Elaboration of Consensus Clinical Endpoints to Evaluate Antimicrobial Treatment Efficacy in Future Hospital-acquired/Ventilator-associated Bacterial Pneumonia Clinical Trials.

BACKGROUND: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. METHODS: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. RESULTS: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). CONCLUSIONS: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.

Why have trials of inhaled antibiotics for ventilator-associated infections failed?

PURPOSE OF REVIEW: Two recent large randomized placebo-controlled clinical trials of adjunctive inhaled therapy for the treatment of ventilator-associated pneumonia failed to show a mortality effect or more rapid resolution of pneumonia symptoms. Does the failure of these studies to reach their endpoints suggest the end of inhaled therapy? This review will explain why inhaled therapy may still have an important role in the treatment of ventilated patients. RECENT FINDINGS: The recent interest in inhaled antimicrobial therapy is driven by the global emergence of increasingly resistant bacteria to systemic therapy. As fast as the pharmaceutical pipeline delivers more powerful systemic antibiotics to the ICU, the bacteria evolve and develop resistance to them. The hypothesis of recent trials has been that adjunctive inhaled therapy will make systemic treatment more effective. This review summarizes the available data from the two recent multisite randomized Phase 2 and Phase 3 trials of inhaled antimicrobials as adjunctive therapy and suggests why they failed to achieve their endpoints. When given properly, these drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. The results of these trials and the data from many other smaller trials are compelling us to re-examine the indications for inhaled therapy as well as what clinical outcomes are most important. SUMMARY: This review summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated infections. Future investigations need to reevaluate the design and the outcomes that are most important in this era of multidrug-resistant bacteria.

Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis.

BACKGROUND: Nebulization of antiinfective agents is a common but unstandardized practice in critically ill patients. METHODS: A systematic review of 1,435 studies was performed in adults receiving invasive mechanical ventilation. Two different administration strategies (adjunctive and substitute) were considered clinically relevant. Inclusion was restricted to studies using jet, ultrasonic, and vibrating-mesh nebulizers. Studies involving children, colonized-but-not-infected adults, and cystic fibrosis patients were excluded. RESULTS: Five of the 11 studies included had a small sample size (fewer than 50 patients), and only 6 were randomized. Diversity of case-mix, dosage, and devices are sources of bias. Only a few patients had severe hypoxemia. Aminoglycosides and colistin were the most common antibiotics, being safe regarding nephrotoxicity and neurotoxicity, but increased respiratory complications in 9% (95% CI, 0.01 to 0.18; I = 52%), particularly when administered to hypoxemic patients. For tracheobronchitis, a significant decrease in emergence of resistance was evidenced (risk ratio, 0.18; 95% CI, 0.05 to 0.64; I = 0%). Similar findings were observed in pneumonia by susceptible pathogens, without improvement in mortality or ventilation duration. In pneumonia caused by resistant pathogens, higher clinical resolution (odds ratio, 1.96; 95% CI, 1.30 to 2.96; I = 0%) was evidenced. These findings were not consistently evidenced in the assessment of efficacy against pneumonia caused by susceptible pathogens. CONCLUSIONS: Performance of randomized trials evaluating the impact of nebulized antibiotics with more homogeneous populations, standardized drug delivery, predetermined clinical efficacy, and safety outcomes is urgently required. Infections by resistant pathogens might potentially have higher benefit from nebulized antiinfective agents. Nebulization, without concomitant systemic administration of the drug, may reduce nephrotoxicity but may also be associated with higher risk of respiratory complications.

Is There a Role for Inhaled Antibiotics in the Treatment of Ventilator-Associated Infections?

The increasing emergence of multidrug-resistant organisms creates a therapeutic challenge for physicians treating ventilator-associated respiratory infections. As the production of new systemic antibiotics lags far behind the emergence of worsening antibiotic resistance, intensivists are turning to inhaled antibiotics to use as adjunctive therapy. When given properly, these drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. This review summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated infections. Inhaled adjunctive therapy has been described in numerous small nonrandomized studies and in six recent randomized placebo-controlled trials. Inhaled therapy has also been used to treat ventilator-associated tracheobronchitis. These preliminary data suggest aerosolized delivery of antimicrobials may effectively treat resistant pathogens with high minimum inhibitory concentrations when used in time-limited protocols and delivered with devices known to deposit antibiotics in the area of infection. Large, multisite, clinical, randomized placebo-controlled studies are needed to confirm these data.

Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

Executive Summary: Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews.

Ventilator-associated infection: the role for inhaled antibiotics.

PURPOSE OF REVIEW: Despite multiple protocols for the prevention of ventilator-associated pneumonia (VAP), respiratory infections have not been eliminated in the ICU. The profound disruption in both airway integrity and mucociliary clearance caused by the endotracheal tube makes it unlikely there will ever be a zero rate of respiratory infection in critically ill ventilated patients or a 100% cure rate when infection is present. In fact, options for treatment are diminishing as bacteria resistant to most, or in some hospitals all, systemic antibiotics increase in prevalence from our liberal use of systemic antibiotics. Inhaled therapy with proper delivery will result in the high concentrations of antibiotics needed in the treatment of increasingly resistant organisms. RECENT FINDINGS: Data from many recent investigations have focused on inhaled antibiotics as: adjunctive therapy to systemic antibiotic for VAP, monotherapy for VAP, and as monotherapy for ventilator-associated tracheobronchitis. The clinical outcomes of these studies will be reviewed as well as their effect on multidrug-resistant organisms. SUMMARY: The present review will focus on the rationale for inhaled therapy, the current studies examining the delivery and clinical efficacy of inhaled antibiotics, and the potential role for this mode of delivery actually decreasing antibiotic resistance in the respiratory tract.

Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit.

RATIONALE: Multidrug-resistant organisms (MDRO) are the dominant airway pathogens in the intensive care unit (ICU) and present a major treatment challenge to intensivists. Aerosolized antibiotics (AA) result in airway concentrations of drug 100-fold greater than the minimal inhibitory concentration of most bacteria including MDRO. These levels, without systemic toxicity, may eradicate MDRO and reduce the pressure for selection of new resistant organisms. OBJECTIVES: To determine if AA effectively eradicate MDRO in the intubated patient without promoting new resistance. METHODS: In a double-blind placebo-controlled study, critically ill intubated patients were randomized if they exhibited signs of respiratory infection (purulent secretions and Clinical Pulmonary Infection Score ≥6). Using a well-characterized aerosol delivery system, AA or saline placebo was given for 14 days or until extubation. The responsible clinician determined administration of systemic antibiotics for ventilator-associated pneumonia and any other infection. MEASUREMENTS AND MAIN RESULTS: AA eradicated 26 of 27 organisms present at randomization compared with 2 of 23 organisms with placebo (P < 0.0001). AA eradicated the original resistant organism on culture and Gram stain at end of treatment in 14 out of 16 patients compared with 1 of 11 for placebo (P < 0.001). New drug resistance to AA was not seen. Compared with AA, resistance to systemic antibiotics significantly increased in placebo patients (P = 0.03). Compared with placebo, AA significantly reduced Clinical Pulmonary Infection Score (mean ± SEM, 9.3 ± 2.7 to 5.3 ± 2.6 vs. 8.0 ± 23 to 8.6 ± 2.10; P = 0.0008). CONCLUSIONS: In chronically intubated critically ill patients, AA successfully eradicated existing MDRO organisms and reduced the pressure from systemic agents for new respiratory resistance. Clinical trial registered with www.clinicaltrials.gov (NCT 01878643).

The Unfulfilled Promise of Inhaled Therapy in Ventilator-Associated Infections: Where Do We Go from Here?

Respiratory infection is common in intubated/tracheotomized patients and systemic antibiotic therapy is often unrewarding. In 1967, the difficulty in treating Gram-negative respiratory infections led to the use of inhaled gentamicin, targeting therapy directly to the lungs. Fifty-three years later, the effects of topical therapy in the intubated patient remain undefined. Clinical failures with intravenous antibiotics persist and instrumented patients are now infected by many more multidrug-resistant Gram-negative species as well as methicillin-resistant Staphylococcus aureus. Multiple systematic reviews and meta-analyses suggest that there may be a role for inhaled delivery but "more research is needed." Yet there is still no Food and Drug Administration (FDA) approved inhaled antibiotic for the treatment of ventilator-associated infection, the hallmark of which is the foreign body in the upper airway. Current pulmonary and infectious disease guidelines suggest using aerosols only in the setting of Gram-negative infections that are resistant to all systemic antibiotics or not to use them at all. Recently two seemingly well-designed large randomized placebo-controlled Phase 2 and Phase 3 clinical trials of adjunctive inhaled therapy for the treatment of ventilator-associated pneumonia failed to show more rapid resolution of pneumonia symptoms or effect on mortality. Despite evolving technology of delivery devices and more detailed understanding of the factors affecting delivery, treatment effects were no better than placebo. What is wrong with our approach to ventilator- associated infection? Is there a message from the large meta-analyses and these two large recent multisite trials? This review will suggest why current therapies are unpredictable and have not fulfilled the promise of better outcomes. Data suggest that future studies of inhaled therapy, in the milieu of worsening bacterial resistance, require new approaches with completely different indications and endpoints to determine whether inhaled therapy indeed has an important role in the treatment of ventilated patients.

