Patent Grant
12257093
The present application is a continuation of an International Application Number PCT/IN2020/050879, with a filing date of Oct. 13, 2020, the entire disclosure of which is incorporated herein by reference for all purposes. The present application claims the benefit of foreign priority application number IN201941041658, with a filing date of Oct. 15, 2019, the entire disclosure of which is incorporated herein by reference for all purposes.
The present invention relates to a method for the estimation of lung morphometry through aerosol deposition measurements through the use of gamma scintigraphy scan and adaptive image threshold technique.
The lung is one of the internal vital organs, which is constantly exposed to the external environment. This is the underlying cause of several respiratory infections. However, it is also well known that certain people are more prone to infections while others are not. According to World Health Organization (WHO), out of the top 10 causes of global deaths, the deaths caused by chronic obstructive pulmonary disease (COPD), lower respiratory infections and cancers of trachea, bronchus and lung occupy 3rd, 4th and 6th positions respectively.
Personalized medicine is an emerging field due to the fact that ‘one size does not fit all’. The challenges for personalization in pulmonary therapeutics are daunting and therefore still remain unaddressed. Though respiratory diseases impose an immense worldwide health burden, the diagnostic tests used to detect the early occurrence of respiratory diseases are insensitive to the patient symptoms and disease. For example, in the case of diseases such as asthma or COPD, the treatment is advocated based on measurements of lung function data obtained from spirometry which does not give any information about the regional deposition happening inside the lung. This leads to the prescribed medications not being effectively delivered to essential sites of infection. Current focus of research in personalized medicine being creation of patient specific prototype models with the aid of imaging tools, and the creation and analysis of such a model is extremely cumbersome. Such a model is possible only from CT derived data and also for initial few generations of the lung only. It is difficult to obtain the dimensions of smaller airways at the distal end using current imaging tools and techniques. Existing technologies are also expensive due to the need to build customized models for each individual based on identification of specific markers that could segregate the regional deposition of a given dose of aerosol. In this scenario, more sensitive markers for accurate detection and treatment of respiratory diseases are a compelling need of the decade.
Inhalation is the commonly sought route for administration of drugs to treat various respiratory diseases, and also the most viable route for respirable pathogens to enter and trigger infection of any kind. The deposition of a drug in lung is considered to be a measure of local bioavailability thus serving to be a surrogate to identify clinical response of inhaled drugs. When it comes to the dosage of drug at the essential site, inter-subject variability in drug deposition plays a major role. The minor morphometric changes of the lung from generation 5 till the end, causes variability in alveolar deposition. Thus, essentially the changes in morphological features of the lung could explain inter-subject variability in deposition. The prediction of human lung morphometry for any given individual would be clinically relevant while personalizing the treatment. There are no studies which report the realistic lung morphometry for a given individual. Thus, prediction of length and diameter of each generation of the respiratory tract and the alveolar diameter through deposition measurement would do a great benefit to the medical practitioners, so that the dose could be engineered to the needs of the individual.
EP1011423A1 discloses a non-invasive process for the analysis of an internal element in a body of a human or animal. The process comprises of the steps: providing a contrast agent to the patient in any suitable form, such as neat liquid, aerosol, vapor, or emulsion; receiving scanned data reflective of a portion of a human or animal body in a processor; and processing the scanned data in the processor into three-dimensional volume and functional data based on the mathematical model representative of the internal body element. The abnormality of the airways is determined based on the comparison between the scanned data and the baseline data. It is possible to assess diseases down to approximately the 12th through 17th generation bronchi which are about 1 mm diameter in the adult.
US20090285763A1 discloses a delivery system and a method for the delivery of an aerosol drug to an infant. It comprises a diagnostic module configured to provide geometrical properties of the nasal airway of the infant as the output. A computer program is used to determine the aerosol drug dose based on the said geometrical properties of the nasal airway. The required geometrical information is obtained by a suitable method such as CT, Cone Beam Computed Tomography, X-ray, fluoroscopy, ultrasound, PET, or gamma scintigraphy.
Counter W B et al. of McMaster University published an article titled ‘Airway and pulmonary vascular measurements using contrast-enhanced micro-CT in rodents’ discloses a method to visualize both the pulmonary airways and vasculature of the Sprague-Dawley rat and BALB/c mouse in situ using contrast-enhanced micro-CT imaging. From these images, parameters such as diameter, length, and branching angles were automatically measured to create an anatomical database for normal rodent lungs. Contrast agent was infused in the airways using a perfusion pump. Images for rats were reconstructed using a Feldkamp filtered back-projection algorithm. In the rat lung, an average of 562 airways was segmented. Their diameters ranged from 0.23 to 2 mm over 20 generations.
