Rational use of mucoactive medications to treat pediatric airway disease.

Many airway diseases in children, notably bronchiolitis, cystic fibrosis (CF), non-CF bronchiectasis including primary ciliary dyskinesia, pneumonia, and severe asthma are associated with retention of airway secretions. Medications to improve secretions clearance, the mucoactive medications, are employed to treat these diseases with varying degrees of success. This manuscript reviews evidence for the use of these medications and future directions of study.

Management of children with chronic wet cough and protracted bacterial bronchitis: CHEST guideline and expert panel report

BACKGROUND: Wet or productive cough is common in children with chronic cough. We formulated recommendations based on systematic reviews related to the management of chronic wet cough in children (aged ≤ 14 years) based on two key questions: (1) how effective are antibiotics in improving the resolution of cough? If so, what antibiotic should be used and for how long? and (2) when should children be referred for further investigations? METHODS: We used the CHEST expert cough panel's protocol for systematic reviews and the American College of Chest Physicians (CHEST) methodologic guidelines and GRADE framework (the Grading of Recommendations Assessment, Development and Evaluation). Data from the systematic reviews in conjunction with patients' values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain consensus for the recommendations/suggestions made. RESULTS: Combining data from the systematic reviews, we found high-quality evidence in children aged ≤ 14 years with chronic (> 4 weeks' duration) wet/productive cough that using appropriate antibiotics improves cough resolution, and further investigations (eg, flexible bronchoscopy, chest CT scans, immunity tests) should be undertaken when specific cough pointers (eg, digital clubbing) are present. When the wet cough does not improve following 4 weeks of antibiotic treatment, there is moderate-quality evidence that further investigations should be considered to look for an underlying disease. New recommendations include the recognition of the clinical diagnostic entity of protracted bacterial bronchitis. CONCLUSIONS: Compared with the 2006 Cough Guidelines, there is now high-quality evidence for some, but not all, aspects of the management of chronic wet cough in specialist settings. However, further studies particularly in primary health) are required.

Effect of a single 1200 Mg dose of Mucinex® on mucociliary and cough clearance during an acute respiratory tract infection.

BACKGROUND: Observational studies suggest that orally administered guaifenesin (GGE) may thin lower respiratory tract secretions but none have examined its effects on mucociliary and cough clearance (MCC/CC) during a respiratory tract infection (RTI). The current study was a randomized, parallel-group, double-blind, placebo-controlled study in non-smoking adults who suffered from an acute upper RTI. METHODS: We assessed the effects of a single dose of Mucinex(®) 1200 mg (2 × 600 mg extended release tablets) (ER GGE) on 1) MCC/CC by assessing the rate of removal from the lung of inhaled radioactive tracer particles (Tc99m-sulfur colloid), 2) sputum dynamic rheology by stress/strain creep transformation over the linear part of the curve, 3) sessile drop interfacial tension by the deNouy ring technique, and 4) subjective symptom measures. MCC was measured during the morning (period 1) and compared to that in the afternoon 4 h later (period 2) immediately following either drug (n = 19) or placebo (n = 19). For both period 1 and 2 subjects performed 60 voluntary coughs from 60 to 90 min after inhalation of radio-labeled aerosol for a measure of CC. Sputum properties were measured from subjects who expectorated sputum during the cough period post treatment (n = 8-12 for each cohort). RESULTS: We found no effect of ER GGE on MCC or CC compared to placebo. MCC through 60 min for period 1 vs. 2 = 8.3 vs. 11.8% (placebo) and = 9.7 vs. 11.1% (drug) (NS) and CC for period 1 vs. 2 was 9.9 vs. 9.1% (placebo) and 10.8 vs. 5.6% (drug) (NS). There was no significant difference in sputum biophysical properties after administration of drug or placebo. CONCLUSIONS: There was no significant effect of a single dose of ER GGE on MCC/CC or on sputum biophysical properties compared to placebo in this population of adult patients with an acute RTI. ClinicalTrials.gov Identifier: NCT01114581.

