Review

Authors: Victor Kim, Gerard J Criner

Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can develop CB, and small airway pathology has been linked to worse clinical outcomes, such as increased mortality and lesser improvement in lung function after lung volume reduction surgery. However, in recent years, a greater understanding of the importance of CB as a phenotype to identify patients with a beneficial response to therapy has been described. Herein we review the epidemiology of CB, the evidence behind its clinical consequences, the current understanding of the pathophysiology of goblet cell hyperplasia in COPD, and current therapies for CB.

Topics: Adrenergic beta-Agonists; Anti-Bacterial Agents; Antioxidants; Bronchitis, Chronic; Cholinergic Antagonists; Disease Progression; Expectorants; Glucocorticoids; Goblet Cells; Humans; Mucus; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Smoking; Smoking Cessation; Xanthines

PubMed: 23204254
DOI: 10.1164/rccm.201210-1843CI

Review

Authors: Ganesh Raghu, Michael Berk, Peter A Campochiaro...

Oxidative stress, which results in the damage of diverse biological molecules, is a ubiquitous cellular process implicated in the etiology of many illnesses. The sulfhydryl-containing tripeptide glutathione (GSH), which is synthesized and maintained at high concentrations in all cells, is one of the mechanisms by which cells protect themselves from oxidative stress. N-acetylcysteine (NAC), a synthetic derivative of the endogenous amino acid L-cysteine and a precursor of GSH, has been used for several decades as a mucolytic and as an antidote to acetaminophen (paracetamol) poisoning. As a mucolytic, NAC breaks the disulfide bonds of heavily cross-linked mucins, thereby reducing mucus viscosity. In vitro, NAC has antifibrotic effects on lung fibroblasts. As an antidote to acetaminophen poisoning, NAC restores the hepatic GSH pool depleted in the drug detoxification process. More recently, improved knowledge of the mechanisms by which NAC acts has expanded its clinical applications. In particular, the discovery that NAC can modulate the homeostasis of glutamate has prompted studies of NAC in neuropsychiatric diseases characterized by impaired glutamate homeostasis. This narrative review provides an overview of the most relevant and recent evidence on the clinical application of NAC, with a focus on respiratory diseases, acetaminophen poisoning, disorders of the central nervous system (chronic neuropathic pain, depression, schizophrenia, bipolar disorder, and addiction), cardiovascular disease, contrast-induced nephropathy, and ophthalmology (retinitis pigmentosa).

Topics: Acetylcysteine; Antioxidants; Expectorants; Glutathione; Oxidative Stress

PubMed: 33380301
DOI: 10.2174/1570159X19666201230144109

Meta-Analysis

Authors: Peter M Odor, Sohail Bampoe, David Gilhooly...

OBJECTIVE

To identify, appraise, and synthesise the best available evidence on the efficacy of perioperative interventions to reduce postoperative pulmonary complications (PPCs) in adult patients undergoing non-cardiac surgery.

DESIGN

Systematic review and meta-analysis of randomised controlled trials.

DATA SOURCES

Medline, Embase, CINHAL, and CENTRAL from January 1990 to December 2017.

ELIGIBILITY CRITERIA

Randomised controlled trials investigating short term, protocolised medical interventions conducted before, during, or after non-cardiac surgery were included. Trials with clinical diagnostic criteria for PPC outcomes were included. Studies of surgical technique or physiological or biochemical outcomes were excluded.

DATA EXTRACTION AND SYNTHESIS

Reviewers independently identified studies, extracted data, and assessed the quality of evidence. Meta-analyses were conducted to calculate risk ratios with 95% confidence intervals. Quality of evidence was summarised in accordance with GRADE methods. The primary outcome was the incidence of PPCs. Secondary outcomes were respiratory infection, atelectasis, length of hospital stay, and mortality. Trial sequential analysis was used to investigate the reliability and conclusiveness of available evidence. Adverse effects of interventions were not measured or compared.

