Bronchial asthma with normal forced expiratory volume in 1 second (FEV1) compared with low FEV1.

Background: Cough variant asthma (CVA) is characterized by cough as a sole symptom and normal pulmonary function. However, it is unclear whether CVA really common among asthmatic patients with normal forced expiratory volume in 1 second (FEV1). The aim of this study was to evaluate the incidence of cough alone symptom among the subjects with normal FEV1 and to evaluate their differences from ordinary asthmatic subjects. Methods: We defined normal FEV1 as ≥90% predicted based on the article of Kotti GH. Of the patients with normal FEV1, we chose subjects without wheeze, and the duration of cough was not to ask, since the symptoms often occurred with acute exacerbation and timing of visiting a doctor depended on each patient's perception. Test for airway hyperresponsiveness was not performed in this study. Visual analogue scale (VAS) scores for cough and dyspnea, FEV1, and fractional exhaled nitric oxide (FeNO) responsiveness to inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) treatment were compared in patients with normal FEV1 and with low FEV1 <90%. Correlations of changes in symptoms with changes of FEV1, FeNO, peripheral eosinophil count, and serum immunoglobulin E (IgE) at single time point were also examined in each group and in overall patients. Results: The participants were 329 physician-diagnosed treatment-naive patients with asthma who were divided into 187 in normal FEV1 and 142 in low FEV1 groups. Cough without dyspnea was present in 16 patients (8.6%) in the normal FEV1 group, suggesting candidates for CVA in this analysis were quite few. Improvement in symptoms after treatment was similar between both groups. But VAS scores of dyspnea were still higher in the low FEV1 group. The degree of improvement in FEV1 after ICS/LABA treatment was less in the normal FEV1 group than in the low FEV1 group, but was still evident. Peripheral eosinophil count, serum IgE, and FeNO values before treatment were lower in the normal FEV1 group. In overall patients, improvements of symptoms after treatment were significantly correlated with FEV1 changes. Improvement of dyspnea was also significantly related to peripheral eosinophil count and change of FeNO, whereas improvement of cough was not related to these T helper 2 (Th2) response markers. Conclusions: Candidates for CVA among the patients with asthma with predicted FEV1 ≥90% were few. Participants with normal FEV1 respond well to ICS/LABA treatment for improvement of symptom. The change of FEV1 after treatment, and the pre-treatment blood eosinophil count, serum IgE, and FeNO were lower in normal FEV1 cases than in low FEV1 cases. These observations suggest asthmatic patients with normal FEV1, including candidates for CVA having just common mild asthma. In overall participants, symptoms of cough and dyspnea were similar, but were not identical in relation to the Th2 background.

Proposal of selective wedge instillation of pulmonary surfactant for COVID-19 pneumonia based on computational fluid dynamics simulation.

BACKGROUND: The most important target cell of SARS-CoV-2 is Type II pneumocyte which produces and secretes pulmonary surfactant (PS) that prevents alveolar collapse. PS instillation therapy is dramatically effective for infant respiratory distress syndrome but has been clinically ineffective for ARDS. Nowadays, ARDS is regarded as non-cardiogenic pulmonary edema with vascular hyper-permeability regardless of direct relation to PS dysfunction. However, there is a possibility that this ineffectiveness of PS instillation for ARDS is caused by insufficient delivery. Then, we performed PS instillation simulation with realistic human airway models by the use of computational fluid dynamics, and investigated how instilled PS would move in the liquid layer covering the airway wall and reach to alveolar regions. METHODS: Two types of 3D human airway models were prepared: one was from the trachea to the lobular bronchi and the other was from a subsegmental bronchus to respiratory bronchioles. The thickness of the liquid layer covering the airway was assigned as 14 % of the inner radius of the airway segment. The liquid layer was assumed to be replaced by an instilled PS. The flow rate of the instilled PS was assigned a constant value, which was determined by the total amount and instillation time in clinical use. The PS concentration of the liquid layer during instillation was computed by solving the advective-diffusion equation. RESULTS: The driving pressure from the trachea to respiratory bronchioles was calculated at 317 cmH2O, which is about 20 times of a standard value in conventional PS instillation method where the driving pressure was given by difference between inspiratory and end-expiratory pressures of a ventilator. It means that almost all PS does not reach the alveolar regions but moves to and fro within the airway according to the change in ventilator pressure. The driving pressure from subsegmental bronchus was calculated at 273 cm H2O, that is clinically possible by wedge instillation under bronchoscopic observation. CONCLUSIONS: The simulation study has revealed that selective wedge instillation under bronchoscopic observation should be tried for COVID-19 pneumonia before the onset of ARDS. It will be also useful for preventing secondary lung fibrosis.