Ventilator-associated infection.

PURPOSE OF REVIEW: Ventilator-associated pneumonia (VAP) is the most serious and controversial of the infections of the critically ill patient. The accuracy of standard methods of diagnosis remains under constant scrutiny, and at the same time there is increasing debate about whether it is a preventable disease. This review focuses on the pathophysiology of respiratory tract infection in the ventilated patient, and how the latest advances have grown from our current understanding of its pathogenesis. RECENT FINDINGS: Data from many recent investigations have focused on the role of proximal airway infection, ventilator-associated tracheobronchitis (VAT), in respiratory tract infection. The goals of recent trials include reducing the morbidity associated with the progression of airway colonization to VAT or with the progression of VAT to VAP. Continuous subglottic secretion suctioning, innovative types of endotracheal tubes and targeted therapy for VAT in recent investigations have shown promise in improving clinical outcomes in the critically ill patient. However, even with diligent attention to all the modifiable risk factors for respiratory infection, complete elimination of VAT and VAP remains unlikely. As long as a patient requires an endotracheal tube that disturbs airway integrity, host defenses will be impaired, and resistant virulent organisms that result from our liberal use of systemic antibiotics will continue to challenge critical care specialists. SUMMARY: This review will focus on: the current understanding of the pathogenesis of VAT and VAP, modifiable risk factors and new approaches to treatment, and bacterial resistance challenges.

Aerosolized antibiotics in critically ill ventilated patients.

PURPOSE OF REVIEW: This review will summarize recent clinical data examining the efficacy of aerosolized antimicrobial therapy in treating respiratory tract infections in mechanically ventilated patients in the ICU. RECENT FINDINGS: Aerosolized antibiotics provide high levels of drug in the lung and reduce the systemic toxicity associated with intravenous antibiotics. First introduced in the 1970s as a form of prophylaxis for ventilator-associated pneumonia (VAP), now, more than 30 years later, there is a resurgence of interest in using this mode of delivery as primary or adjunctive treatment for ventilator-associated tracheobronchitis (VAT) or VAP. Increasingly resistant organisms are colonizing and infecting critically ill patients, and direct delivery of antibiotic to the lung is being re-evaluated as a means to treat these highly resistant organisms that may not respond to systemic therapy. There are new data emerging that suggest these agents may effectively treat these pathogens when used in targeted, time limited protocols. SUMMARY: Aerosolized antibiotic therapy may provide an efficacious means of treating respiratory tract infection when targeted at mechanically ventilated patients with proximal airway infection, VAT (with or without VAP) and with highly resistant organisms.

Humidification and secretion volume in mechanically ventilated patients.

OBJECTIVE: To determine potential effects of humidification on the volume of airway secretions in mechanically ventilated patients. METHODS: Water vapor delivery from devices providing non-heated-wire humidification, heated-wire humidification, and heat and moisture exchanger (HME) were quantified on the bench. Then, patients requiring 24-hour mechanical ventilation were exposed sequentially to each of these humidification devices, and secretions were removed and measured by suctioning every hour during the last 4 hours of the 24-hour study period. RESULTS: In vitro water vapor delivery was greater using non-heated-wire humidification, compared to heated-wire humidification and HME. In vivo, a total of 9 patients were studied. Secretion volume following humidification by non-heated-wire humidification was significantly greater than for heated-wire humidification and HME (P=.004). CONCLUSIONS: The volume of secretions appeared to be linked to humidification, as greater water vapor delivery measured in vitro was associated with greater secretion volume in vivo.

Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit.

