Effect of Wearing a Face Mask on Hand-to-Face Contact by Children in a Simulated School Environment: The Back-to-School COVID-19 Simulation Randomized Clinical Trial.

Importance: Wearing a face mask in school can reduce SARS-CoV-2 transmission but it may also lead to increased hand-to-face contact, which in turn could increase infection risk through self-inoculation. Objective: To evaluate the effect of wearing a face mask on hand-to-face contact by children while at school. Design, Setting, and Participants: This prospective randomized clinical trial randomized students from junior kindergarten to grade 12 at 2 schools in Toronto, Ontario, Canada, during August 2020 in a 1:1 ratio to either a mask or control class during a 2-day school simulation. Classes were video recorded from 4 angles to accurately capture outcomes. Interventions: Participants in the mask arm were instructed to bring their own mask and wear it at all times. Students assigned to control classes were not required to mask at any time (grade 4 and lower) or in the classroom where physical distancing could be maintained (grade 5 and up). Main Outcomes and Measures: The primary outcome was the number of hand-to-face contacts per student per hour on day 2 of the simulation. Secondary outcomes included hand-to-mucosa contacts and hand-to-nonmucosa contacts. A mixed Poisson regression model was used to derive rate ratios (RRs), adjusted for age and sex with a random intercept for class with bootstrapped 95% CIs. Results: A total of 174 students underwent randomization and 171 students (mask group, 50.6% male; control group, 52.4% male) attended school on day 2. The rate of hand-to-face contacts did not differ significantly between the mask and the control groups (88.2 vs 88.7 events per student per hour; RR, 1.00; 95% CI, 0.78-1.28; P = >.99). When compared with the control group, the rate of hand-to-mucosa contacts was significantly lower in the mask group (RR, 0.12; 95% CI, 0.07-0.21), while the rate of hand-to-nonmucosa contacts was higher (RR, 1.40; 95% CI, 1.08-1.82). Conclusions and Relevance: In this clinical trial of simulated school attendance, hand-to-face contacts did not differ among students required to wear face masks vs students not required to wear face masks; however, hand-to-mucosa contracts were lower in the face mask group. This suggests that mask wearing is unlikely to increase infection risk through self-inoculation. Trial Registration: ClinicalTrials.gov Identifier: NCT04531254.

Rapid pulmonary delivery of inhaled tobramycin for Pseudomonas infection in cystic fibrosis: a pilot project.

BACKGROUND: Patients with cystic fibrosis spend as much 30 min a day inhaling tobramycin. Could a new rapid system deposit the equivalent amount of tobramycin faster? METHODS: Six healthy adult males inhaled 5 ml (300 mg) of tobramycin from a breath enhanced nebulizer and either 125 mg (n = 3) or 150 mg (n = 3) from a vibrating membrane system with a large or small aerosol mixing chamber respectively. A radiolabel was added to the solution and shown to "track" with the tobramycin. Imaging was done with a dual headed gamma camera. Because the radiolabel will be cleared by mucociliary action during administration, algorithms were developed to allow the comparison of a slower system to a faster one. RESULTS: Both formulations were well tolerated. The lung deposition was 16.6 +/- 3.2% (mean +/- SD) of the charge dose delivered in 10.9 +/- 1.0 min for the breath enhanced nebulizer versus 32.0 +/- 5.1% delivered in 2.5 +/- 0.4 min from the vibrating membrane system. The absolute pulmonary delivery of tobramycin was 49.9 +/- 9.6 versus 43.9 +/- 4.8 mg for the two systems respectively, differences that were statistically significant (pair t-test) but unlikely to be clinically significant. There was a similar deposition of tobramycin for the 125 and 150 mg dose. CONCLUSIONS: It is possible to deliver an equivalent amount of tobramycin in a shorter period of time with the new vibrating membrane system and a more concentrated formulation. These data will allow the design of a comparison in patients with CF.

The challenges of quantitative measurement of lung deposition using 99mTc-DTPA from delivery systems with very different delivery times.