RESULTS

117 trials enrolled 21 940 participants, investigating 11 categories of intervention. 95 randomised controlled trials enrolling 18 062 participants were included in meta-analysis; 22 trials were excluded from meta-analysis because the interventions were not sufficiently similar to be pooled. No high quality evidence was found for interventions to reduce the primary outcome (incidence of PPCs). Seven interventions had low or moderate quality evidence with confidence intervals indicating a probable reduction in PPCs: enhanced recovery pathways (risk ratio 0.35, 95% confidence interval 0.21 to 0.58), prophylactic mucolytics (0.40, 0.23 to 0.67), postoperative continuous positive airway pressure ventilation (0.49, 0.24 to 0.99), lung protective intraoperative ventilation (0.52, 0.30 to 0.88), prophylactic respiratory physiotherapy (0.55, 0.32 to 0.93), epidural analgesia (0.77, 0.65 to 0.92), and goal directed haemodynamic therapy (0.87, 0.77 to 0.98). Moderate quality evidence showed no benefit for incentive spirometry in preventing PPCs. Trial sequential analysis adjustment confidently supported a relative risk reduction of 25% in PPCs for prophylactic respiratory physiotherapy, epidural analgesia, enhanced recovery pathways, and goal directed haemodynamic therapies. Insufficient data were available to support or refute equivalent relative risk reductions for other interventions.

CONCLUSIONS

Predominantly low quality evidence favours multiple perioperative PPC reduction strategies. Clinicians may choose to reassess their perioperative care pathways, but the results indicate that new trials with a low risk of bias are needed to obtain conclusive evidence of efficacy for many of these interventions.

STUDY REGISTRATION

Prospero CRD42016035662.

Topics: Analgesia, Epidural; Critical Pathways; Expectorants; Fluid Therapy; Hemodynamics; Humans; Intraoperative Care; Physical Therapy Modalities; Postoperative Complications; Respiratory Therapy; Respiratory Tract Diseases; Vasoconstrictor Agents

PubMed: 32161042
DOI: 10.1136/bmj.m540

Review

Authors: Katherine O'Neill, Anne E O'Donnell, Judy M Bradley...

This paper aims to provide physiological rationale for airway clearance, mucoactive therapy and pulmonary rehabilitation (PR) (or exercise interventions) in bronchiectasis. There is increasing emphasis on the role of airway clearance techniques (ACT) in the management of bronchiectasis. No single ACT has currently shown superior effect over another. Given the large range of different techniques available, consideration of the physiological effects underpinning a technique including expiratory flow, ventilation and oscillation, is essential to effectively personalize ACT. Key clinical trials of mucoactives in bronchiectasis are underway and will provide clarity on the role of these agents in the management of patients with bronchiectasis. Prescription of mucoactive therapies should be done in conjunction with ACT and therefore the mechanism of action of mucoactive drugs and their timing with ACT should be taken into consideration. PR and/or exercise training are recommended in all current bronchiectasis guidelines. There is a clear physiological rationale that muscle weakness and physical inactivity may play a role in disease progression as well as impacting health-related quality of life, frequency of pulmonary exacerbations and ability to mobilize sputum. However, there are residual unanswered questions surrounding the delivery and accessibility to PR. This review summarizes the physiological principles and supporting evidence for airway clearance, mucoactive medication and PR, which are key components in the management of bronchiectasis.

Topics: Breathing Exercises; Bronchiectasis; Disease Progression; Exercise Therapy; Expectorants; Humans; Mucociliary Clearance; Quality of Life; Respiratory Therapy; Sputum

PubMed: 30650472
DOI: 10.1111/resp.13459

Review

Authors: Julia Fashner, Kevin Ericson, Sarah Werner...

The common cold, or upper respiratory tract infection, is one of the leading reasons for physician visits. Generally caused by viruses, the common cold is treated symptomatically. Antibiotics are not effective in children or adults. In children, there is a potential for harm and no benefits with over-the-counter cough and cold medications; therefore, they should not be used in children younger than four years. Other commonly used medications, such as inhaled corticosteroids, oral prednisolone, and Echinacea, also are ineffective in children. Products that improve symptoms in children include vapor rub, zinc sulfate, Pelargonium sidoides (geranium) extract, and buckwheat honey. Prophylactic probiotics, zinc sulfate, nasal saline irrigation, and the herbal preparation Chizukit reduce the incidence of colds in children. For adults, antihistamines, intranasal corticosteroids, codeine, nasal saline irrigation, Echinacea angustifolia preparations, and steam inhalation are ineffective at relieving cold symptoms. Pseudoephedrine, phenylephrine, inhaled ipratropium, and zinc (acetate or gluconate) modestly reduce the severity and duration of symptoms for adults. Nonsteroidal anti-inflammatory drugs and some herbal preparations, including Echinacea purpurea, improve symptoms in adults. Prophylactic use of garlic may decrease the frequency of colds in adults, but has no effect on duration of symptoms. Hand hygiene reduces the spread of viruses that cause cold illnesses. Prophylactic vitamin C modestly reduces cold symptom duration in adults and children.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antitussive Agents; Child; Cholinergic Antagonists; Common Cold; Complementary Therapies; Expectorants; Histamine Antagonists; Humans; Nasal Decongestants; Nasal Lavage; Nonprescription Drugs