Micrometer aerosol deposition in normal and emphysematous subacinar models.

Emphysema is a chronic respiratory disease characterized by interalveolar septa destruction and enlarged air sacs. How the inhalation dosimetry in the pulmonary acini varies in the time course of emphysema is still unclear. The aim of this study is to numerically evaluate the impact of septal destructions on particle deposition in a pyramid-shape subacinar model that is composed of 496 alveoli. Four emphysematous models were generated by progressively removing the inter-alveolar septa from the normal geometry. Spatial distribution and temporal evolution of particle deposition were quantified in expanding/contracting subacinar models on both total and regional basis using a well-validated discrete-phase Lagrangian model. Airflow fields in the subacinar cavities are sensitive to the septal raptures, with regular, radial streamlines in the proximal alveoli in the normal geometry in contrast to unsymmetrical and recirculating flows in the emphysematous subacini. Intensified collateral ventilation and significantly increased doses in the outer wall and base are observed in disease than heath. The deposition rate of small particles (1-1.5 µm) is more sensitive to the level of septal rapture than large particles (2.5-3 µm). Unexpectedly, more particles per unit area deposit on the outer wall and at the base of the subacinus than on the inner septal walls. The subacinus-averaged doses increase with progressing septal destructions, suggesting an escalating risk factor to the acinar health at the late stages of emphysema.

[Pneumodynamics: Respiratory Physiology Related to Anesthesiology].

Although pneumodynamics is the most basic research field in the respiratory management, the number of the researchers is rapidly decreasing in this century. This is not because of the maturing of pneumodynamics but because the conventional theory has been wrong. The authors have been investigating this area theoretically and experimentally for more than ten years and propsed novel pneumodynamics based on dynamic imaging technique during breathing and computational fluid dynamics. In this paper, we first indicate the dynamic collapse of the intra-mediastinal airway during maximum forced expiration in emphysematous patients visualized by 4D-CT images, and explain its mechanism in terms of fluid dynamics where the turbulence of airflow in the large airway plays an important role. Although conventional pneumodynamics is based on electric circuit analogy, it has a crucial defect that the turbulence of airflow is never contained. Then, we will introduce a 4D alveolar model which explains how the alveolar shape changes during breathing based on experimental images, and indicate that the essential morphological change in diffuse alveolar damage (DAD) is the alveolar collapse, which has been misrecognized as "thickening of the alveolar wall". The new era of respiratory physiology has just begun in Japan.

Estimation of the site of wheezes in pulmonary emphysema: airflow simulation study by the use of A 4D lung model.

Adventitious lung sounds in pulmonary emphysema, wheezes, are continuous musical sounds during expiration with 400 Hz or more. The textbook tells that expiratory airflow limitation in emphysema occurs at the peripheral airways and that wheezes are generated there. We have recently proposed a novel hypothesis based on image analysis and theoretical consideration that expiratory airflow limitation in emphysema occurs at the intra-mediastinal airway (trachea, main bronchi, and right lobar bronchi) due to compression by overinflated lungs. We performed expiratory airflow simulation by the use of a 4D finite element lung model, and found periodical vortex release with 300-900 Hz at the end of protrusion of the the tracheal posterior wall. Relationship between the peak frequency of pressure fluctuation and airflow velocity was in agreement with Strahal's law either in normal or emphysematous condition. Contrarily, airflow simulation in a small bronchus (1.5 mm in diameter) indicated no apparent periodic vortex release.