CONTEXT: In critically ill intubated patients, signs of respiratory infection often persist despite treatment with potent systemic antibiotics. OBJECTIVE: The purpose of this study was to determine whether aerosolized antibiotics, which achieve high drug concentrations in the target organ, would more effectively treat respiratory infection and decrease the need for systemic antibiotics. DESIGN: Double-blind, randomized, placebo-controlled study performed from 2003 through 2004. SETTING: The medical and surgical intensive care units of a university hospital. PATIENTS: Critically ill intubated patients were randomized if: 1) > or = 18 yrs of age, intubated for a minimum of 3 days, and expected to survive at least 14 days; and 2) had ventilator-associated tracheobronchitis defined as the production of purulent secretions (> or = 2 mL during 4 hrs) with organism(s) on Gram stain. Of 104 patients monitored, 43 consented for treatment and completed the study. No patients were withdrawn from the study for adverse events. INTERVENTION: Aerosol antibiotic (AA) or aerosol saline placebo was given for 14 days or until extubation. The responsible clinician determined the administration of systemic antibiotics (SA). Patients were followed for 28 days. MAIN OUTCOME MEASURES: Primary: Centers for Disease Control National Nosocomial Infection Survey diagnostic criteria for ventilator-associated pneumonia (VAP) and clinical pulmonary infection score. Secondary: white blood cell count, SA use, acquired antibiotic resistance, and weaning from mechanical ventilation. RESULTS: Most patients had VAP at randomization. With treatment, the AA group had reduced signs of respiratory infection: reduced Centers for Disease Control National Nosocomial Infection Survey VAP (14/19; 73.6%) to (5/14; 35.7%) vs. placebo (18/24; 75%) to (11/14; 78.6%), reduction in clinical pulmonary infection score, lower white blood cell count at day 14, reduced bacterial resistance, reduced use of SA, and increased weaning (all p < or = .05). CONCLUSIONS: In critically ill patients with ventilator-associated tracheobronchitis, AA decrease VAP and other signs and symptoms of respiratory infection, facilitate weaning, and reduce bacterial resistance and use of systemic antibiotics.

Inhaled Antibiotics for Ventilator-Associated Infections.

Multidrug-resistant organisms are creating a challenge for physicians treating the critically ill. As new antibiotics lag behind the emergence of worsening resistance, intensivists in countries with high rates of extensively drug-resistant bacteria are turning to inhaled antibiotics as adjunctive therapy. These drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. This article summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated pneumonia and ventilator-associated tracheobronchitis. Preliminary data suggest aerosolized antimicrobials may effectively treat resistant pathogens with high minimum inhibitory concentrations.

Assessing the effects of racemic and single-enantiomer albuterol on airway secretions in long-term intubated patients.

OBJECTIVE: In vitro data suggest that the S-enantiomer of albuterol can induce mucociliary dysfunction. This clinical study assesses the clinical significance of standard doses of the S-enantiomer on airway secretions in long-term intubated patients by comparing a racemic formulation of albuterol, an R-enantiomer formulation, and normal saline solution. DESIGN: A placebo-controlled crossover study. PATIENTS: Fourteen stable intubated patients with a median duration of intubation of 21 months and a median age of 72 years. SETTING: Long-term ventilator unit in skilled nursing facility. INTERVENTIONS: Following a 2-week washout period during which regularly scheduled beta2-agonists were discontinued, tracheal aspirates were collected for 4 h/d for a 5-day period to establish baseline values, and the patients were then randomized in crossover manner to each of three nebulized treatments: normal saline solution, racemic albuterol, and R-albuterol. Each treatment was administered three times daily for 5 days, followed by a 2-day washout. MEASUREMENTS: Tracheal aspirates were analyzed for volume, sodium, chloride, bicarbonate, interleukin (IL)-8, IL-1beta, soluble intercellular adhesion molecule, and tumor necrosis factor-alpha. RESULTS: There were no consistent significant differences among the three treatment periods either in terms of volume of secretions or in the concentrations of the electrolytes or the inflammatory indexes. However, all three treatments, including saline solution, were associated with increased secretion volume after the first dose, but this effect was not apparent on subsequent doses. CONCLUSION: There were no significant differences between racemic albuterol and R-albuterol observed in this study for any of the parameters studied, suggesting that the S-enantiomer does not adversely affect airway secretions at recommended doses. In addition, the routine administration of nebulized beta(2)-sympathomimetic agonists to stable patients undergoing prolonged intubation, for the sole purpose of changing the volume and composition of secretions of airway secretions, is not supported by the results of this study.