PubMed: 22962927
DOI: No ID Found

Meta-Analysis Review

Authors: Susan M Smith, Knut Schroeder, Tom Fahey...

BACKGROUND

Acute cough due to upper respiratory tract infection (URTI) is a common symptom. Non-prescription, over-the-counter (OTC) medicines are frequently recommended as a first-line treatment, but there is little evidence as to whether these drugs are effective.

OBJECTIVES

To assess the effects of oral OTC cough preparations for acute cough in children and adults in community settings.

SEARCH METHODS

We searched CENTRAL (2014, Issue 1), MEDLINE (January 1966 to March week 3 2014), EMBASE (January 1974 to March 2014), CINAHL (January 2010 to March 2014), LILACS (January 2010 to March 2014), Web of Science (January 2010 to March 2014) and the UK Department of Health National Research Register (March 2010).

SELECTION CRITERIA

Randomised controlled trials (RCTs) comparing oral OTC cough preparations with placebo in children and adults suffering from acute cough in community settings. We considered all cough outcomes; secondary outcomes of interest were adverse effects.

DATA COLLECTION AND ANALYSIS

Two review authors independently screened potentially relevant citations, extracted data and assessed study quality. We performed quantitative analysis where appropriate.

MAIN RESULTS

Due to the small numbers of trials in each category, the limited quantitative data available and the marked differences between trials in terms of participants, interventions and outcome measurement, we felt that pooling of the results was inappropriate.We included 29 trials (19 in adults, 10 in children) involving 4835 people (3799 adults and 1036 children). All studies were placebo-controlled RCTs. However, assessment of the risk of bias of the included studies was limited by poor reporting, particularly for the earlier studies.In the adult studies, six trials compared antitussives with placebo and had variable results. Three trials compared the expectorant guaifenesin with placebo; one indicated significant benefit, whereas the other two did not. One trial found that a mucolytic reduced cough frequency and symptom scores. Two studies examined antihistamine-decongestant combinations and found conflicting results. Four studies compared other combinations of drugs with placebo and indicated some benefit in reducing cough symptoms. Three trials found that antihistamines were no more effective than placebo in relieving cough symptoms.In the child studies, antitussives (data from three studies), antihistamines (data from three studies), antihistamine-decongestants (two studies) and antitussive/bronchodilator combinations (one study) were no more effective than placebo. No studies using expectorants met our inclusion criteria. The results of one trial favoured active treatment with mucolytics over placebo. One trial tested two paediatric cough syrups and both preparations showed a 'satisfactory response' in 46% and 56% of children compared to 21% of children in the placebo group. One new trial indicated that three types of honey were more effective than placebo over a three-day period.Twenty-one studies reported adverse effects. There was a wide range across studies, with higher numbers of adverse effects in participants taking preparations containing antihistamines and dextromethorphan.

AUTHORS' CONCLUSIONS

The results of this review have to be interpreted with caution because the number of studies in each category of cough preparations was small. Availability, dosing and duration of use of over-the-counter cough medicines vary significantly in different countries. Many studies were poorly reported making assessment of risk of bias difficult and studies were also very different from each other, making evaluation of overall efficacy difficult. There is no good evidence for or against the effectiveness of OTC medicines in acute cough. This should be taken into account when considering prescribing antihistamines and centrally active antitussive agents in children; drugs that are known to have the potential to cause serious harm.