Tossici-Bolt et al. of Southampton University Hospital NHS Trust, University of Southampton and Cyber Medicine published articles (Analytical technique to recover the third dimension in planar imaging of inhaled aerosols: (1) Impact on spatial quantification, and (2) Estimation of the deposition per airway generation). The articles disclose methods to recover 3D information from theoretically generated planar images. The results obtained from their technique were compared in terms of conducting and bronchial airway deposition fraction obtained from SPECT study. It was concluded that the approximate estimates of 3D airway distribution parameters can be derived from planar imaging. However, the errors are significantly higher than with SPECT.
Belchi et al. of University of Southampton published an article titled ‘Lung Topology Characteristics in patients with Chronic Obstructive Pulmonary Disease’ which discloses an analytical tool based on persistent homology that extracts quantitative features from chest CT scans to describe the geometric structure of the airways inside the lungs. It is claimed that the new radiomic features stratify COPD patients in agreement with the GOLD guidelines for COPD and can distinguish between inspiratory and expiratory scans. It also claimed that the results of the study are a proof of concept that topological methods can enhance the standard methodology to create a finer classification of COPD and increase the possibilities of more personalized treatment.
However, these prior art studies fail to specifically address the morphology differences among individuals that bring about the inter-subject variability in deposition. For accurate customized drug dosage, it is essential to have a cost-effective technique that would also be capable of providing lung morphometry of even the last generation of lung airways. In addition, the prior art does not disclose any method to quantify the deep lung dimensions, especially those associated with the bronchioles from the 17th to 23rd generations.
The present invention provides a method which would in future evolve into a walk-in lab test, wherein patients get their lung map through an imaging means such as a conventional gamma scan. This test can identify and quantify features in the distal end of the lung which is the most important part of the lung from a functional point of view that is difficult to be imaged using existing imaging techniques.
The principal object of the present invention is to develop a walk-in lab test for estimating the lung morphometry for determination of length and diameter of distal lung airways, mean alveolar diameter and lung boundary based on aerosol deposition characteristics.
The present invention provides a method for measuring lung morphometry using adaptive image threshold technique. The method of the present invention comprises radio-aerosol deposition in a subject, and capturing a series of lung images using an imaging means post-inhalation of said radio-aerosol from t=0 to upto t=24 hours. Said adaptive image threshold technique is applied to the obtained images for determining the ratio of the deposition of said radio-aerosol in the central region to the deposition of said radio-aerosol to the peripheral region of lung (C/P ratio) for identifying lung boundary. The parameters of the lung morphometry including the length (P8) and diameter (P9), and mean alveolar diameter (dalv) of the 17th generation lung airway to the 23rd generation lung airway are measured using said radio-aerosol deposition and clearance data comprising the time, volume, or percentage of said radio-aerosol in the central region and the peripheral region of the lungs. Said adaptive image threshold technique comprises using automated iterative procedures for drawing a Region of Interest (ROI) on the images of the lung, for determining a Central region (C) of said ROI, and determining a Peripheral region (P) of said ROI, to determine the ratio of radio-aerosol deposition in the Central region to the radio-aerosol deposition in the Peripheral region (C/P) of the lung based on the characteristics of said radio-aerosol deposition in said Central region and said Peripheral region, thereby determining the lung morphometry. Said adaptive image threshold technique comprises ofconverting images obtained from imaging at t=0 hours and upto t=24 hours post-inhalation of the radio-aerosol to gray scale images; cropping said gray scale images to make the right lung as the only focus and obtaining uniform dimensions of said gray scale images for all the subjects; calculating the lung boundary of the image by extracting the boundaries of the lung outline at a given threshold through an automated iterative procedure until a threshold value for obtaining maximum lung boundary is achieved; obtaining the area of the right lung by superimposing lung boundary over the first image obtained immediately post-inhalation of radio-aerosol; calculating the C/P ratio from the ratio of the area of the central region to the area of the peripheral region based on the image intensities in the central region (C) and the peripheral region (P); and shrinking right lung area to create an C/P ratio using an iterative procedure, wherein said iterative procedure comprises calculating and recalculating the boundaries of said central region and peripheral region based on the threshold values and image intensities until the central region is shrunk to one-third of the right lung boundary. Said adaptive image threshold technique is used for determining the parameters of the lung morphometry based on said C/P ratio through an optimization procedure comprising minimizing an error function.
