Evaluation of clinically and physiologically atypical asthma: If it doesn't wheeze it may still be asthma.

OBJECTIVE: Children with asthma-like symptoms may not clinically wheeze. The objectives of this study were to evaluate if children, without physician-documented wheeze, wheeze during bronchial-challenge-testing (BCT), and if measurements of O2Sat and respiratory rate during BCT improve the BCT sensitivity? METHODS: Seven hundred and twenty-four children, who were referred for suspicion of asthma, performed a BCT. Positive BCT was determined by the provocation concentration (PC) which resulted in a 20% decrease in FEV1 (PC20), (in those who were able to perform spirometry, group B), or (in those unable to perform spirometry, group A) a 50% increase in respiratory rate (PCRR), or a 5% decrease in oxygen-saturation (PCO2-Sat) or appearance of wheezing (PCwheeze). RESULTS: Five hundred and seven BCTs were positive: group A n = 89 age, median (IQR), 3 (2.5-3.7) years (17.6%), were unable to perform spirometry, and group B n = 418 age 10.7 (6.8-15.6) years (82.4%), were able to perform spirometry. Children, without physician-documented wheeze in the total population (groups A plus B), were more likely (65.5%) to have a positive BCT without wheeze compared with those with physician-documented wheeze (41.0%, P < 0.001). In group A, adding PCRR and PCO2-Sat increased BCT sensitivity by 23.6%. CONCLUSIONS: Many children in both groups did not wheeze despite reaching BCT endpoints. Children without physician-documented wheeze tended not to wheeze at BCT. This may result in clinical under-diagnosis of asthma if depending on the presence of wheeze. In young children, adding PCRR and PCO2-Sat substantially increases BCT sensitivity and may improve asthma diagnosis.

Deposition of small particles in the developing lung.

Infancy is a time of marked and rapid changes in respiratory tract development. Infants (0-1 year of age) and young children (1- 3 years of age) are a unique subpopulation with regard to therapeutic aerosols. Anatomical, physiological and emotional factors, peculiar to these age groups, present significant challenges for aerosol delivery to the respiratory tract. Most studies with inhaled corticosteroids (ICS) have administered aerosols with relatively large particles, frequently > 3 µm in mass median aerodynamic diameter (MMAD). These drugs were designed for use in adults and older children and were administered with masks which were frequently rejected by children under age 3-4 years. We review the reasons that large-particle aerosols are likely to be less effective in infants and young children. We suggest that the benefit of inhaled medications in this age group requires further evaluation to determine if better therapeutic outcomes might be achieved using smaller particles and more patient-friendly delivery systems.

Factors that affect the efficacy of inhaled corticosteroids for infants and young children.

Infants (0-1 years of age) and young children (1-3 years of age) are a unique subpopulation with regard to inhaled therapies. There are various anatomic, physiological, and emotional factors peculiar to this age group that present significant difficulties and challenges for aerosol delivery. Most studies of therapeutic aerosols that have been performed with patients of this age group, particularly recent studies with inhaled corticosteroids (ICSs), administered aerosols with relatively large particles (ie, >3 microm in mass median aerodynamic diameter). These drugs were designed for use in adults and older children and were administered with masks, which are frequently rejected by patients. Based on these studies, it was recently suggested that ICSs might not be as therapeutically effective in infants and young children as in adults. We review the reasons that large-particle corticosteroid aerosols are not likely to be effective in infants and young children. This patient population differs from adults in airway anatomy and physiology, as well as in behavior and adherence to therapy. We suggest that the benefit of ICSs in this age group requires further evaluation to determine whether better therapeutic outcomes might be achieved with smaller particles.

Asthma and COVID-19: In Defense of Evidence-Based SABA.

There have recently been major objections to the use of short-acting beta-agonist (SABA) in episodic acute asthma culminating in a call for replacing SABA with combination of inhaled corticosteroids and long-acting beta-agonists despite little evidence supporting this point of view. It is regrettable to note that this attack on SABA occurs in the midst of an unprecedented demand for, and shortage of, SABA inhalers during the current COVID-19 pandemic, and the worldwide efforts to increase SABA supplies. In this commentary, we defend the well-established role of SABA and argue that the call for the phase out of SABA is inappropriate, since it is not solidly evidence based.

Dead space variability of face masks for valved holding chambers.

BACKGROUND: Valved holding chambers with masks are commonly used to deliver inhaled medications to young children with asthma. Optimal mask properties such as their dead space volume have received little attention. The smaller the mask the more likely it is that a greater proportion of the dose in the VHC will be inhaled with each breath, thus speeding VHC emptying and improving overall aerosol delivery efficiency and dose. Masks may have different DSV and thus different performance. OBJECTIVES: To compare both physical dead space and functional dead space of different face masks under various applied pressures. METHODS: The DSV of three commonly used face masks of VHCs was measured by water displacement both under various pressures (to simulate real-life application, dynamic DSV) and under no pressure (static DSV). RESULTS: There was a great variability of both static and dynamic dead space among various face mask for VHCs, which is probably related to their flexibility. CONCLUSIONS: Different masks have different DSV characteristics. This variability should be taken into account when comparing the clinical efficacy of various VHCs.