IL-33 stimulates CXCL8/IL-8 secretion in goblet cells but not normally differentiated airway cells.

BACKGROUND: IL-13, a helper T cell type 2 (Th2) cytokine, transforms cultured airway epithelial cells to goblet cells, and this is not inhibited by corticosteroids. IL-33 stimulates Th2 cytokines and is highly expressed in airways of persons with asthma. The effect of IL-33 on goblet cell differentiation and cytokine secretion has not been described. OBJECTIVE: We examined the effect of IL-33 on CXCL8/IL-8 secretion from goblet or normally differentiated human bronchial epithelial (NHBE) cells and signalling pathways associated with IL-33 activation in these cells. METHODS: Normal human bronchial epithelial cells were grown to goblet or normally differentiated ciliated cell phenotype at air-liquid interface in the presence or absence of IL-13. After 14 days, differentiated cells were exposed to IL-33 for 24 h. RESULTS: CXCL8/IL-8 secretion into the apical (air) side of the goblet cells was greater than from normally differentiated cells (P < 0.01), and IL-33 stimulated apical CXCL8/IL-8 release from goblet cells, but not from normally differentiated cells (P < 0.01). IL-33 increased ERK 1/2 phosphorylation in goblet cells (P < 0.05), and PD98059, a MAPK/ERK kinase inhibitor, attenuated IL-33-stimulated CXCL8/IL-8 secretion from goblet cells (P < 0.001). IL-13 induced ST2 mRNA (P < 0.02) and membrane-bound ST2 protein expression on the apical side surface of goblet cells compared with normally differentiated cells, and neutralization with anti-ST2R antibody attenuated IL-33-induced apical CXCL8/IL-8 secretion from goblet cells (P < 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Goblet cells secrete CXCL8/IL-8, and this is increased by IL-33 through ST2R-ERK pathway, suggesting a mechanism for enhanced airway inflammation in the asthmatic airway with goblet cell metaplasia.

Bordetella bronchiseptica in a paediatric cystic fibrosis patient: possible transmission from a household cat.

Bordetella bronchiseptica is a zoonotic respiratory pathogen commonly found in domesticated farm and companion animals, including dogs and cats. Here, we report isolation of B. bronchiseptica from a sputum sample of a cystic fibrosis patient recently exposed to a kitten with an acute respiratory illness. Genetic characterization of the isolate and comparison with other isolates of human or feline origin strongly suggest that the kitten was the source of infection.

IL-13-induced MUC5AC production and goblet cell differentiation is steroid resistant in human airway cells.

BACKGROUND: Glucocorticosteroids (GCS) are used to treat bronchial asthma, but are not uniformly effective, especially in severe asthma. IL-13 is a T helper type 2 cytokine implicated in the pathogenesis of asthma, and IL-13 induces mucus production and goblet cell hyperplasia in airway epithelial cells. The effect of GCS on IL-13-induced mucin production is not well characterized. OBJECTIVE: The aim of this study was to evaluate the effect of dexamethasone (Dex), a potent synthetic GCS, on IL-13-induced MUC5AC mucin expression and goblet cell proliferation in differentiated normal human bronchial epithelial cells (NHBECs). METHODS: NHBECs were cultured for 14 days at an air-liquid interface with IL-13, with or without Dex. MUC5AC protein secretion and mRNA expression was determined using ELISA and quantitative real-time PCR. IL-8 production was assayed using ELISA. Histochemical analysis was performed using H&E and periodic acid-Schiff stain, and MUC5AC immunostaining. RESULTS: Although Dex dose dependently inhibited IL-8 release induced by 5 ng/mL IL-13, Dex 0.001-1 µg/mL had no effect on IL-13 induced MUC5AC protein secretion or mRNA expression. Dex paradoxically increased MUC5AC induced by IL-13 at 0.5 and 1 ng/mL, but had no effect alone or with IL-13 at 0.1 ng/mL. Dex 0.001-1 µg/mL did not inhibit the differentiation of cells into goblet cells and MUC5AC-positive cells induced by IL-13. CONCLUSION AND CLINICAL RELEVANCE: Dex at therapeutic concentrations did not inhibit the effects of IL-13 on goblet cell differentiation, characteristic of severe asthma. Paradoxically, MUC5AC production was increased with lower dose IL-13 exposure. This may lead to airway mucus obstruction commonly seen in life-threatening asthma.