The summary of the present invention, as well as the detailed description, are better understood when read in conjunction with the accompanying drawings that illustrate one or more possible embodiments of the present invention, of which:
The present invention is related to a method for estimating lung morphometry including the length and diameter of distal lung airways, mean alveolar diameter and lung boundary based on the aerosol deposition characteristics obtained by an imaging means. According to the embodiments of the present invention, the imaging means may be for example, a gamma camera. According to the present invention, adaptive image threshold technique is applied for the estimation of the lung morphometry.
According to an embodiment of the present invention, the proposed method can create a morphology map as well as any required regional deposition map for any given subject.
According to an embodiment of the present invention, the radio-aerosol used for measuring deposition characteristics includes but is not limited to 99mTechnetium phytate radio-aerosol generated using a Biodex® Venti-scan® radio-aerosol delivery system.
According to an embodiment of the present invention, the camera used for acquiring lung images includes but is not limited to gamma camera.
The radio-aerosol is delivered to the lungs using any oral or nasal compliance. As an exemplary case in the present invention, a radio-aerosol such as 99mTechnetium phytate generated using a Biodex® Venti-scan® radio-aerosol delivery system is given to the subject through a mouth piece. The nose is clamped and the subject is instructed to breathe through their mouth. The radio-aerosol solution contains 20 mCi of radioactivity. The subject inhales the aerosol for about three minutes so that about 2 mCi, i.e., one-tenth of the total preparation is deposited inside the thorax.
An imaging means such as gamma scintigraphy is used to acquire lung images at time intervals (t) of 0, 4 and 22 hours. In the subsequent analysis, only the first image post-inhalation is used for extracting the C/P ratio in which case the original test dosage of the radio-aerosol could be further reduced.
The C/P ratio is defined as the ratio of deposition in the central to peripheral region of the lung. It responds to changes in important factors that influence the deposition characteristics in the lung such as particle size, inhaled airflow rate, and airway patency. The peripheral zone comprises mostly of small airways and alveoli. The central zone consists of larger central airways. Said characteristics of said radio-aerosol deposition include retention data and clearance data of aerosol in lungs, wherein said retention data and clearance data of said radio-aerosol in lungs include the time, volume or percentage of said radio-aerosol in the lungs.
The conventional method of obtaining the C/P ratio is to draw a region of interest (ROI) on the right lung to demarcate the central (C) and peripheral (P) regions of the lung. The time activity curves are obtained for each of the two regions. After correcting the counts for decay and background, the central to periphery ratio of counts C/P is obtained from the initial image, post-inhalation of the radio-aerosol. There are various methods available in the literature to draw these regions of interest. One of the methods is intended to find the C/P ratio of which the central region is one-third of the lung area and the remaining two-third region is considered as the peripheral lung region. The present invention implements the adaptive image threshold method for the calculation of C/P ratio, and estimation of the lung morphometry.
In order to find the lung area, the first image is recorded at t=0 hour. It is important to minimize user induced variability in drawing the region of interest (ROI) based on which the central to peripheral ratio is calculated. In the present invention, an adaptive image threshold technique in MATLAB® was used for finding the lung outline to draw the region of interest (ROI). Thus, the C/P ratio found using this technique is free of inter-subject variability in drawing ROI manually. The gray scale level or the image threshold in MATLAB® is automated for the subjects based on the intensity of the pixels in the image to provide the lung outline. In each subject, there is a particular threshold value which gives the maximum lung area. Increasing the image threshold above this value decreases the lung area drastically. All the other intensity threshold values below this particular threshold yield a lower lung area. This particular threshold value helps detect all the connected components of the image giving rise to the maximum lung area. The adaptive technique is used to effectively identify the lung boundary.
According to the embodiments of the present invention, the morphometric parameters for an individual subject are determined from the aerosol deposition and clearance data. The morphometric parameters considered in accordance with the present invention include length (P8) and diameter (P9) of the last generations, i.e., the 17th generation airway to the 23rd generation airway, and the mean alveolar diameter (dalv). These three parameters determine the airway morphometry in the distal lung.
