Lung Deposition of Air Pollutants and Inhaled Drugs in Patients with Chronic Obstructive Pulmonary Disease (COPD) and Those on Non-Invasive Ventilation (NIV): Is It Still Challenging?

Abstract

Chronic Obstructive Pulmonary Disease (COPD) ranks among the leading causes of mortality worldwide, particularly in low- and middle-income nations. The primary risk factors for the development of COPD are tobacco smoking and the inhalation of pollutants from both indoor and outdoor sources. The exacerbation of COPD resulting from the mentioned factors significantly affects the patient’s quality of life and is often associated with frequent hospitalizations and the potential need for mechanical ventilation. Regarding drug administration, the inhalation route is the most efficient way to deliver drugs directly to the lungs and target organs, while reducing systematic side effects. When evaluating the deposition of inhaled drugs in the lungs, the most frequently employed techniques are in vivo, scintigraphy, and functional respiratory imaging (FRI). Aside from bronchodilator therapy and corticosteroids, antibiotics, anti-inflammatory drugs, vaccines, and monoclonal antibodies are currently being studied for their potential benefits, particularly in patients receiving invasive or non-invasive mechanical ventilation.

1. Introduction

Based on recent data from the Global Initiative for Chronic Obstructive Lung Disease (GOLD), Chronic Obstructive Pulmonary Disease (COPD) ranks among the top three leading causes of death worldwide, particularly in low- and middle-income nations. The disease is characterized by respiratory symptoms, such as dyspnea, coughing, and exacerbation of symptoms in conditions that affect the airways (bronchitis/bronchiolitis) and/or the alveoli (emphysema). This leads to persistent and often progressive obstruction of the airways. The primary risk factors for the development of COPD are tobacco smoking and the inhalation of toxic particles from both indoor and outdoor sources [1]. This topic will focus on the subject of air pollution and its mechanisms of action, as well as the deposition of drugs in the lungs and the impact of this deposition on patients who are on mechanical ventilation.

2. Air pollutants and mechanism of action

According to data from the World Health Organization (WHO), ambient air pollution is responsible for 43% of cases of COPD, 29% of lung cancer cases, 25% of ischemic heart attack cases, and 24% of stroke-related deaths [2]. Air pollution refers to the presence of one or more substances in the air at concentrations or durations that exceed their normal levels, leading to harmful effects [3]. Certain air pollutants are of anthropogenic origin, arising from activities such as the combustion of fossil fuels. Others are a result of natural processes, such as particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), ozone, carbon dioxide (CO₂), and sulfur dioxide (SO2) [4]. Figure 1 illustrates classification of air pollutants, outdoor and indoor pollutants [5]. Their mode of operation may vary. Ozone causes the oxidation of proteins and lipids in the fluid-lined compartments of the lungs, resulting in inflammation, increased permeability of the lungs, and the activation of pro-inflammatory cytokines, proteolytic enzymes, and reactive oxygen species (ROS). Ozone primarily affects the terminal bronchioles, the junction between the bronchioles and alveolar ducts, and the proximal alveolar regions. Lung inflammation caused by the inhalation of particulate matter is mediated by macrophages and epithelial cells. Alveolar macrophages have a significant impact on lung inflammation caused by particles, as they promote the production of interleukin 13 (IL-13) and interleukin 25 (IL-25) [6]. The mechanism of action of PM in COPD is illustrated in Figure 2 [7].

Figure 1.

Classification of air pollutants. CO-carbon monoxide, CO₂-carbon dioxide, NO_X- nitrogen oxides, PM- particle matter, PM0.1-particulate matter with particles of aerodynamic diameter < 0.1 μm, PM2.5- particulate matter with particles of aerodynamic diameter < 2.5 μm, PM10-particulate matter with particles of aerodynamic diameter < 10 μm, SO_X-sulfur oxide, SO₂-sulfur dioxide, VOC_s- volatile organic compounds.

Figure 2.

Impact of PM2.5 and PM10 on COPD development.

Despite the anatomical positioning of the respiratory tract and its constant exposure to air pollutants in the atmosphere, many scientists continue to consider this topic to be controversial. A study involved over 400,000 patients who were exposed to various concentrations of air pollutants, including particulate matter (PM2.5 and PM10), nitrogen dioxide (NO₂), and nitrogen oxides (NOx). Their findings showed that individuals who had significant exposure to pollutants, an unfavorable lifestyle, and a high genetic predisposition were at a heightened risk of developing COPD [8].