In quantifying aerosol delivery, the drug is often mixed with a radiolabel such as (99m)Tc-DTPA whose deposition is used as a proxy for the drug. (99m)Tc-DTPA deposited in the lung is cleared by a combination of absorption into the pulmonary circulation and mucociliary clearance. If administration is not instantaneous, the image will not include that clearance during administration, a problem raised if comparing devices with different administration times. However, if rates of clearance are measured, it will be possible to "correct" the initial image for the clearance that occurred during administration and before counting. Five adult males inhaled a 5-mL solution containing (99m)Tc-DTPA from a breath enhanced jet nebulizer (LC Plus)over the course of 10 min and a 1.25-mL solution from a vibrating membrane device (eFlow), which was delivered in 2.5 min. Quality assurance was the radioactivity count balance (RCB) defined as the difference in the total radioactivity pre-nebulization less post, divided by pre, and expressed as a percentage. Attenuation calculations used a (57)Co flood source (Macey and Marshall). The "correction" for the clearance of (99m)Tc-DTPA was 0.91 +/- 0.04 (mean +/- SD) for the LC Plus) and 0.96 +/- 0.02 for the eFlow). RCB was -0.6 +/- 3.5% for the LC Plus and -4.7 +/- 6.4% for the eFlow, implying acceptable accuracy. For the LC Plus, lung deposition was 15.9(13.4, 18.4)% (mean and 95% CI) of the charge dose, and for the eFlow it was 32.0(29.0, 35.0)%. This technique gave an acceptable level of accuracy for quantitative planar imaging and allowed the comparison of delivery from devices with very different rates of delivery.

Calculating expected lung deposition of aerosolized administration of AAV vector in human clinical studies.

BACKGROUND: Cystic fibrosis is an autosomal recessive disease affecting approximately 1 in 2500 live births. Introducing the cDNA that codes for normal cystic fibrosis transmembrane conductance regulator (CFTR) to the small airways of the lung could result in restoring the CFTR function. A number of vectors for lung gene therapy have been tried and adeno-associated virus (AAV) vectors offer promise. The vector is delivered to the lung using a breath-actuated jet nebulizer. The purpose of this project was to determine the aerosolized AAV (tgAAVCF) particle size distribution (PSD) in order to calculate target doses for lung delivery. METHODS: A tgAAVCF solution was nebulized using the Pari LC Plus (n = 3), and the PSD was determined by coupling laser diffraction and inertial impaction (NGI) techniques. The NGI allowed for quantification of the tgAAVCF at each stage of impaction, ensuring that rAAV-CFTR vector is present and not empty particles. Applying the results to mathematical algorithms allowed for the calculation of expected pulmonary deposition. RESULTS: The mass median diameter (MMD) for the tgAAVCF was 2.78 +/- 0.43 microm. If the system works ideally and the patient only receives aerosol on inspiration, the patient would receive 47 +/- 0% of the initial dose placed in the nebulizer, with 72 +/- 0.73% of this being deposited beyond the vocal cords. CONCLUSIONS: This technology for categorizing the pulmonary delivery system for lung gene therapy vectors can be adapted for advanced aerosol delivery systems or other vectors.

Comparison of three valved holding chambers for the delivery of fluticasone propionate-HFA to an infant face model.

The purpose of this study was to compare three valved holding chambers (VHC) with facemasks attached. One VHC (AeroChamber Max[TM] with medium mask) was made with materials that dissipate surface electrostatic charge, and the others (OptiChamber Advantage and ProChamber[TM] with pediatric facemask) were made from non-conducting materials. The OptiChamber Advantage and ProChamber VHCs were each washed with an ionic detergent and drip dried before testing to minimize surface electrostatic charge. The AeroChamber Max VHCs were tested "out of the package" and also after wash, rinse, and drying. An infant face model incorporating an electrostatic filter in the oral cavity was connected to a breath simulator using a standard waveform for a small child. The fit of each VHC with facemask was demonstrated by agreement of inspiratory flow measurements between a pneumotachograph connected to the system with those set on the simulator. An HFA-fluticasone propionate metered dose inhaler (MDI; 125 microg/dose) was inserted into the VHC, two actuations were delivered, and the filters were subsequently assayed using high-pressure liquid chromatography (HPLC). Testing and sample assay order was randomized, and HPLC assays were undertaken blinded. Drug delivery efficiency expressed as a percentage of the total dose of fluticasone propionate (250 microg) for the AeroChamber Max VHC "out-of-the-package" was 22.0(0.7)% (mean [99% CI]) and 21.2(1.5)% when pre-washed/rinsed. Results for the pre-washed ProChamber and OptiChamber Advantage VHCs were 10.2(0.55)% and 8.8(1.9)%, respectively. The more efficient delivery of medication via VHCs made from electrostatic charge dissipative materials should be considered when choosing doses for small children.