4D model generator of the human lung, "Lung4Cer".

We have developed a free software applications which generates 4D (= 3D + time) lung models for the purpose of studying lung anatomy, physiology, and pathophysiology. The coinage of 4C is originated from Japanese words, Catachi (= shape, structure) and Calacli (= machine, function). Lung4Cer makes 4D finite element models from the trachea to alveoli, which allow airflow simulation by means of computational fluid dynamics. Visualization of the generated models is expected to use a popular free software application, ParaView. There are several versions of Lung4Cer from basic lung morphology to advanced airflow computations simulating various clinical pulmonary function tests (PFT4Cer). All versions are designed so as to be operated on a common PC. Users can select model types and the element number according to their purposes and available computer resources.

[The origin of frequency dependence of respiratory resistance: airflow simulation study by the use of a 4D pulmonary lobule model].

BACKGROUND AND OBJECTIVE: The origin of frequency dependence of respiratory resistance has been explained by ventilation inhomogeneity, however it is unclear which components in the respiratory system generate the frequency dependence. The author constructed a 4D pulmonary lobule model and analyzed relationships between airflow rate, pressure and airway resistance by the use of computational fluid dynamics (CFD). METHODS: The lobule model contained bifurcated bronchioles with two adjacent acini in which deformable inter-acinar septa and alveolar duct walls were designed. Constrictive conditions of respective bronchioles were designed, too. 4D finite element models for CFD were generated and airflow simulations were performed under moving boundary conditions of the arbitrary Lagrangean-Eulerean method. From the simulation results, airway resistances for various conditions were calculated. RESULTS: Tissue resistance emerged under the condition of different acinar pressures caused by unequal airway resistances. If the inter-acinar septum was shifted so as to cancel the pressure difference, the acinar pressures were equal in spite of unequal airway resistances, and hence, tissue resistances did not emerge. Therefore, the tissue resistance in the former case is thought to be an index of alveolar pressure inequality (which could be canceled by mechanical interaction of lung parenchyma), rather than a material property of the tissue itself. CONCLUSIONS: Inequality of alveolar pressure decreases as the input oscillatory frequency increases. Therefore, frequency dependence of the respiratory resistance should be regarded as a conditional index of the alveolar pressure inequality caused by heterogeneous changes in the intra-pulmonary airway and/or the lung parenchyma.

The origin of frequency dependence of respiratory resistance: an airflow simulation study using a 4D pulmonary lobule model.

BACKGROUND AND OBJECTIVE: The origin of frequency dependence of respiratory resistance has been explained by ventilation inhomogeneity; however, it is unclear which components in the respiratory system generate the frequency dependence. The author constructed a 4D pulmonary lobule model and analysed relationships between airflow rate, pressure and airway resistance by the use of computational fluid dynamics. METHODS: The lobule model contained bifurcated bronchioles with two adjacent acini in which deformable inter-acinar septa and alveolar duct walls were designed. Constrictive conditions of respective bronchioles were designed, too. 4D finite element models for computational fluid dynamics were generated and airflow simulations were performed under moving boundary conditions of the arbitrary Lagrangean-Eulerean method. From the simulation results, airway resistances for various conditions were calculated. RESULTS: Tissue resistance emerged under the condition of different acinar pressures caused by unequal airway resistances. If the inter-acinar septum was shifted so as to cancel the pressure difference, the acinar pressures were equal in spite of unequal airway resistances, and hence, tissue resistances did not emerge. Therefore, the tissue resistance in the former case is thought to be an index of alveolar pressure inequality (which could be cancelled by mechanical interaction of lung parenchyma), rather than a material property of the tissue itself. CONCLUSIONS: Inequality of alveolar pressure decreases as the input oscillatory frequency increases. Therefore, frequency dependence of the respiratory resistance should be regarded as a conditional index of the alveolar pressure inequality caused by heterogeneous changes in the intra-pulmonary airway and/or the lung parenchyma.