In order to identify the morphometric parameters, an error function (ε) is postulated as a normed difference between the numerical predictions of (C/P)m ratio and experimentally determined values C/P ratio, specifically, ε=|C/P−(C/P)m|. The numerical predictions of (C/P)m are derived using the model proposed by Devi et al (Designing aerosol size distribution to minimize inter-subject variability of alveolar deposition, Journal of Aerosol Science, 2016). The parameters P8, P9, and dalv are determined by minimizing this error. The proposed method which uses C/P ratio is robust, convergent and predicts physically relevant values for the parameters. The total lung capacity of each subject is used as constraint in the minimization process. The corresponding lengths and diameters of the bronchioles at various generations are calculated using these parameters and Weibel's morphometry.
According to the various embodiments of the present invention, the method for estimating lung morphometry comprises delivering radio-aerosol in a subject, generating a plurality of images of the lung of said subject post-inhalation of the radio-aerosol using an imaging means, wherein said images are obtained from imaging at t=0 hours and upto t=24 hours post-inhalation of said radio-aerosol, applying an adaptive image threshold technique to draw a Region of Interest (ROI) on said images of the lung for determining ratio of said radio-aerosol deposition in the Central region (C) to said radio-aerosol deposition in the Peripheral region (P) of the lung (C/P ratio), and determining the parameters of lung morphometry based on said C/P ratio through an optimization procedure comprising minimizing an error function. Said adaptive image threshold technique comprises (i) converting said images obtained from imaging at t=0 hours and upto t=24 hours post-inhalation of said radio-aerosol to gray scale images; (ii) cropping said gray scale images to make the right lung as the only focus and obtain uniform dimensions of said gray scale images for all the subjects; (iii) calculating the lung boundary of said image obtained post-inhalation of said radio-aerosol by extracting the boundaries of the lung outline at a given threshold through an automated iterative procedure until a threshold value for obtaining maximum lung boundary is achieved; iv) obtaining the area of the right lung by superimposing said lung boundary over the first image obtained immediately after the inhalation of said radio-aerosol; (v) calculating the C/P ratio from the ratio of the area of the central region to the area of the peripheral region; and shrinking said right lung area to create an area ratio obtained in step (v) using an iterative procedure.
In the adaptive image threshold technique of the present invention, said ratio of the area of the central region to the area of the peripheral region is obtained through an iterative procedure, wherein said iterative procedure includes calculating and recalculating the boundaries of said central region and peripheral region based on the threshold values and image intensities until the central region is shrunk to one-third of the right lung boundary.
While certain preferred embodiments and examples are disclosed herein, it is to be understood that these embodiments and examples are only illustrative, and the inventive subject matter is not limited to the specifically disclosed embodiments. Rather, the scope of the invention extends to other alternative embodiments, uses, modifications, and equivalents thereof.
Study Design and Participants:
In this study, six healthy, non-smoking individuals with pulmonary function tests within the normal range and no respiratory illness were selected. In all the cases, a detailed history was considered and a thorough physical examination was carried out especially focusing on the respiratory system. In all the subjects, a chest radiograph (postero-anterior view) was also taken to ascertain normal lung structure. Lung volumes were determined using spirometry. The anthropometric and spirometry data of the subjects under study are listed in Table 1.
In the gamma scintigraphy study, the 99mTechnetium phytate radio-aerosol was generated using a Biodex® Venti-scan® radio-aerosol delivery system. The mass median aerodynamic diameter (MMAD) of aerosol produced by the nebulizer is 0.5 μm.
Aerosol Administration and Image Acquisition:
The subjects were made to sit comfortably in a chair and relax for 10 minutes. Then 99mTechnetium phytate radio-aerosol generated using a Biodex® Venti-scan® radio-aerosol delivery system was given through a mouth piece. The nose was clamped and the subjects were instructed to breathe through their mouth. The radio-aerosol solution used on all subjects contained 20 mCi of radioactivity. The subjects inhaled the aerosol for about three minutes so that about 2 mCi, i.e. one-tenth of total preparation was deposited inside the thorax. As an exemplary case, the procedure followed by Guleria et al, was followed in acquiring the images at t=0 hour, 4 hours and 22 hours. In the subsequent analysis, only the first image for extracting the C/P ratio was considered. Hence, the original test dosage of the radio-aerosol could be further reduced.
Determination of C/P Ratio:
According to the embodiments of the present invention, in order to find the lung area, the first image was recorded initially at t=0 hour, i.e., immediately after inhalation. It is important to minimize user induced variability in drawing the ROI based on which the central to peripheral ratio is calculated.