Nebulized therapies for childhood pulmonary hypertension: an in vitro model.

OBJECTIVES: Sildenafil, tezosentan, and prostacyclin reduce pulmonary vascular pressures in pulmonary hypertension, but have potential to vasodilate the systemic circulation. Nebulized vasodilators allow targeted drug delivery, high local drug concentrations, less systemic hypotension, and better matching of the lung's ventilation and perfusion. We aimed to estimate pulmonary deposition of these drugs from commonly employed nebulizers using in vitro techniques and to create a mathematical model to predict inspired mass of aerosol. DESIGN: Lung deposition was estimated by characterization of drug output and particle size distribution (PSD) of nebulizers using helium-neon laser diffraction techniques. A mathematical model for each device was created to estimate pulmonary deposition using patients' breathing patterns and was verified with a mechanical-breathing model. RESULTS: Total output and PSD were similar for the Hudson Updraft II and Whisperjet nebulizers, consisting of half the nebulizer's charge, with (1/4) of particles < or = 5 microm, in the respirable fraction (RF). Drug output increased with inspiratory flow for the Pari LC Star. Differences were noted in device performance, depending on the drug tested. Estimated pulmonary deposition (mean, 95% CI) was 8.1 (7.2, 9.0)% of the initial drug charge for the Hudson Updraft II, 6.4 (5.8, 7.0)% for the Whisperjet, and 33.0 (28.3, 37.9)% for the Pari LC Star. A mechanical model was consistent with our mathematical model. CONCLUSIONS: All drugs could be nebulized, but expected pulmonary deposition varied depending on the nebulizer and drug.

How many infective viral particles are necessary for successful mass measles immunization by aerosol?

OBJECTIVES: This study characterized the performance of the "Classical Mexican Device", which immunized 4 million children against measles, demonstrating the efficacy of aerosol vaccination. METHODS: Using plaque-forming units to quantify virus, the particle size distribution (Next Generation Pharmaceutical Impactor) and rate of output coupled with age specific patterns of breathing allowed the calculation of expected pulmonary deposition. RESULTS: The estimated immunization dose for infants was 30 pfu's, for small children 50, and for older children and adolescents it was 130 and 225, respectively. CONCLUSIONS: These performance characteristics can be used to develop newer battery operable devices that are licensable.

Use of the next generation pharmaceutical impactor for particle size distribution measurements of live viral aerosol vaccines.

Aerosol administration of live measles vaccine virus has proven to be extremely efficacious in field trials using an industrial compressor coupled to a disposable nebulizer (IPI). To develop a new system for administration, it is necessary to characterize the operating characteristics of the old system. There are no standardized techniques for measuring particle size of live biological agents. This study evaluated the Next Generation Pharmaceutical Impactor's (NGI) ability to particle size wet aerosols in an effort to measure the particle size distribution of live measles vaccine from the IPI nebulizer. As a control albuterol was aerosolized using a Pari LC Star, since the soluble albuterol is evenly distributed throughout the droplets and laser diffraction measurements should agree with those from the NGI, as long as the NGI is cooled to prevent heat transfer to the aerosol. Albuterol was also used as a control for the IPI using quantitative ultraviolet spectrophotometry. There was close agreement in MMD (mean +/- 95% CI) for the LC Star, measured by laser diffraction (3.24 +/- 0.06 microm) and the NGI (2.93 +/- 0.22 microm) and the IPI (4.26 +/- 0.17 and 4.26 +/- 0.24 microm, respectively). For the measles vaccine assayed for plaque forming units, there were significant differences between the NGI MMD (6.14 +/- 0.39 microm) compared to laser diffraction (4.95 +/- 0.16 microm) indicating that the vaccine is not evenly distributed among the droplets of various sizes. This is likely clumping of the virus due to gelatin in the formulation. These data indicate that the NGI is capable of particle sizing live biological agents.

Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter.