Intratracheal Administration of Antimicrobial Agents in Mechanically Ventilated Adults: An International Survey on Delivery Practices and Safety.

BACKGROUND: Intratracheal antibiotic administration is increasingly used for treating respiratory infections. Limited information is available on delivery devices, techniques, and safety. METHODS: An online survey on intratracheal administration of anti-infective agents in mechanically ventilated adults was answered by health-care workers from 192 ICUs to assess the most commonly used devices, current delivery practices, and safety issues. We investigated whether ICU usage experience (≥3 y) impacted its performance. RESULTS: Intratracheal antibiotic administration was a current practice in 87 ICUs (45.3%), with 40 (46%) having experience with the technique (≥3 y). Sixty-six (78.6%) of 84 health-care workers reported avoiding intratracheal antibiotic administration due to an absence of evidence-based guidelines (78.6%). Jet nebulizers were the most commonly used devices for delivery, in 24 less experienced ICUs (27.6%) and in 18 (20.7%) experienced ICUs. Direct tracheal instillation (6; 6.9%) was still considered for drug prescription in 12 ICUs (6.9%). More experience resulted in neither greater adherence to measures improving the drug's delivery efficiency (93 measures in the experienced group; 27.9%) nor a greater adoption of measures to increase safety. Indeed, the expiratory filter was changed after each nebulization in only 2 experienced ICUs (6.9%), whereas 15 (51.7%) changed it daily instead. CONCLUSIONS: Intratracheal antibiotic administration is a common therapeutic modality in ICUs, but inadequate practices were widely encountered, independent of the level of experience with the technique. This suggests a need to develop standardization to reduce variability and improve safety and efficacy.

Stable patients receiving prolonged mechanical ventilation have a high alveolar burden of bacteria.

INTRODUCTION: In patients receiving prolonged mechanical ventilation (PMV), quantitative bronchoscopic culture has not been validated for the diagnosis of ventilator-associated pneumonia (VAP). OBJECTIVE: To measure the alveolar burden of bacteria in patients receiving PMV. SETTING: Respiratory care units of a university hospital and a long-term care facility. PATIENTS: Fourteen patients requiring PMV without clinical evidence of pneumonia. MEASUREMENTS: Quantitative culture of BAL from the right middle lobe and lingula. RESULTS: In 29 of 32 lobes, there was growth of at least one organism at > 10(4) cfu/mL. Most lobes had polymicrobial growth. CONCLUSIONS: Stable patients receiving PMV without clinical pneumonia have a high alveolar burden of bacteria. The bacterial burden in most patients exceeds the commonly accepted threshold for diagnosing VAP. The utility of quantitative bronchoscopic culture in the diagnosis of VAP in this patient population requires further study.

Antiprotease function of airway secretions in purulent tracheobronchitis.

STUDY OBJECTIVES: Unopposed activity of the serine protease, human leukocyte elastase (HLE), is detectable in the airways of patients with purulent tracheobronchitis. The aim of this study was to assess the compartmentalization of HLE activity in the liquid sol phase and the solid gel phase of airway secretions. DESIGN: Seventy samples of tracheobrochial aspirates were obtained from patients who had hypersecretion and were receiving mechanical ventilation. METHODS: Samples were separated into sol and gel ("mucous pellet") phases, and HLE activity was measured using chromogenic substrate degradation. HLE was eluted from the mucous pellet using hypertonic saline solution, 1 mol/L, or bovine pancreatic deoxyribonuclease (DNase), 16 micromol/L. RESULTS: HLE activity partitioned between the sol and gel phases of the secretions, with most of the activity present in the gel phase (32:1 ratio of gel to sol HLE activity). The activity of HLE was 95% inhibited when bound to the gel phase, but activity appeared to be largely restored after elution from the gel phase. The gel phase was capable of binding additional exogenous HLE, and its binding capacity for exogenous HLE was not saturated by concentrations that exceeded the highest clinically relevant HLE levels (1.1 mg/mL). Hypertonic saline solution and DNase I efficiently liberated endogenous and exogenous gel phase-bound HLE activity, suggesting that electrostatic bonds and DNA, respectively, play important roles in binding HLE to the gel phase. CONCLUSIONS: The solid phase of airway secretions is a more important modulator of elastase-antielastase balance than has been previously recognized.