The procedure to draw ROI using adaptive threshold technique comprises of:
In accordance with some of the embodiments of the present invention, the area ratio between the central and peripheral regions is 0.33. The ratio of the total pixels in both the regions corresponds to the C/P ratio.
Using the above method, the total number of pixels versus the gray scale level for each of the subjects is shown in
Determination of Subject-Specific Morphometric Markers:
In accordance with the embodiments of the present invention, the morphometric parameters for an individual subject are identified from the aerosol deposition and clearance data. From the present invention, three parameters, P8, P9, and dalv have been identified as important lung morphometry markers.
In order to identify the morphometric parameters, the error function (ε) was employed. The parameters obtained using said approach are tabulated in Table 2. Table 2 shows the predicted parameters as well as their deviation from the Weibel values (in percentage terms). The corresponding lengths and diameters of the bronchioles at various generations calculated using these parameters and Weibel's morphometry model are also graphically depicted in
Total Lung Capacity (TLC) is another physiologically relevant parameter.
Table 3 shows the deviation of lung surface areas and total lung volumes for each subject from an average individual to indicate inter-subject variability. Lung surface area is an important factor influencing drug deposition. According to the embodiments of the present invention, the change in surface area for subject 5 amounts to about 8%. As the surface area for subject 5 is reduced by 8%, the drug absorption would also be reduced in this subject compared to an average individual. The percentage change in alveolar volumes for each subject is considerably greater than the volume changes of the airway passages.
According to the embodiments of the present invention, the alveolar volume, while being only about one-third of the total lung capacity, is a primary cause of inter-subject variation in morphometry. As the lung surface area and alveolar volume are fundamentally important parameters in drug delivery and absorption, it is important to estimate these parameters for an individual subject. Therefore, predicting the parameters would help the physician in personalizing the dosage and therapy of the patient.
According to a preferred embodiment, the method for estimating lung morphometry comprises delivering radio-aerosol in a subject, generating a plurality of images of the lung of said subject post-inhalation of the radio-aerosol using an imaging means wherein said images are obtained from imaging at t=0 hours and upto t=24 hours post-inhalation of said radio-aerosol, applying an adaptive image threshold technique to draw a Region of Interest (ROI) on said images of the lung for determining the ratio of said radio-aerosol deposition in the Central region (C) to said radio-aerosol deposition in the Peripheral region of the lung (C/P ratio), and determining the parameters of the lung morphometry based on said C/P ratio through an optimization procedure comprising minimizing an error function. An error function was postulated as normed difference between the numerical predictions of C/P ratio and the experimentally measured values of the C/P ratios. The adaptive threshold technique comprises of converting the initial image obtained at t=0 hour post-inhalation and after upto twenty four hours post-inhalation of said radio-aerosol, to gray scale images; cropping said images to make the right lung as the only focus and obtain uniform dimensions for all the subjects; calculating the lung boundary of the image obtained post-inhalation of said radio-aerosol by extracting the boundaries of the lung outline at a given threshold through an automated iterative procedure until a threshold value for obtaining maximum lung boundary is achieved; obtaining the right lung area by superimposing the lung boundary over the first image obtained immediately after the inhalation of said radio-aerosol; calculating the C/P ratio from the ratio of the area of the central to the area of the peripheral region based on the image intensities in the central region and the peripheral region; and shrinking said right lung area to create said area ratio using an iterative procedure wherein the boundaries of said central and peripheral regions are calculated and recalculated based on the threshold values and image intensities until the central region is shrunk to one-third of the right lung boundary. Based on said C/P ratio, the parameters of the lung morphometry including the length (P8) and diameter (P9) of the 17th generation lung airway to the 23rd generation lung airway, and the mean alveolar diameter (dalv) of said lung airways are determined through an optimization procedure comprising minimizing an error function.
It is to be understood, however, that the present invention would not be limited by any means to the techniques, and approaches that are not specifically described, and any change and modifications to the techniques and approaches can be made without departing from the spirit and scope described in the present invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201941041658 | Oct 2019 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IN2020/050879 | 10/13/2020 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2021/074923 | 4/22/2021 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20090285763 | Finlay et al. | Nov 2009 | A1 |
| Number | Date | Country |
|---|---|---|
| 2622987 | Feb 2018 | CA |
| 1011423 | Jun 2000 | EP |
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| Number | Date | Country | |
|---|---|---|---|
| 20220354366 A1 | Nov 2022 | US |