BACKGROUND: Poor transduction of the ciliated airway epithelium and inefficient airway delivery of viral vectors are common difficulties encountered in lung gene therapy trials with large animals and humans. METHODS: We delivered a helper-dependent adenovirus vector, incorporating a human epithelial cell-specific expression cassette, to rabbit lung. An intratracheal device was used to aerosolize a moderate dose of virus (5 x 10(11) particles), mixed with the enhancing agent LPC (L-alpha-lysophosphatidylcholine), directly into the airways. Lung mechanics, body weight and temperature, transgene expression and histopathology were studied at day 5. RESULTS: Transgene expression was seen in the epithelium of large and small airways, from trachea to terminal bronchioles, with a strong tendency toward the right lung. All cell types of the surface epithelium were transduced. Extensive transduction of the epithelium (66% of cells in trachea) was obtained using virus formulated in isotonic 0.1% LPC, while virus formulated in 0.01% LPC transduced fewer cells (24% in trachea). A transient decrease in dynamic lung compliance was observed immediately following aerosol delivery. Fever and mild-to-moderate patchy pneumonia without edema were also observed. CONCLUSION: These data demonstrate a strategy for efficient and effective transduction of airway epithelium in a large animal.

Bronchial constriction and inhaled colistin in cystic fibrosis.

STUDY OBJECTIVE: Inhaled colistin is used for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients despite reports of chest tightness and bronchospasm. The main objective of the study was to assess whether bronchospasm occurred in pediatric CF patients with or without clinical evidence of airway hyperreactivity. DESIGN AND METHODS: A prospective placebo-controlled clinical trial with crossover design was devised using challenge tests with 75 mg colistin in 4 mL saline solution and a placebo solution of the same osmolarity using a breath-enhanced nebulizer for administration. Subjects were recruited as follows: high risk (HR) for bronchospasm due to a personal history of recurrent wheezing, a family history of asthma and/or atopy, or bronchial lability, as demonstrated in pulmonary function tests; or low risk (LR) without these characteristics. RESULTS: The mean FEV(1) (expressed as the mean [+/- SD] fall from baseline) of the HR group (n = 12) fell 12 +/- 9% after placebo was administered, and fell 17 +/- 10% after colistin was administered. For the LR group (n = 8), the mean FEV(1) fell 9 +/- 4% following placebo administration and 13 +/- 8% following colistin administration. There was a greater number of subjects in the HR group compared to the LR group, which had a mean fall in FEV(1) of >/= 15% (p < 0.01) after inhaling colistin. The differences between placebo and colistin therapy in the LR group were not significant. CONCLUSION: The results demonstrated that colistin can cause bronchospasm, particularly in those patients with coexisting CF and asthma.

Comparison of breath-enhanced to breath-actuated nebulizers for rate, consistency, and efficiency.

OBJECTIVES: To evaluate differences between three new-generation nebulizers-Pari LC Star (Pari Respiratory Equipment; Mississauga, ON, Canada), AeroEclipse (Trudell Medical International, London, ON, Canada), and Halolite (Medic-Aid Limited, West Sussex, UK)-in terms of rate and amount of expected deposition as well as the consistency of the doses delivered. METHODS: The in vitro performance characteristics were determined and then coupled to the respiratory pattern of seven patients with cystic fibrosis (age range, 4 to 18 years) in order to calculate expected deposition. The Pari LC Star and AeroEclipse were characterized while being driven by the Pari ProNeb Ultra compressor (Pari Respiratory Equipment) for home use, and by a 50-psi medical air hospital source. The Halolite has its own self-contained compressor. Algorithms for the rate of output for the inspiratory flow were developed for each device. Patient flow patterns were divided into 5-ms epochs, and the expected deposition for each epoch was calculated from the algorithms. Summed over a breath, this allowed the calculation of the estimated deposition for each patient's particular pattern of breathing. RESULTS: The rate of deposition was highest for the Pari LC Star and lowest for the Halolite. Rate of deposition was independent of respiratory pattern for the Pari LC Star and AeroEclipse, but proportional to respiratory rate for the Halolite. The differences between the Pari LC Star and AeroEclipse were less when driven by the 50-psi source. The AeroEclipse had the least amount of drug wastage. As designed, the Halolite delivered a predetermined amount of drug very accurately, whereas expected deposition when run to dryness of the other two devices had significant variations. CONCLUSIONS: To minimize treatment time, the Pari LC Star would be best. To minimize drug wastage, the AeroEclipse would be best. To accurately deliver a specific drug dose, the Halolite would be best.