 5; I(2) = 0%). It was not possible to combine the results for adverse events, and we deemed the quality of this evidence to be low.A single study compared subcutaneous mepolizumab to placebo in 385 adults with severe eosinophilic asthma and found an improvement in HRQoL scores and a reduction in asthma exacerbations, including exacerbations requiring admission to hospital.
It is not possible to draw firm conclusions from this review with respect to the role of mepolizumab in patients with asthma. Our confidence in the results of this review are limited by the fact that the intravenous route is not currently licensed for mepolizumab, and the evidence for the currently licenced subcutaneous route is limited to a single study in participants with severe eosinophilic asthma.The currently available studies provide evidence that mepolizumab can lead to an improvement in health-related quality of life scores and reduce asthma exacerbations in people with severe eosinophilic asthma.Further research is needed to clarify which subgroups of patients with asthma could potentially benefit from this treatment. Dosage, ideal dosing regimens and duration of treatment need to be clarified, as the studies included in this review differed in their protocols. There are no studies reporting results from children, so we cannot comment on treatment for this age group. At the present time, larger studies using licenced treatment regimens are required to establish the role of mepolizumab in the treatment of severe asthma.
Macrolide antibiotics for bronchiectasis Kelly, Carol; Chalmers, James D; Crossingham, Iain ...
Cochrane database of systematic reviews,
03/2018, Volume:
2018, Issue:
10
Journal Article
Peer reviewed
Open access
Background
Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways ...leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long‐term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance.
Objectives
To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis.
Search methods
We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018.
Selection criteria
We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long‐term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high‐resolution computed tomography. We excluded studies in which participants had received continuous or high‐dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events.
Data collection and analysis
Two review authors independently screened the titles and s of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane.
Main results
We included 14 parallel‐group RCTs and one cross‐over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin.
We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention.
In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I2 = 65%; moderate‐quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate‐quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD ‐8.90, 95% CI ‐13.13 to ‐4.67; 68 participants; one study; moderate‐quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I2 = 0%; low‐quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non‐respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I2 = 0%; low‐quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I2 = 28%) in adults with macrolides compared with placebo.
In children, exacerbation frequency was reduced more with macrolides than with placebo (IRR 0.50, 95% CI 0.35 to 0.71; 89 children; one study; low‐quality evidence). However there was no significant difference in this age group with regard to: hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low‐quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low‐quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide‐resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children.
Authors' conclusions
Long‐term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.
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