[Aerosol therapy in infants].

Infants are a unique subpopulation with regard to aerosol therapy. There are various anatomical, physiological and emotional factors peculiar to infants that present significant difficulties and challenges for aerosol delivery. Most studies about the factors determining lung deposition of therapeutic aerosols are based on data from adults or older children which cannot simply be extrapolated directly to infants. The present review describes why infants/toddlers are very different with respect to two major issues--namely their anatomy/physiology and their behaviour. We suggest possible solutions and future research directions aimed at improving clinical outcomes in this age group.

The effect of biphasic inhalation profiles on the deposition and clearance of coarse (6.5 microm) bolus aerosols.

The influence of particle size upon deposition in the human airways is well understood. Pharmaceutical aerosol formulators strive to generate fine aerosols with the potential to penetrate into the deep lung. However, flow rate can also have a major influence on deposition, particularly with coarse aerosols. This study investigated the use of biphasic flow profiles with low flow in the proximal conducting airway as a means of effecting efficient delivery of a coarse aerosol. The study shows that 6.5-microm MMAD aerosol droplets can be deposited in the lung with high efficiency. The delivery technique achieved greater than 70% of the inhaled dose deposited in the whole lung and greater than 50% deposited in the lung periphery. Furthermore, the biphasic flow profiles used, with initial low flow segments of between 300 mL and 900 mL inhaled volume at 8 L/min, are practical flow regimens that should be acceptable to patients and that can be applied to single-breath dry powder inhalers. Twenty-four-hour clearance and Penetration Index measurements were used as a marker for peripheral deposition, and the data show a clear correlation between Penetration Index and 24-h retention.

Measurement of peak inspiratory flow with in-check dial device to simulate low-resistance (Diskus) and high-resistance (Turbohaler) dry powder inhalers in children with asthma.

Drug delivery and lung deposition from a dry powder inhaler (DPI) are dependent on the peak inspiratory flow (PIF) through the DPI. Therefore, when prescribing a DPI, it is important to know whether a child is able to generate sufficient PIF through a particular device. Using a PIF meter (In-Check Dial) that mimics the internal resistance of DPIs, two commonly used devices (high-resistance Turbohaler (TH) and low-resistance Diskus (DK)) determined the PIF generated by asthmatic children through each of them. Two hundred and twenty-three children were studied, of whom 100 (mean age, 9.1 +/- 3.0 years; range, 3-15 years) were experienced with the use of a DPI (>1 month of regular DPI use), and 123 (mean, 5.5 +/- 1.9 years; range, 3-9 years) were inexperienced (no previous DPI use). All of the experienced patients generated more than 30 l/min through both devices, but a PIF of 60 l/min through the TH was obtained by only 68 (68%) of them. The age above which a minimal PIF of 30 l/min (for DK) or 60 l/min (for TH) could be achieved in new DPI users (inexperienced) was 4 years and 9 years, respectively. Even among experienced patients, many young children may not generate optimal PIFs through high-resistance DPIs. When DPI treatment is considered for young children, some devices may be successfully introduced at a younger age. It may thus be important to measure PIF in children who use a DPI or in whom DPI use is contemplated. This evaluation can be easily undertaken in the clinic with the In-Check Dial device.

More Realistic Face Model Surface Improves Relevance of Pediatric In-Vitro Aerosol Studies.

BACKGROUND: Various hard face models are commonly used to evaluate the efficiency of aerosol face masks. Softer more realistic "face" surface materials, like skin, deform upon mask application and should provide more relevant in-vitro tests. Studies that simultaneously take into consideration many of the factors characteristic of the in vivo face are lacking. These include airways, various application forces, comparison of various devices, comparison with a hard-surface model and use of a more representative model face based on large numbers of actual faces. AIM: To compare mask to "face" seal and aerosol delivery of two pediatric masks using a soft vs. a hard, appropriately representative, pediatric face model under various applied forces. METHODS: Two identical face models and upper airways replicas were constructed, the only difference being the suppleness and compressibility of the surface layer of the "face." Integrity of the seal and aerosol delivery of two different masks [AeroChamber (AC) and SootherMask (SM)] were compared using a breath simulator, filter collection and realistic applied forces. RESULTS: The soft "face" significantly increased the delivery efficiency and the sealing characteristics of both masks. Aerosol delivery with the soft "face" was significantly greater for the SM compared to the AC (p< 0.01). No statistically significant difference between the two masks was observed with the hard "face." CONCLUSIONS: The material and pliability of the model "face" surface has a significant influence on both the seal and delivery efficiency of face masks. This finding should be taken into account during in-vitro aerosol studies.

Computerized Dead-Space Volume Measurement of Face Masks Applied to Simulated Faces.