Topics: Acute Disease; Administration, Oral; Adult; Ambulatory Care; Antitussive Agents; Child; Cough; Drug Therapy, Combination; Expectorants; Histamine H1 Antagonists; Humans; Nonprescription Drugs; Randomized Controlled Trials as Topic

PubMed: 25420096
DOI: 10.1002/14651858.CD001831.pub5

Authors: Phillippa Poole, Kavin Sathananthan, Rebecca Fortescue...

BACKGROUND

Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume or purulence of sputum, or both. Personal and healthcare costs associated with exacerbations indicate that therapies that reduce the occurrence of exacerbations are likely to be useful. Mucolytics are oral medicines that are believed to increase expectoration of sputum by reducing its viscosity, thus making it easier to cough it up. Improved expectoration of sputum may lead to a reduction in exacerbations of COPD.

OBJECTIVES

Primary objective• To determine whether treatment with mucolytics reduces exacerbations and/or days of disability in patients with chronic bronchitis or COPDSecondary objectives• To assess whether mucolytics lead to improvement in lung function or quality of life• To determine frequency of adverse effects associated with use of mucolytics SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register and reference lists of articles on 12 separate occasions, most recently on 23 April 2019.

SELECTION CRITERIA

We included randomised studies that compared oral mucolytic therapy versus placebo for at least two months in adults with chronic bronchitis or COPD. We excluded studies of people with asthma and cystic fibrosis.

DATA COLLECTION AND ANALYSIS

This review analysed summary data only, most derived from published studies. For earlier versions, one review author extracted data, which were rechecked in subsequent updates. In later versions, review authors double-checked extracted data and then entered data into RevMan 5.3 for analysis.

MAIN RESULTS

We added four studies for the 2019 update. The review now includes 38 trials, recruiting a total of 10,377 participants. Studies lasted between two months and three years and investigated a range of mucolytics, including N-acetylcysteine, carbocysteine, erdosteine, and ambroxol, given at least once daily. Many studies did not clearly describe allocation concealment, and we had concerns about blinding and high levels of attrition in some studies. The primary outcomes were exacerbations and number of days of disability.Results of 28 studies including 6723 participants show that receiving mucolytics may be more likely to be exacerbation-free during the study period compared to those given placebo (Peto odds ratio (OR) 1.73, 95% confidence interval (CI) 1.56 to 1.91; moderate-certainty evidence). However, more recent studies show less benefit of treatment than was reported in earlier studies in this review. The overall number needed to treat with mucolytics for an average of nine months to keep an additional participant free from exacerbations was eight (NNTB 8, 95% CI 7 to 10). High heterogeneity was noted for this outcome (I² = 62%), so results need to be interpreted with caution. The type or dose of mucolytic did not seem to alter the effect size, nor did the severity of COPD, including exacerbation history. Longer studies showed smaller effects of mucolytics than were reported in shorter studies.Mucolytic use was associated with a reduction of 0.43 days of disability per participant per month compared with use of placebo (95% CI -0.56 to -0.30; studies = 9; I² = 61%; moderate-certainty evidence). With mucolytics, the number of people with one or more hospitalisations was reduced, but study results were not consistent (Peto OR 0.68, 95% CI 0.52 to 0.89; participants = 1788; studies = 4; I² = 58%; moderate-certainty evidence). Investigators reported improved quality of life with mucolytics (mean difference (MD) -1.37, 95% CI -2.85 to 0.11; participants = 2721; studies = 7; I² = 64%; moderate-certainty evidence). However, the mean difference did not reach the minimal clinically important difference of -4 units, and the confidence interval includes no difference. Mucolytic treatment was associated with a possible reduction in adverse events (OR 0.84, 95% CI 0.74 to 0.94; participants = 7264; studies = 24; I² = 46%; moderate-certainty evidence), but the pooled effect includes no difference if a random-effects model is used. Several studies that could not be included in the meta-analysis reported high numbers of adverse events, up to a mean of five events per person during follow-up. There was no clear difference between mucolytics and placebo for mortality, but the confidence interval is too wide to confirm that treatment has no effect on mortality (Peto OR 0.98, 95% CI 0.51 to 1.87; participants = 3527; studies = 11; I² = 0%; moderate-certainty evidence).