Alternative mechanisms for tiotropium.

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.

Macrolide antibiotics, bacterial populations and inflammatory airway disease.

Chronic obstructive pulmonary disease (COPD) and other inflammatory airway conditions are major causes of morbidity and mortality worldwide. Antibiotics are used to treat acute infectious exacerbations of airway disease. However, for the macrolides, a significant and growing body of evidence indicates that anti-inflammatory effects of these antibiotics, which may be independent of their antibacterial effects, are at least partially responsible for their beneficial effect. In this review, we describe current thinking on the means whereby anti-inflammatory effects of macrolides impact chronic airway disease. The current data indicate that some macrolides have immunomodulatory activity, mediated at least in part by effects on the activation of gene transcription mediated by NF-kappabeta activation that may be separable from their antimicrobial activities, and could explain their surprising efficacy in asthma and viral infections for which the role of bacteria is not established. Other, provocative work indicates that subclinical doses of macrolides may also affect signalling within and between bacterial communities, and thus impact developmental processes such as biofilm formation that are important in the establishment and persistence of chronic infections. The current data clearly suggest that activities beyond antimicrobial effects contribute significantly to the beneficial effect of macrolide therapy on inflammatory conditions.

Aerosol therapy for children.

Pediatric aerosol therapy encompasses a range of patients from premature neonates with birth weights as low as 500 grams to adult size teenagers. This article focuses on the care of smaller infants and children in whom anatomic differences present substantial challenges for aerosol delivery.

Sputum processing for evaluation of inflammatory mediators.

Neutrophil-dominated inflammation is prominent in the cystic fibrosis (CF) and chronic bronchitis (CB) airways. We assessed the degree of airway inflammation by measuring the sputum concentrations of interleukin (IL)-8, myeloperoxidase (MPO), and deoxyribonucleic acid (DNA). We determined the relationship among the concentrations of these mediators and investigated methodological problems that may be responsible for reported variability in measurements. Sputa obtained from 31 patients were solubilized with phosphate-buffered saline, dithiothreitol (DTT) (0.1% or 1%), or dornase alfa (0.2 mg/mL). The sputum concentration of IL-8 and MPO was measured by enzyme-linked immunosorbent assay (ELISA), and DNA was measured using microfluorimetry. There was a significant relationship among sputum IL-8, MPO, and DNA. For MPO (means +/- SD), CF was 1,392 +/- 771 vs. CB at 75 +/- 65 mcg/mL; P < 0.0001. For IL-8: CF was 239 +/- 154 vs. CB at 121 +/- 108 ng/mL; P = 0.0002. For DNA, CF was 1.707 +/- 1.25 vs. CB at 0.184 +/- 0.272 mg/mL; P < 0.0001. The MPO concentration in CF sputum was approximately double after in vitro treatment with dornase alfa (P < 0.0001). There is a greater concentration of IL-8, MPO, and DNA in CF than in CB sputa. There is a significant relationship among these inflammatory markers in sputum. DNA polymers bind myeloperoxidase in the sputum, and we speculate that treatment with dornase alfa may remove a source of MPO inhibition.

Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis.