BACKGROUND: The dead-space volume (VD) of face masks for metered-dose inhaler treatments is particularly important in infants and young children with asthma, who have relatively low tidal volumes. Data about VD have been traditionally obtained from water displacement measurements, in which masks are held against a flat surface. Because, in real life, masks are placed against the face, VD is likely to differ considerably between masks depending upon their contour and fit. The aim of this study was to develop an accurate and reliable way to measure VD electronically and to apply this technique by comparing the electronic VD of commonly available face masks. METHODS: Average digital faces were obtained from 3-dimensional images of 270 infants and children. Commonly used face masks (small and medium) from various manufacturers (Monaghan Medical, Pari Respiratory Equipment, Philips Respironics, and InspiRx) were scanned and digitized by means of computed tomography. Each mask was electronically applied to its respective digital face, and the VD enclosed (mL) was computerized and precisely measured. RESULTS: VD varied between 22.6 mL (SootherMask, InspiRx) and 43.1 mL (Vortex, Pari) for small masks and between 41.7 mL (SootherMask) and 71.5 mL (AeroChamber, Monaghan Medical) for medium masks. These values were significantly lower and less variable than measurements obtained by water displacement. CONCLUSIONS: Computerized techniques provide an innovative and relatively simple way of accurately measuring the VD of face masks applied to digital faces. As determined by computerized measurement using average-size virtual faces, the InspiRx masks had a significantly smaller VD for both small and medium masks compared with the other masks. This is of considerable importance with respect to aerosol dose and delivery time, particularly in young children. (ClinicalTrials.gov registration NCT01274299.).

Nasal versus oral aerosol delivery to the "lungs" in infants and toddlers.

OBJECTIVES: The oral route has been considered superior to the nasal route for aerosol delivery to the lower respiratory tract (LRT) in adults and children. However, there are no data comparing aerosol delivery via the oral and nasal routes in infants. The aim of this study was to compare nasal and oral delivery of aerosol in anatomically correct replicas of infants' faces containing both nasal and oral upper airways. METHODS: Three CT-derived upper respiratory tract ("URT") replicas representing infants/toddlers aged 5, 14 and 20 months were studied and aerosol delivery to the "lower respiratory tract" (LRT) by either the oral or nasal route for each of the replicas was measured at the "tracheal" opening. A radio-labeled (99mDTPA) normal saline solution aerosol was generated by a soft-mist inhaler (SMIRespimat® Boehringer Ingelheim, Germany) and aerosol was delivered via a valved holding chamber (Respichamber® TMI, London, Canada) and an air-tight mask (Unomedical, Inc., McAllen, TX). A breath simulator was connected to the replicas and an absolute filter at the "tracheal" opening captured the aerosol representing "LRT" dose. Age-appropriate mask dimensions and breathing patterns were employed for each of the airway replicas. Two different tidal volumes (Vt ) were used for comparing the nasal versus oral routes. RESULTS: Nasal delivery to the LRT exceeded that of oral delivery in the 5- and 14-month models and was equivalent in the 20-month model. Differences between nasal and oral delivery diminished with "age"/size. Similar findings were observed with lower and higher tidal volumes (Vt ). CONCLUSION: Nasal breathing for aerosol delivery to the "LRT" is similar to, or more efficient than, mouth breathing in infant/toddler models, contrary to what is observed in older children and adults. Pediatr Pulmonol. 2015; 50:276-283. © 2014 Wiley Periodicals, Inc.

Beta-agonist aerosol distribution in respiratory syncytial virus bronchiolitis in infants.

UNLABELLED: Bronchodilator aerosols are frequently administered to infants with bronchiolitis but with little success. The efficacy of aerosol treatments depends mainly on adequate targeting of the aerosol particles to the inflamed airways. This study evaluated the lower respiratory tract distribution characteristics of nebulized bronchodilators in infants with acute bronchiolitis. METHODS: Twelve infants (mean age +/- SD, 8 mo +/- 4 mo) who were admitted for acute respiratory syncytial virus bronchiolitis were treated with (99m)Tc-albuterol aerosol. Gamma-scintigraphy was used to assess total body and lung deposition as well as pulmonary distribution of the medication. RESULTS: Of the total 6-min nebulized dose (i.e., drug aerosol dose leaving the nebulizer [not the nebulizer charge]), 1.5% +/- 0.7% reached the right lung, with only approximately one third of that (0.6%) penetrating to the peripheral lung zone. There was 7.8% +/- 4.9% deposition in the upper respiratory and gastrointestinal tracts and 10%-12% remained on the face. No correlation was found between any of the deposition indices and the clinical response data or any of the demographic parameters (e.g., height, weight, body surface area, or clinical score). CONCLUSION: Poor total aerosol deposition in infants may be related as much to their small conducting airways as to the disease state. There is considerable room for improvement in aerosol delivery in this age group, with greater emphasis on targeting narrowed peripheral airways with superfine aerosols.