3. Lung deposition—definition and main mechanism

The exacerbation of COPD resulting from the factors mentioned above significantly affects the quality of life for patients. This can lead to frequent hospitalizations and, in severe cases, the need for mechanical ventilation. A deposition is a process that determines what fraction of the inspired particles is caught in the lung and, thus fails to exit with expired air [9].

The primary mechanisms responsible for the transport and deposition of aerosols in the lungs are gravitational sedimentation, Brownian diffusion, and inertial impaction.

• Inertia is the resistance to changes in a moving object’s speed and direction. It is a significant mechanism that applies to particles with diameters exceeding 2 μm. This mechanism necessitates a rapid flow and the deposition caused by inertial impaction will be influenced by the average flow. As per literature, inertia typically arises within the first 10 generations of the lungs due to high air velocity and turbulent airflow. As the size of particles decreases, the significance of inertia diminishes while the significance of diffusion increases.

• Gravitational sedimentation is the process by which particles settle due to the force of gravity. This phenomenon primarily occurs in narrow airways and alveolar cavities, where the particles have a short distance to travel before coming into contact with the walls.

• Brownian diffusion occurs due to random movements of particles resulting from their collisions with gas molecules. This phenomenon is especially prevalent in the acinar region of the lung, where air velocities are low. This mechanism dominates in the deposition of particles smaller than 0.5 μm [9, 10, 11].

4. Inhaled drugs in COPD

In terms of delivering drugs to the lungs and minimizing side effects throughout the body, the most efficient approach is through inhalation. Bronchodilatory therapy is frequently used in patients with COPD/asthma through dry powder inhalers (DPIs), soft-mist inhalers, nebulizers, and pressurized metered-dose inhalers (pMDIs). The therapeutic effects of inhaled medications are dependent upon various lung barriers, including humidity, mucociliary clearance, alveolar macrophages, and airway geometry. There is a positive correlation between the depth of deposition and the values of forced expiratory volume in the first second (FEV1). Patients with reduced FEV1 values will experience central deposition of the aerosolized drug in the lungs, unlike individuals with normal lung function. During an exacerbation, approximately 50% of the radio aerosol was eliminated from the lung within 97 minutes in patients with an FEV1 of 30–40%. In contrast, the clearance rate was less than 10% when the FEV1 was above 80%. A significant correlation was identified in cystic fibrosis (CF) [12, 13]. Scientific interest is focused on bronchodilator therapy, corticosteroids, antibiotics, anti-inflammatory drugs, vaccines, and monoclonal antibodies.

4.1 Inhaled antibiotics

Their administration aims to increase the local availability of drugs at the site of respiratory infections while minimizing systemic side effects. The most frequently administered antibiotics are aminoglycosides and fluoroquinolones due to their ability to attain the highest concentration in the respiratory system and exhibit the most potent antimicrobial activity. The administration of these drugs typically occurs through nebulization, inhalation, or aerosolization. Liposomal formulations of antibiotics and polymers represent the future of inhaled medications [14, 15]. The inhalable antibiotics that have been approved in Europe and the USA are listed in Table 1 [23].

	Antibiotic	Agency	Approved indications	References
1	Aztreonam inhalation solution (Cayston^®)	EMA/FDA	To suppress chronic pulmonary infections due to Pseudomonas aeruginosa in patients with CF, 6 years of age and FEV1 25–75% predicted (EU)	CAYSTON^® summary of product characteristics [16]
			To improve respiratory symptoms in CF patients with P. aeruginosa, 7 years of age and with FEV1 25–75% predicted (US)	CAYSTON^® prescribing information [17]
			Treatment schedule is 28-days-on drug alternating with 28-days-off drug
2	Colistimethate sodium inhalation solution (Colistin)	EMA	Colistin: For management of chronic infections due to P. aeruginosa in patients with CF, adults and children	Promixin^® summary of product characteristics [18]
	Colistimethate sodium inhalation powder (Colobreathe^®)		Colobreathe^®: For management of chronic infections due to P. aeruginosa in patients with CF aged ≥6 years	Colobreathe^® summary of product characteristics [19]
			Treatment schedule is a continuous regimen
3	Levofloxacin nebulizer solution (QUINSAIR^®)	EMA/FDA	For management of chronic pulmonary infections due to P. aeruginosa in adult patients with CF	Quinsair^® summary of product characteristics [20]
			Treatment schedule is 28-days-on drug alternating with 28-days-off drug
4	Tobramycin inhalation solution (TOBI^®)	EMA/FDA	TOBI^®: For management of CF patients with P. aeruginosa, 6 years of age and with FEV1 25–75% predicted	TOBI^® prescribing information [21]
			TOBI^® Podhaler^™: For management of CF patients with P. aeruginosa, 6 years of age and with FEV1 25–80% predicted (US) or 25–75% predicted (EU)	TOBI^® Podhaler^™ prescribing information [22]
	Tobramycin inhalation powder (TOBI^® Podhaler^™)
			Treatment schedule is 28-days-on drug alternating with 28-days-off drug