AUTHORS' CONCLUSIONS

In participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics leads to a small reduction in the likelihood of having an acute exacerbation, in days of disability per month and possibly hospitalisations, but is not associated with an increase in adverse events. There appears to be limited impact on lung function or health-related quality of life. Results are too imprecise to be certain whether or not there is an effect on mortality. Our confidence in the results is reduced by high levels of heterogeneity in many of the outcomes and the fact that effects on exacerbations shown in early trials were larger than those reported by more recent studies. This may be a result of greater risk of selection or publication bias in earlier trials, thus benefits of treatment may not be as great as was suggested by previous evidence.

Topics: Bronchitis, Chronic; Disease Progression; Expectorants; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome

PubMed: 31107966
DOI: 10.1002/14651858.CD001287.pub6

Review

Authors: Cecile Magis-Escurra, Monique He Reijers

INTRODUCTION

Bronchiectasis is usually a complication of previous lower respiratory infection and/or inflammation. It causes chronic cough, copious production of sputum (often purulent), and recurrent infections, and may cause airway obstruction bearing some similarities with that seen in COPD. It may complicate respiratory conditions such as asthma or COPD. It can be associated with primary ciliary dyskinesia, primary immunodeficiencies, certain systemic diseases such as inflammatory bowel disease and rheumatoid arthritis, and foreign body inhalation. Bronchiectasis can be due to cystic fibrosis but this is excluded from this review.

METHODS AND OUTCOMES

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with non-cystic fibrosis (non-CF) bronchiectasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.

RESULTS

We found 23 studies that met our inclusion criteria.

CONCLUSIONS

In this systematic review we present information relating to the effectiveness and safety of the following interventions: airway clearance techniques, corticosteroids (inhaled), exercise or physical training, hyperosmolar agents (inhaled), mucolytics, prolonged-use antibiotics, and surgery.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Bacterial Agents; Bronchiectasis; Cough; Exercise; Expectorants; Humans; Treatment Outcome

PubMed: 25715965
DOI: No ID Found

Review

Authors: Peter Wark

INTRODUCTION

Acute bronchitis affects more than 40 in 1000 adults per year in the UK. The causes are usually considered to be infective, but only around half of people have identifiable pathogens. The role of smoking or of environmental tobacco smoke inhalation in predisposing to acute bronchitis is unclear. One third of people may have longer-term symptoms or recurrence.

METHODS AND OUTCOMES

We conducted a systematic review, aiming to answer the following clinical question: What are the effects of treatments for acute bronchitis in people without chronic respiratory disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2015 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).

RESULTS

At this update, searching of electronic databases retrieved 420 studies. After deduplication and removal of conference abstracts, 306 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 245 studies and the further review of 61 full publications. Of the 61 full articles evaluated, three updated systematic reviews and three RCTs were added at this update. We performed a GRADE evaluation for 12 PICO combinations.

CONCLUSIONS

In this systematic review we categorised the efficacy for six intervention-comparison combinations, based on information about the effectiveness and safety of the following interventions: antibiotics, antihistamines, antitussives, beta2 agonists (inhaled), and expectorants/mucolytics.

Topics: Acute Disease; Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Anti-Bacterial Agents; Antitussive Agents; Bronchitis; Expectorants; Histamine Antagonists; Humans; Treatment Outcome

PubMed: 26186368
DOI: No ID Found

Review

Authors: R Balsamo, L Lanata, C G Egan...

Mucus hypersecretion is a clinical feature of severe respiratory diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Airway mucosal infection and/or inflammation associated with these diseases often gives rise to inflammatory products, including neutrophil-derived DNA and filamentous actin, in addition to bacteria, apoptotic cells and cellular debris, that may collectively increase mucus production and viscosity. Mucoactive agents have been the medication of choice for the treatment of respiratory diseases in which mucus hypersecretion is a clinical complication. The main purpose of mucoactive drugs is to increase the ability to expectorate sputum and/or decrease mucus hypersecretion. Many mucoactive drugs are currently available and can be classified according to their putative mechanism of action. Mucoactive medications include expectorants, mucoregulators, mucolytics and mucokinetics. By developing our understanding of the specific effects of mucoactive agents, we may result in improved therapeutic use of these drugs. The present review provides a summary of the most clinically relevant mucoactive drugs in addition to their potential mechanism of action.

Topics: Expectorants; Humans; Mucus; Pulmonary Disease, Chronic Obstructive

PubMed: 20956181
DOI: 10.1183/09059180.00003510