The diaphragm: a hidden but essential organ for the mammal and the human.

The diaphragm is the only organ which only and all mammals have and without which no mammals can live. The human is the only mammal which keeps the diaphragm parallel to the ground even during locomotion. Abdominal breathing mode maximizes the diaphragmatic motion using abdominal muscles, and control precisely exhaled air velocity. Controlled exhaled airflow generates sophisticated vocalization, singing, and finally the language. We propose novel nomenclatures for the mammal and the human. The former be the diaphragmal, and the latter be the horizontal diaphragmal, alias Homo cantale.

A novel interpretation of closing volume based on single-breath nitrogen washout curve simulation.

Although closing volume is regarded as a clinical test for the early detection of peripheral airway closure, its grounds are not clear. There have been no simulation studies for phase IV in the single-breath nitrogen washout (SBNW) curve, even though several mathematical models for phase III have been proposed. We modeled the lung tissue deformation during slow expiration in which the tissue was regarded as a porous elastic body similar to a sponge. We assigned the maximum tissue density of lung parenchyma over which the lung tissue could not be contracted according to several experimental reports in literature. SBNW curves were then simulated by computing expired air volume and nitrogen concentration for respective acini in the lung model. The simulated SBNW curves well reproduced phase IV, cardiac oscillation, and its postural changes. We found that the higher lung compliance increased closing volume, but decreased residual volume. The smaller maximum tissue density generated larger closing volume and larger residual volume. It suggested that phase IV reflected the alveolar contractility, and the increase of closing volume in emphysema could be explained by an insufficient contraction of alveoli. We also found that the distribution of maximum tissue density affected the onset of Phase IV. A constant value of density generated a clear onset, but a wide distribution of it corresponding to peripheral airway closure obscured it. We suggest that the airway closure was not necessary for phase IV appearance in both normal and emphysematous lung.

A 4-dimensional model of the alveolar structure.

The alveolar structure, a space-filling branching duct system with alveolar openings, is one of the most complicated structures in the living body. Although its deformation during ventilation is the basic knowledge for lung physiology, there has been no consensus on it because of technical difficulties of dynamic 3-dimensional observation in vivo. It is known that the alveolar duct wall (primary septa) in the fetal lung is deformed so as to obtain the largest inner space and the widest surface area, and that the secondary septa grow just before birth and their free ridges form the alveolar entrance rings (mouths) containing abundant elastin fibers. We have constructed a 4-dimensional alveolar model according to this morphogenetic process, where the alveolar deformation is modeled by a combination of springs and hinges, corresponding to elastin fibers at alveolar mouths and junctions of alveolar septa, respectively. The model includes a hypothesis that alveolar mouths are closed at minimum volume and that closed alveoli are stabilized by the alveolar lining liquid film containing a surfactant. Morphometric characteristics of the model were consistent with previous reports. Furthermore, the model explained how the alveolar number and size could change during ventilation. Using in vivo microscopy, we validated our model by an analysis of the dynamic inflation and deflation of subpleural alveoli. Our model, including the alveolar mouth-closure hypothesis, can explain the origin of phase IV in a single breath nitrogen washout curve (closing volume) and mechanism of alveolar recruitment/derecruitment.

Computational morphology of the lung and its virtual imaging.

The author proposes an entirely new approach called 'virtual imaging' of an organ based on 'computational morphology'. Computational morphology describes mathematically design as principles of an organ structure to generate the organ model via computer, which can be called virtual organ. Virtual imaging simulates image data using the virtual organ. The virtual organ is divided into cubic voxels, and the CT value or other intensity value for each voxel is calculated according to the tissue properties within the voxel. The validity of the model is examined by comparing virtual images with clinical images. Computational image analysis methods can be developed based on validated models. In this paper, computational anatomy of the lung and its virtual X-ray imaging are introduced.