OBJECTIVE: To evaluate the effect of recombinant human deoxyribonuclease I (rhDNase) in shortening the length of the hospitalization and improving the chest radiographs (CXRs) in hospitalized infants with respiratory syncytial virus (RSV) infection as a result of its mucolytic properties. METHODS: Randomized, double-blind, placebo-controlled investigation of 75 patients with RSV bronchiolitis. The study was conducted at the University of Michigan Medical Center and St. Joseph Mercy Hospital, both in Ann Arbor, MI. RESULTS: The respiratory rate, wheezing, and retraction difference scores, obtained by subtracting the hospital discharge score from the corresponding hospital admission score, show no difference between the two groups, but the CXR difference scores show that the rhDNase group improved by 0.46 while the placebo group worsened by 0.60 (p < 0.001). Analysis of covariance for the hospital discharge CXR score after adjusting for the hospital admission score for both groups was done. There was a difference in scores between the two groups, with adjusted mean for the study group of 2.03, and 2.76 for the placebo group (p < 0.001). Paired t test statistics in each of the two groups were computed. For the placebo group, the mean increase of 0.60 was significant (p = 0.02), and the mean decrease of 0.46 for the rhDNase group was also significant (p = 0.02). A one-way analysis of covariance with the hospital discharge CXR scores as the dependent variable and the hospital admission score as the covariate showed that there was a significant difference between the groups (p = 0.01). CONCLUSION: In patients with RSV bronchiolitis, there was significant improvement in the CXRs with the use of rhDNase compared to significant worsening in the placebo group. To our knowledge, this is the first report of the use of rhDNase to treat RSV bronchiolitis.

Regulation of secretion from mucous and serous cells in the excised ferret trachea.

Mucus hypersecretion is an important characteristic of many airway diseases. Mucin is the major component of mucus, and is secreted from surface goblet cells of the airway epithelium and mucous cells of submucosal glands. Lysozyme is an enzyme secreted by serous cells of airway submucosal glands. We hypothesized that secretagogues acting through different pathways would have different effects on tracheal mucin and lysozyme secretion. We used a sandwich enzyme-linked lectin assay (ELLA) to measure mucin-like glycoprotein secretion and a spectrophotometric method to measure lysozyme secretion from isolated ferret tracheal segments. We evaluated the secretory response to four secretagogues; prostaglandin F(2alpha) (PGF(2alpha)), adenosine triphosphate (ATP), methacholine (MCh), and human neutrophil elastase (HNE). Each agent stimulated mucin and lysozyme secretion. The relative potency was PGF(2alpha)< or =ATP

Propofol and methohexital have no significant effect on mucus secretion or clearance in the anesthetized dog.

OBJECTIVE: Anecdotal reports suggest that propofol (Diprivan) may stimulate mucus hypersecretion in patients without pulmonary disease. The purpose of this study was to evaluate the effect of methohexital or propofol anesthesia on the physical and transport properties of airway mucus in spontaneously breathing dogs. DESIGN: Randomized, controlled, crossover laboratory study. SETTING: University laboratory. SUBJECTS: Four healthy, purpose-bred female beagle dogs. INTERVENTIONS: Dogs were anesthetized with 5 mg/kg of propofol by intravenous bolus followed by a maintenance infusion at 0.4 mg x kg(-1) x min(-1) or 4 mg/kg of methohexital followed by an infusion at 0.3 mg x kg(-1) x min(-1). Premedication with 0.05 mg/kg of acepromazine was given, and either atropine (0.2 mg) or saline was given by intravenous bolus at the time of induction. Dogs were intubated but spontaneously breathing throughout the experiment. Tracheal secretions were collected after induction and again after 40 mins. MEASUREMENTS AND MAIN RESULTS: The volume of secretions collected on the endotracheal tube during the 1.5-hr experiment and on a bronchoscopy brush over 10 mins during the experiment was measured. Tracheal epithelial potential difference was measured bronchoscopically by saturated agar bridges, and tracheal mucus transport velocity was determined by timing particle transport. The dynamic viscoelasticity of collected mucus was assessed by microrheometry, and secretion mucociliary transportability was measured in vitro. There were no differences in any physical or transport properties of airway secretions that could be attributed to the anesthetic agent. Secretion volume was significantly lower (p < .05) and epithelial potential difference was significantly higher (p = .03) with atropine premedication. Despite this, there were no differences in tracheal mucus transport velocity, viscoelasticity, or secretion mucociliary transportability with either anesthetic agent or with atropine. CONCLUSIONS: This study suggests that neither methohexital nor propofol significantly affects mucus secretion or clearance in healthy dogs.

Respiratory-related quality of life: relation to pulmonary function, functional exercise capacity, and sputum biophysical properties.