Table 1.

Inhaled antibiotics in Europe and USA.

CF, cystic fibrosis; EMA, European Medicines Agency; EU, European Union; FDA, US Food and Drug Administration; FEV₁, forced expiratory volume in 1 second; US, United States.

4.2 Anti-inflammatory drugs

Phosphodiesterase 4 (PDE4) inhibitors are frequently used. They do not directly affect systemic inflammation, but they can indirectly enhance the anti-inflammatory response, as shown by a decrease in exacerbations [24, 25]. The phosphatidylinositol 3-kinase (PI3K) plays a crucial role in COPD. PI3K activates various intracellular processes related to cell growth, proliferation, metabolism, and survival by facilitating the synthesis of phosphatidylinositol-3,4,5-triphosphate (PIP3). The most crucial component is nemiralisib, which, when used initially, has been found to enhance lung function for a duration of 3 months by mitigation [26]. The p38 mitogen-activated protein kinases (MAPK) regulate the apoptosis of macrophages and neutrophils, as well as induce the release of cytokines and chemokines from these cells, including interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin 8 (IL-8), interleukin 17A (IL-17A), and interleukin 17F (IL-17F). This collective action facilitates the recruitment and activation of neutrophils. The significance of blocking p38 MAPKs in COPD is demonstrated by all of these effects [27].

4.3 Inhaled vaccines

The administration of vaccines through inhalation allows for targeting all areas of the respiratory system and has the potential to serve as a needle-free alternative. The vaccine can be administered directly, stimulating a localized immune response aided by immunoglobulin A (IgA) antibodies. It can also be administered to the respiratory mucosa, inducing systematic immunoglobulin G (IgG)-mediated and cell-mediated responses. Vaccines must possess specific properties to be administered via inhalation:

1. Due to the insufficient ability to induce an immune response when used alone, the antigen must be presented in a particulate form and always be administered together with an adjuvant that is effective in stimulating the mucosal immune system.

2. The formulation must have the ability to be administered through an appropriate device.

Traditionally, vaccines have been produced in liquid and powder forms. However, in recent years, researchers have developed dried vaccines that can maintain their in vivo efficacy [22, 28].

4.4 Monoclonal antibodies (mAbs)

Administering monoclonal antibodies (mAbs) via inhalation is currently a complex and appealing practice in the field of medicine. Delivering mAbs in this manner is characterized by a quick onset of action, enhanced effectiveness at lower doses, minimal systematic exposure, and reduced likelihood of negative drug reactions. The drug’s mechanism of action involves specifically targeting the airways and the tissue site of cytokine expression. The lungs possess a large surface area, with airway epithelium that is extremely thin and well vascularized. As a result, absorption occurs quickly and the onset of action is rapid. The most frequently mentioned mAbs are pharmacokinetics (PK) and pharmacodinamics (PD) of CSJ117 was evaluated in one study. A randomized, placebo-controlled, participant- and investigator-blinded study was conducted at multiple centers to evaluate the impact of CSJ117 on individuals with COPD. The main result analyzed was the difference in the Evaluating Respiratory Symptoms (E-RS) score compared to the baseline value. The study was concluded in 2022, and there are currently no available results. In addition, it is necessary to conduct randomized control trials (RCTs) to evaluate the possible effectiveness of these drugs in treating COPD [16].