One of the difficulties in assessing mucoactive therapy is selecting clinical outcome variables that reflect the impact of clearing airway secretions on quality of life (QOL). Petty and colleagues developed a questionnaire designed to evaluate the clinical impact of mucoactive therapy in patients with chronic bronchitis (CB). We evaluated this questionnaire in a multicenter study of a mucolytic medication used in patients with CB and hypothesized that spirometry, exercise capacity, and sputum clearability changes would correlate with QOL changes. This was a multicenter trial in 159 patients with stable CB (111 completed the 16-week study). Spirometry, plethysmography, the 6-minute walk test (6MWT), and Petty score as a measure of QOL were assessed at each visit. Sputum was collected at each visit. Cough transportability was measured in a cough machine, and mucociliary transportability was measured on the frog palate. Cohesivity was measured in a filancemeter, interfacial tension by de Noüy ring, and wettability by contact angle analysis. Within the entire data set of 694 evaluations, there was no correlation between pulmonary function and QOL. There was an inverse correlation with distance covered in a 6MWT (R(2) = 0.041, p < 0.0001). Sputum CTR was directly correlated with QOL (R(2) = 0.027, p < 0.0001). Change from baseline (mean of first three visits) was computed and compared the change in the mean of values at the 8- and 12-week visits (n = 108 sets of data pairs). This was analyzed as a percentage of change for continuous measurements, and as QOL is normative, we calculated the absolute change in QOL. There was no relation between QOL and 6MWT changes. There was an inverse relation between change in forced expiratory volume in 1 second and QOL (R(2) = 0.092, p = 0.0021) as well as between forced vital capacity and QOL (R(2) = 0.05, p = 0.024). There was a direct relation between CTR and QOL (R(2) = 0.039, p = 0.048). The relation between QOL and 6-minute walk distance was expected but weak. The consistent relation between CTR and QOL (suggesting that improved CTR of sputum is associated with decreased QOL) is difficult to explain. A change in forced expiratory volume in 1 second and forced vital capacity did correlate with a change in QOL. There is a need for a good QOL tool to evaluate mucus clearance devices or medications. The Petty questionnaire was designed specifically for this task, but the effect on sputum properties by current mucoactive agents may be too small to elicit a significant change in the Petty score.

Evaluating the efficacy of mucoactive aerosol therapy.

The aerosol route is attractive for the delivery of mucoactive medications. Mucoactive medications include mucolytics, which depolymerize polymers of mucin (classic mucolytics) or DNA/actin (peptide mucolytics), mucokinetic agents, which increase cough clearance, mucoregulatory medications, which decrease abnormal mucus secretion, and expectorants and ion channel modifiers. Despite the widespread use of these medications, there are few well conducted studies and thus few data clearly supporting (or failing to support) their use. This will change as our understanding of mucociliary physiology and pharmacology increases and as well designed and well powered clinical trials are conducted with appropriate outcome measurements. Effective mucoactive therapy should make a profound impact on the care of patients with chronic bronchitis, asthma, cystic fibrosis, and inflammatory airways disease, and will be essential for the effective delivery of gene therapy vectors and bioactive peptides to the airway epithelium.

Experimental macromolecular aerosol therapy.

These novel and experimental therapies have the potential of drastically altering our understanding of and approach to airway disease. We indeed live in interesting times.

Macrolide antibiotics as biological response modifiers.

Erythromycin was first isolated in the 1950s from a Philippine soil sample, and the derivatives of erythromycin A, called the macrolide antibiotics, have been used as effective antibacterial agents ever since. It has long been suspected that the 14-membered macrolides have immunomodulatory activity as demonstrated by their early use as adjunctive therapy for asthma and their astounding effectiveness for the therapy of diffuse panbronchiolitis. It is now clear, that the macrolides and their cousins, the 15-membered azalides, and perhaps the ketolides, have a broad range of biological response modifying effects on inflammation, tumor cells, airway secretions and host defenses. This review highlights some exciting new data, as well as controversies related to understanding the mechanism of action for these diverse effects.