5. Scintigraphy and functional respiratory imaging (FRI)

The effectiveness of delivering drugs to the lungs is determined by a combination of several factors: the physicochemical characteristics of the drug, the drug’s formulation, the type of inhalation device used (such as pressurized metered-dose inhalers, dry powder inhalers, nebulizers, or soft-mist inhalers), as well as factors related to the patient and the disease (such as breathing pattern and airway constriction). Except for bronchoalveolar lavage and tissue biopsies, which have inherent limitations, accurately measuring drug concentrations in the lung tissue of humans is an arduous task. Non-invasive nuclear medicine imaging techniques have significant potential. The imaging techniques used for this purpose are planar gamma scintigraphy, single-photon emission computed tomography (SPECT), and positron emission tomography (PET). Nuclear medicine imaging techniques enable the dynamic measurement of radiolabeled molecule concentrations in the lungs, known as radiotracers. There are three ways in which these imaging techniques can be utilized. The first method involves the process of radiolabeling a component of the drug formulation, such as solid particles or solvent, with the assumption that this component will exhibit similar behavior to the drug present in the formulation. This approach is commonly utilized in lung deposition studies. The second method involves the process of radiolabeling the drug molecule directly. The said process is technically more demanding due to the requirement of devising a radiolabeling strategy for the desired medication and subsequently incorporating the radiolabeled drug into the inhalation device. It provides a significant benefit, such as the ability to evaluate the drug’s retention in the lungs over time as well as clearance processes from the lungs. The third approach utilizes an imaging biomarker to assess the impact of the inhaled drug, specifically by measuring target receptor occupancy. Although this method will yield important information regarding the effectiveness of delivering drugs to the lungs, it depends on understanding the specific drug target and having a radiotracer available to measure the binding of the inhaled drug to this target (Figure 3) [17].

Figure 3.

Illustration of the three access of nuclear medicine imaging methods in lung deposition: (I) planar gamma scintigraphy with radiolabeled inhalation formulations to assess initial pulmonary drug deposition, (II) PET imaging studies with radiolabeled drugs to assess their intrapulmonary pharmacokinetics and (III) receptor occupancy studies to quantify the pharmacodynamic effect of an inhaled drug.

Functional respiratory imaging (FRI) involves the application of non-invasive, three-dimensional lung models created from high-resolution computed tomography scans (HRCT). These models are then analyzed using computational fluid dynamics (CFD). Compared to scintigraphy, FRI enables the modeling of patient-specific deposition in peripheral airways without requiring patient recruitment. This technique is based on three phases:

1. Medical imaging: The process commences by obtaining a low-dose, high-resolution computed tomography (HRCT) scan of the patient.

2. Imaging processing: Measurements are conducted on the segmented three-dimensional geometries obtained from these scans.

3. Flow simulation: CFD is used to quantify airflow and exposure to inhaled particles [18].

In one study, Pseudomonas aeruginosa was treated with inhaled levofloxacin in CF patients. The antibiotic’s lung deposition was predicted using FRI. The FRI demonstrated substantial intrathoracic deposition of levofloxacin, with a preference for distribution in the lower lung lobes. The ratio of central to peripheral deposition (C/P) was influenced by the decline in FEV1. In addition, structural distinctions between patients with mild and moderate CF were identified by the three-dimensional rendering of CF airways [19].

6. Inhaled drugs and non-invasive ventilation (NIV)

Non-invasive ventilation (NIV) is defined as positive pressure ventilation in the airway without the use of an invasive artificial airway, endotracheal, or tracheostomy tube [20]. Despite appearances, medicated aerosols are typically delivered to mechanically ventilated patients using a nebulizer and a pressurized metered-dose inhaler (pMDI) attached to an adapter or spacer that fits into the ventilated circuit.

Many factors influence inhaled drug deposition in the lungs during NIV, including the type and position of an aerosol generator, the humidity of the circuit, the characteristics of aerosolized particles, gas density, the type of patient interface, ventilator parameters, and patient-related factors. In vitro, in vivo, and ex vivo models are used to study aerosol delivery and deposition during mechanical ventilation. These models are dependent on the technique used to quantitatively or qualitatively measure the deposited aerosol.In vitro models could be used to calculate total emitted doses from various aerosol-generating devices or to characterize the aerodynamics of deposited inhaled medications. In vivo models rely on extracting drugs from biological samples to determine concentration and bioavailability (pharmacokinetic model) or on radioactive aerosol imaging techniques [21, 29].

7. Conclusion

The inhalation route is the most efficient way to deliver drugs directly to the lungs and target organs, while reducing systematic side effects, especially in those patients on NIV. This way of drug application was recognized a couple of decades ago but it is still unknown to physicians. It is necessary to educate physicians about groups of drugs that are applied in this way, the way of their application, and the methods by which the concentration of the inhaled drug is monitored.